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Luo SQ, Dai L, Zhou YJ, He T, Wang FJ, Jin XR, Wang Q. Multiple primary tumors patient developed microsatellite stable gastric cancer after cadonilimab treatment for liver cancer: A case report. World J Clin Oncol 2025; 16:102418. [PMID: 40290697 PMCID: PMC12019263 DOI: 10.5306/wjco.v16.i4.102418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/22/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Multiple primary malignant tumors refer to the occurrence of two or more primary malignant tumors in the same organ or multiple organs or tissues at the same time or successively in the same patient, and can occur anywhere in the body. The treatment guidelines for patients with multiple primary malignant tumors are currently controversial. CASE SUMMARY A 51-year-old male patient with liver cancer and portal hypertension received 42 months of co-treatment with atezolizumab and bevacizumab. After that, the disease was rated stable disease. The patient was then diagnosed with gastric cancer. Since the patient was not sensitive to anti-programmed death ligand 1 immunosuppressive agents, a co-treatment with oxaliplatin, tegafur, apatinib, and cadonilimab was selected after multidisciplinary consultation and the patient's agreement. After four cycles of treatment, partial response and stable disease were observed in gastric and liver cancers, respectively. Surgical treatment was performed considering the high-risk factors of gastrointestinal bleeding in patients with gastroesophageal varices. Postoperative pathology showed that the Tumor Regression Grade was 1. Moreover, the genetic testing of postoperative tumor specimens indicated negative programmed death ligand 1 and microsatellite stability. In addition, the latest follow-up indicated an 8 and 40-month progression-free survival in gastric and liver cancer patients, respectively. Currently, the patient is receiving postoperative immunotherapy with cadonilimab. CONCLUSION Cadonilimab not only treats microsatellite stability gastric cancer patients but can also be used for liver cancer treatment.
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Affiliation(s)
- Si-Qi Luo
- Department of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Li Dai
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yong-Jin Zhou
- Department of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Tong He
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Fang-Jie Wang
- Department of Emergency, The People’s Hospital of Xishui, Zunyi 564600, Guizhou Province, China
| | - Xiang-Ren Jin
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Qian Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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Amodio V, Vitiello PP, Bardelli A, Germano G. DNA repair-dependent immunogenic liabilities in colorectal cancer: opportunities from errors. Br J Cancer 2024; 131:1576-1590. [PMID: 39271762 PMCID: PMC11554791 DOI: 10.1038/s41416-024-02848-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the major causes of cancer death worldwide. Chemotherapy continues to serve as the primary treatment modality, while immunotherapy is largely ineffective for the majority of CRC patients. Seminal discoveries have emphasized that modifying DNA damage response (DDR) mechanisms confers both cell-autonomous and immune-related vulnerabilities across various cancers. In CRC, approximately 15% of tumours exhibit alterations in the mismatch repair (MMR) machinery, resulting in a high number of neoantigens and the activation of the type I interferon response. These factors, in conjunction with immune checkpoint blockades, collectively stimulate anticancer immunity. Furthermore, although less frequently, somatic alterations in the homologous recombination (HR) pathway are observed in CRC; these defects lead to genome instability and telomere alterations, supporting the use of poly (ADP-ribose) polymerase (PARP) inhibitors in HR-deficient CRC patients. Additionally, other DDR inhibitors, such as Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, have shown some efficacy both in preclinical models and in the clinical setting, irrespective of MMR proficiency. The aim of this review is to elucidate how preexisting or induced vulnerabilities in DNA repair pathways represent an opportunity to increase tumour sensitivity to immune-based therapies in CRC.
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Affiliation(s)
- V Amodio
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy
- Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126, Turin, Italy
| | - P P Vitiello
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy
- Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126, Turin, Italy
| | - A Bardelli
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy.
- Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126, Turin, Italy.
| | - G Germano
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy.
- Department of Medical Biotechnologies and Translational Medicine, University of Milano, 20133, Milan, Italy.
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Zhang P, Li X, Wang X, Yang Y, Wang J, Cao D. SHR-8068 combined with adebrelimab and bevacizumab in the treatment of refractory advanced colorectal cancer: study protocol for a single-arm, phase Ib/II study. Front Immunol 2024; 15:1450533. [PMID: 39445023 PMCID: PMC11496094 DOI: 10.3389/fimmu.2024.1450533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Background The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC. Method This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint. Discussion This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.
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Affiliation(s)
- Pei Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaofen Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Wang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jianfei Wang
- Jiangsu Hengrui Pharmaceuticals Co., Ltd,
Shanghai, China
| | - Dan Cao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Lentz RW, Friedrich TJ, Blatchford PJ, Jordan KR, Pitts TM, Robinson HR, Davis SL, Kim SS, Leal AD, Lee MR, Waring MR, Martin AC, Dominguez AT, Bagby SM, Hartman SJ, Eckhardt SG, Messersmith WA, Lieu CH. A Phase II Study of Potentiation of Pembrolizumab with Binimetinib and Bevacizumab in Refractory Microsatellite-Stable Colorectal Cancer. Clin Cancer Res 2024; 30:3768-3778. [PMID: 38869830 PMCID: PMC11369619 DOI: 10.1158/1078-0432.ccr-24-0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/17/2024] [Accepted: 06/11/2024] [Indexed: 06/14/2024]
Abstract
PURPOSE In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSIONS Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.
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Affiliation(s)
- Robert W. Lentz
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Tyler J. Friedrich
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Patrick J. Blatchford
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Kimberly R. Jordan
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.
| | - Todd M. Pitts
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Hannah R. Robinson
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - S. Lindsey Davis
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Sunnie S. Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Alexis D. Leal
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Mathew R. Lee
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Meredith R.N. Waring
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Anne C. Martin
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Adrian T.A. Dominguez
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Stacey M. Bagby
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Sarah J. Hartman
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - S. Gail Eckhardt
- Department of Oncology, The University of Texas at Austin Dell Medical School, Austin, Texas.
| | - Wells A. Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Christopher H. Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Salva de Torres C, Baraibar I, Saoudi González N, Ros J, Salva F, Rodríguez-Castells M, Alcaraz A, García A, Tabernero J, Élez E. Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer. Int J Mol Sci 2024; 25:6967. [PMID: 39000083 PMCID: PMC11241496 DOI: 10.3390/ijms25136967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.
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Affiliation(s)
| | - Iosune Baraibar
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Nadia Saoudi González
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Javier Ros
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Francesc Salva
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Marta Rodríguez-Castells
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Adriana Alcaraz
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Ariadna García
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Josep Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Elena Élez
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
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Overman MJ, Gelsomino F, Aglietta M, Wong M, Limon Miron ML, Leonard G, García-Alfonso P, Hill AG, Cubillo Gracian A, Van Cutsem E, El-Rayes B, McCraith SM, He B, Lei M, Lonardi S. Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Immunother Cancer 2024; 12:e008689. [PMID: 38821718 PMCID: PMC11149130 DOI: 10.1136/jitc-2023-008689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER NCT02060188.
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Affiliation(s)
- Michael J Overman
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital Modena, Modena, Italy
| | - Massimo Aglietta
- Department of Medical Oncology, Istituto di Candiolo, FPO IRCCS, Candiolo, Italy
| | - Mark Wong
- Department of Medical Oncology, Westmead Hospital The Crown Princess Mary Cancer Centre, Sydney, New South Wales, Australia
| | | | - Gregory Leonard
- Medical Oncology, University College Hospital, Galway, Ireland
| | - Pilar García-Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Andrew G Hill
- Tasman Oncology Research, Ltd, Southport, Queensland, Australia
| | - Antonio Cubillo Gracian
- Hospital Universitario HM Sanchinarro, Centro Integral Oncológico Clara Campal HM CIOCC, Madrid, Spain
| | - Eric Van Cutsem
- Department of Digestive Oncology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | - Bassel El-Rayes
- Department of Medicine, Emory University Hospital, Atlanta, Georgia, USA
| | - Stephen M McCraith
- Department of Translational Medicine, Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Beilei He
- Department of Translational Medicine, Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Ming Lei
- Global Biostatistics and Data Science, Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCSS, Padova, Italy
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Mignini I, Piccirilli G, Galasso L, Termite F, Esposto G, Ainora ME, Gasbarrini A, Zocco MA. From the Colon to the Liver: How Gut Microbiota May Influence Colorectal Cancer Metastatic Potential. J Clin Med 2024; 13:420. [PMID: 38256554 PMCID: PMC10815973 DOI: 10.3390/jcm13020420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
The gut microbiota's influence on human tumorigenesis is a burning topic in medical research. With the new ontological perspective, which considers the human body and its pathophysiological processes as the result of the interaction between its own eukaryotic cells and prokaryotic microorganisms living in different body niches, great interest has arisen in the role of the gut microbiota on carcinogenesis. Indeed, dysbiosis is currently recognized as a cancer-promoting condition, and multiple molecular mechanisms have been described by which the gut microbiota may drive tumor development, especially colorectal cancer (CRC). Metastatic power is undoubtedly one of the most fearsome features of neoplastic tissues. Therefore, understanding the underlying mechanisms is of utmost importance to improve patients' prognosis. The liver is the most frequent target of CRC metastasis, and new evidence reveals that the gut microbiota may yield an effect on CRC diffusion to the liver, thus defining an intriguing new facet of the so-called "gut-liver axis". In this review, we aim to summarize the most recent data about the microbiota's role in promoting or preventing hepatic metastasis from CRC, highlighting some potential future therapeutic targets.
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Affiliation(s)
| | | | | | | | | | | | | | - Maria Assunta Zocco
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (I.M.); (G.P.); (L.G.); (F.T.); (G.E.); (M.E.A.); (A.G.)
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8
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Fakih M, Wang C, Sandhu J, Ye J, Egelston C, Li X. Immunotherapy response in microsatellite stable metastatic colorectal cancer is influenced by site of metastases. Eur J Cancer 2024; 196:113437. [PMID: 37980853 DOI: 10.1016/j.ejca.2023.113437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Prior studies indicate that colorectal cancer patients with liver metastases did not benefit from regorafenib, nivolumab (REGONIVO) or regorafenib, ipilimumab, nivolumab (RIN) treatments, while those without liver metastases showed significant response. This study explores the impact of metastatic sites on treatment outcomes. METHODS Chemotherapy-refractory colorectal cancer patients treated with REGONIVO or RIN were evaluated, focusing on 2-month organ-specific response, ORR, PFS and OS based on metastatic sites. RESULTS Of the 96 patients analyzed (58 REGONIVO, 38 RIN), liver or peritoneal metastases led to poor outcomes, with 0 % ORR, and median PFS of 2.0 and 1.5 months respectively. In contrast, lung-only metastases had an ORR of 56.3 % and a PFS of 14 months. The presence of concurrent LN or other extrahepatic metastatic disease in patients with lung metastatic disease diminished but did not prohibit responses. The 2-month response assessment revealed activity in the lungs, soft tissues, and distant lymph nodes. CONCLUSIONS REGONIVO and RIN were most active in lung-only metastases. Liver and peritoneal metastases were resistant. Future checkpoint inhibitor trials in MSS colorectal cancer should stratify patients based on metastatic locations.
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Affiliation(s)
- Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Jaideep Sandhu
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Jian Ye
- Department of Immuno-oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Colt Egelston
- Department of Immuno-oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Xiaochen Li
- Division of Biostatistics, Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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9
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Chen EX, Loree JM, Titmuss E, Jonker DJ, Kennecke HF, Berry S, Couture F, Ahmad CE, Goffin JR, Kavan P, Harb M, Colwell B, Samimi S, Samson B, Abbas T, Aucoin N, Aubin F, Koski S, Wei AC, Tu D, O’Callaghan CJ. Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open 2023; 6:e2346094. [PMID: 38051531 PMCID: PMC10698621 DOI: 10.1001/jamanetworkopen.2023.46094] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/09/2023] [Indexed: 12/07/2023] Open
Abstract
Importance Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.
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Affiliation(s)
- Eric X. Chen
- Princess Margaret Cancer Center, Toronto, Ontario, Canada
| | | | - Emma Titmuss
- British Columbia Cancer Agency, Vancouver, Canada
| | - Derek J. Jonker
- The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Hagen F. Kennecke
- Portland Providence Cancer Center, Earle Chiles Research Institute, Portland, Oregon
| | - Scott Berry
- Department of Oncology, Queen’s University, Kingston, Ontario, Canada
| | | | | | | | - Petr Kavan
- Segal Cancer Center, Montreal, Quebec, Canada
| | | | - Bruce Colwell
- Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada
| | - Setareh Samimi
- Hôpital Sacré-Coeur de Montréal, Montreal, Quebec, Canada
| | - Benoit Samson
- Charles LeMoyne Hospital Cancer Centre, Sherbrooke, Quebec, Canada
| | - Tahir Abbas
- Saskatoon Cancer Center, Saskatoon, Saskatoon, Canada
| | | | - Francine Aubin
- Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
| | | | - Alice C. Wei
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dongsheng Tu
- Canadian Cancer Trials Group, Kingston, Ontario, Canada
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10
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Ballarò C, Quaranta V, Giannelli G. Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers (Basel) 2023; 15:5359. [PMID: 38001618 PMCID: PMC10670198 DOI: 10.3390/cancers15225359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/20/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.
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Affiliation(s)
- Costanza Ballarò
- Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Valeria Quaranta
- Laboratory of Personalized Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
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11
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Day D, Park JJ, Coward J, Markman B, Lemech C, Kuo JC, Prawira A, Brown MP, Bishnoi S, Kotasek D, Strother RM, Cosman R, Su R, Ma Y, Yue Z, Hu HH, Wu R, Li P, Tse AN. A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer. Br J Cancer 2023; 129:1608-1618. [PMID: 37731023 PMCID: PMC10646086 DOI: 10.1038/s41416-023-02431-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 08/29/2023] [Accepted: 09/06/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION Clinicaltrials.gov (NCT03475251).
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Affiliation(s)
- Daphne Day
- Department of Medical Oncology, Monash Health, Clayton, VIC, Australia.
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
| | - John J Park
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, NSW, Australia
| | - Jermaine Coward
- Medical Oncology, Icon Cancer Care - South Brisbane, South Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Herston, QLD, Australia
| | - Ben Markman
- Department of Medical Oncology, Monash Health, Clayton, VIC, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Charlotte Lemech
- Drug Development, Scientia Clinical Research, Randwick, NSW, Australia
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
| | - James C Kuo
- Drug Development, Scientia Clinical Research, Randwick, NSW, Australia
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Amy Prawira
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
| | - Michael P Brown
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
- School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Sarwan Bishnoi
- Medical Oncology, Ashford Cancer Centre Research and ICON Cancer Centre, Kurralta Park and Division of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Dusan Kotasek
- Medical Oncology, Ashford Cancer Centre Research and ICON Cancer Centre, Kurralta Park and Division of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - R Matthew Strother
- Medical Oncology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
| | - Rasha Cosman
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
| | - Rila Su
- Translational Medicine and Early Development, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Yiding Ma
- Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Zenglian Yue
- Translational Medicine and Early Development, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Hui-Han Hu
- Translational Medicine and Early Development, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Rachel Wu
- Clinical Department, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Peiqi Li
- Translational Medicine and Early Development, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
| | - Archie N Tse
- Translational Medicine and Early Development, CStone Pharmaceuticals (Suzhou) Co., Ltd., Suzhou, China
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12
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Ding Y, Weng S, Zhu N, Mi M, Xu Z, Zhong L, Yuan Y. Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer. Heliyon 2023; 9:e22092. [PMID: 38058653 PMCID: PMC10695980 DOI: 10.1016/j.heliyon.2023.e22092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a "cold tumor" into a "hot tumor," which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.
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Affiliation(s)
- Yuwei Ding
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province, China
| | - Shanshan Weng
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ning Zhu
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province, China
| | - Mi Mi
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province, China
| | - Ziheng Xu
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province, China
| | - Liping Zhong
- Department of Oncology, Huzhou Central Hospital, Huzhou, Zhejiang Province, China
| | - Ying Yuan
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang Province, China
- Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, 310052, China
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13
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Foote MB, Argilés G, Rousseau B, Segal NH. Facts and Hopes in Colorectal Cancer Immunotherapy. Clin Cancer Res 2023; 29:4032-4039. [PMID: 37326624 DOI: 10.1158/1078-0432.ccr-22-2176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
Although a minority of colorectal cancers exhibit mismatch repair deficiency and associated sensitivity to immune checkpoint inhibitors (ICI), the vast majority of colorectal cancers arise in a tolerogenic microenvironment with mismatch repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination ICIs and chemotherapy have broadly failed in mismatch repair-proficient tumors. Similarly, although several small single-arm studies have shown that checkpoint blockade plus radiation or select tyrosine kinase inhibition may show improved outcomes compared with historical controls, this finding has not been clearly validated in randomized trials. An evolving next generation of intelligently engineered checkpoint inhibitors, bispecific T-cell engagers, and emerging CAR-T cell therapies may improve immunorecognition of colorectal tumors. Across these modalities, ongoing translational efforts to better define patient populations and biomarkers associated with immune response, as well as combine biologically sound and mutually amplifying therapies, show promise for a new era of immunotherapy in colorectal cancer.
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Affiliation(s)
- Michael B Foote
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Guillem Argilés
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benoit Rousseau
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Neil H Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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14
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Ye J, Guo W, Wang C, Egelston CA, D'Apuzzo M, Shankar G, Fakih MG, Lee PP. Peritumoral Immune-suppressive Mechanisms Impede Intratumoral Lymphocyte Infiltration into Colorectal Cancer Liver versus Lung Metastases. CANCER RESEARCH COMMUNICATIONS 2023; 3:2082-2095. [PMID: 37768208 PMCID: PMC10569153 DOI: 10.1158/2767-9764.crc-23-0212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/19/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023]
Abstract
Patients with microsatellite stable (MSS) colorectal cancer with liver metastases are resistant to immune checkpoint inhibitor (ICI) therapy, while about one-third of patients with colorectal cancer without liver metastases, particularly those with lung-only metastases, respond to ICI. We analyzed primary colorectal cancer tumors and major metastatic sites (liver, lung, peritoneal) using multiplex immunofluorescence and whole-slide spatial analyses to identify variations in immune contexture and regional localization within the tumor microenvironment. While levels of T and B cells within peritumoral regions were similar, their levels were significantly lower within the tumor core of liver and peritoneal metastases compared with lung metastases. In contrast, antigen-presenting cells (APC) and APC-T cell interactions were more abundant in all regions of lung metastases. We also identified an abundance of lymphoid aggregates throughout lung metastases, but these were present only within peritumoral regions of liver and peritoneal metastases. Larger lymphoid aggregates consistent with features of tertiary lymphoid structures were observed within or adjacent to primary tumors, but not metastatic lesions. Our findings were validated using NanoString GeoMx DSP, which further showed that liver metastases had higher expression of immune-suppressive markers, while lung metastases showed higher proinflammatory activity and T-cell activation markers. Peritoneal metastases demonstrated higher expression of cancer-associated fibroblast-related proteins and upregulated PD-1/PD-L1 signaling molecules. Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer. SIGNIFICANCE Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.
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Affiliation(s)
- Jian Ye
- Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
| | - Weihua Guo
- Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
| | - Colt A. Egelston
- Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
| | - Massimo D'Apuzzo
- Department of Pathology, City of Hope National Medical Center, Duarte, California
| | | | - Marwan G. Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
| | - Peter P. Lee
- Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
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15
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Wang K, Chen Y, Zhang Z, Wu R, Zhou M, Yang W, Wan J, Shen L, Zhang H, Wang Y, Han X, Wang J, Zhang Z, Xia F. RIFLE: a Phase II trial of stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in metastatic colorectal cancer. Gastroenterol Rep (Oxf) 2023; 11:goad063. [PMID: 37842200 PMCID: PMC10568524 DOI: 10.1093/gastro/goad063] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 10/17/2023] Open
Abstract
Background Currently, the prognosis for metastatic colorectal cancer (mCRC) still remains poor. The management of mCRC has become manifold because of the varied advances in the systemic and topical treatment approaches. For patients with limited number of metastases, radical local therapy plus systemic therapy can be a good choice to achieve long-term tumor control. In this study, we aimed to explore the efficacy and safety of the combination of fruquintinib, tislelizumab, and stereotactic ablative radiotherapy (SABR) in mCRC (RIFLE study). Methods RIFLE was designed as a single-center, single-arm, prospective Phase II clinical trial. A total of 68 mCRC patients who have failed the first-line standard treatment will be recruited in the safety run-in phase (n = 6) and the expansion phase (n = 62), respectively. Eligible patients will receive SABR followed by fruquintinib (5 mg, d1-14, once every day) and tislelizumab (200 mg, d1, once every 3 weeks) within 2 weeks from completion of radiation. The expansion phase starts when the safety of the treatment is determined (dose limiting toxicity occur in no more than one-sixth of patients in the run-in phase). The primary end point is the objective response rate. The secondary end points include the disease control rate, duration of response, 3-year progression-free survival rate, 3-year overall survival rate, and toxicity. Conclusions The results of this trial will provide a novel insight into SABR in combination with PD-1 antibody and vascular endothelial growth factor receptor inhibitor in the systematic treatment of metastatic colorectal cancer, which is expected to provide new therapeutic strategies and improve the prognosis for mCRC patients. Trial registration NCT04948034 (ClinicalTrials.gov).
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Affiliation(s)
- Kun Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Zhiyuan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Ruiyan Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Menglong Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Wang Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Xu Han
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Jiazhou Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, P. R. China
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16
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Redman JM, O’Sullivan Coyne G, Reed CT, Madan RA, Strauss J, Steinberg SJ, Marté J, Cordes L, Heery C, Gulley JL. Avelumab in Patients With Metastatic Colorectal Cancer. Oncologist 2023; 28:823-e804. [PMID: 37310790 PMCID: PMC10485289 DOI: 10.1093/oncolo/oyad162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 05/07/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. METHODS Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. RESULTS Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). CONCLUSION As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
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Affiliation(s)
- Jason M Redman
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Geraldine O’Sullivan Coyne
- Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Clay T Reed
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Julius Strauss
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Seth J Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jennifer Marté
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lisa Cordes
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Christopher Heery
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - James L Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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17
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Dai X, Ding W, He Y, Huang S, Liu Y, Wu T. Refractory microsatellite stable metastatic colorectal cancer with ERBB2/ERBB3 mutation may be preferred population for regorafenib plus PD-1 inhibitor therapy: a real-world study. Front Oncol 2023; 13:1227644. [PMID: 37681031 PMCID: PMC10482431 DOI: 10.3389/fonc.2023.1227644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023] Open
Abstract
Background Microsatellite stable (MSS) colorectal cancer (CRC) has been referred to as the "cold tumor" because of almost no response to anti-programmed death-1 (PD-1) antibody. A recent REGONIVO trial showed that regorafenib plus nivolumab had an encouraging efficacy in MSS metastatic CRC (mCRC). However, only a small subset of patients may benefit from the combination therapy. We aim to evaluate the efficacy and safety data of immune checkpoint inhibitors combined with regorafenib in refractory MSS mCRC and to discover biomarkers that can effectively stratify the beneficial patient population. Methods We retrospectively analyzed patients with MSS mCRC who received regorafenib combined with anti-PD-1 antibody therapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and status of gene mutation were reviewed and evaluated. Results Twenty-one patients received combination treatment. At a median treatment duration of 4 months, one patient achieved complete response, three patients achieved partial response, and two patients achieved stable disease as the best response. The ORR and DCR were 19% and 28.5% in the overall population, respectively. The median PFS was 4 months, and the median OS was 25 months. Only erbb2 receptor tyrosine kinase 2/erbb3 receptor tyrosine kinase 3 (ERBB2/ERBB3) mutation status was confirmed to be a potential predictive factor for effective treatment. In patients with ERBB2/ERBB3 mutation, ORR, DCR, and PFS exhibited significant improvements in comparison with that in wild-type patients. Grade 3 or higher treatment-related adverse events occurred in three patients (14.3%). Conclusions Regorafenib in combination with PD-1 inhibitor provides a feasible treatment regimen for refractory MSS mCRC with tolerated toxicity. Patients with ERBB2/ERBB3 mutation may be the preferred population for this combination regimen.
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Affiliation(s)
| | | | | | | | - Yun Liu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingyu Wu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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18
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Quan Y, He J, Zou Q, Zhang L, Sun Q, Huang H, Li W, Xie K, Wei F. Low molecular weight heparin synergistically enhances the efficacy of adoptive and anti-PD-1-based immunotherapy by increasing lymphocyte infiltration in colorectal cancer. J Immunother Cancer 2023; 11:e007080. [PMID: 37597850 PMCID: PMC10441131 DOI: 10.1136/jitc-2023-007080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2023] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Immunotherapy, including adoptive cell therapy (ACT) and immune checkpoint inhibitors (ICIs), has a limited effect in most patients with colorectal cancer (CRC), and the efficacy is further limited in patients with liver metastasis. Lack of antitumor lymphocyte infiltration could be a major cause, and there remains an urgent need for more potent and safer therapies for CRC. METHODS In this study, the antitumoral synergism of low molecular weight heparin (LMWH) combined with immunotherapy in the microsatellite stable (MSS) highly aggressive murine model of CRC was fully evaluated. RESULTS Dual LMWH and ACT objectively mediated the stagnation of tumor growth and inhibition of liver metastasis, neither LMWH nor ACT alone had any antitumoral activity on them. The combination of LMWH and ACT obviously increased the infiltration of intratumor CD8+ T cells, as revealed by multiplex immunohistochemistry, purified CD8+ T-cell transfer assay, and IVIM in vivo imaging. Mechanistically, evaluation of changes in the tumor microenvironment revealed that LMWH improved tumor vascular normalization and facilitated the trafficking of activated CD8+ T cells into tumors. Similarly, LMWH combined with anti-programmed cell death protein 1 (PD-1) therapy provided superior antitumor activity as compared with the single PD-1 blockade in murine CT26 tumor models. CONCLUSIONS LMWH could enhance ACT and ICIs-based immunotherapy by increasing lymphocyte infiltration into tumors, especially cytotoxic CD8+ T cells. These results indicate that combining LMWH with an immunotherapy strategy presents a promising and safe approach for CRC treatment, especially in MSS tumors.
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Affiliation(s)
- Yibo Quan
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Jie He
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Qi Zou
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Liuxi Zhang
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Qihui Sun
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Hongli Huang
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Wanglin Li
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Keping Xie
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
| | - Fang Wei
- Guangzhou Digestive Disease Center, Guangzhou First People's Hospital and The Second Affiliated Hospital, South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
- Center for Pancreatic Cancer Research and Department of Immunology, The South China University of Technology School of Medicine, South China University of Technology, Guangzhou, China
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19
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Fakih M, Sandhu J, Lim D, Li X, Li S, Wang C. Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol 2023; 9:627-634. [PMID: 36892833 PMCID: PMC9999273 DOI: 10.1001/jamaoncol.2022.7845] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/30/2022] [Indexed: 03/10/2023]
Abstract
Importance Immunotherapy combinations with activity in patients with microsatellite stable (MSS) metastatic colorectal cancer need to be identified. Objective To determine the recommended phase 2 dose (RP2D) of regorafenib, ipilimumab, and nivolumab (RIN) and evaluate its activity in an expansion cohort of patients with MSS metastatic colorectal cancer. Design, Setting, and Participants This nonrandomized clinical trial was a single-center 3 + 3 dose de-escalation study with an effectiveness expansion cohort at the RP2D. After the identification of the RP2D, a study amendment was executed to explore a regorafenib dose optimization strategy to mitigate skin-related toxic effects. Study enrollment occurred between May 12, 2020, and January 21, 2022. The trial was conducted at a single academic center. A total of 39 patients with MSS metastatic colorectal cancer whose disease progressed after standard chemotherapy and who had not received prior regorafenib or anti-programmed cell death protein 1 therapy were included. Interventions Patients received regorafenib daily for 21 days every 4 weeks; fixed-dose ipilimumab, 1 mg/kg, intravenously every 6 weeks; and fixed-dose nivolumab, 240 mg intravenously every 2 weeks. Patients were treated until progression, unacceptable toxic effects, or completion of 2 years of therapy. Main Outcomes and Measures The primary end point was RP2D selection. Secondary end points were safety and overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours at the RP2D level. Results A total of 39 patients were enrolled, 23 (59.0%) were female, median age was 54 years (range, 25-75 years), 3 were Black (7.7%), and 26 were White (66.7%). No dose-limiting toxic effects were noted in the first 9 patients at the starting dose of RIN, with regorafenib dosed at 80 mg daily. No dose de-escalation was needed. This dose was declared the RP2D. Twenty more patients were enrolled at this level. The ORR, median progression-free survival (PFS), and overall survival (OS) in the RP2D cohort were 27.6%, 4 months (IQR, 2-9 months), and 20 months (IQR, 7 months to not estimable), respectively. For the 22 patients without liver metastases, the ORR, PFS, and OS were 36.4%, 5 months (IQR, 2-11), and greater than 22 months, respectively. A dose optimization cohort with regorafenib at 40 mg/d on cycle 1 and 80 mg/d on cycle 2 and beyond was associated with lower skin and immune toxic effects but had limited activity with stable disease for 5 of 10 patients as the best response. Conclusions and Relevance Results of this nonrandomized clinical trial suggest that RIN at the RP2D demonstrated interesting clinical activity in patients with advanced MSS colorectal cancer without liver metastases. These findings should be confirmed in randomized clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT04362839.
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Affiliation(s)
- Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Jaideep Sandhu
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Dean Lim
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Xiaochen Li
- Division of Biostatistics, Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Sierra Li
- Division of Biostatistics, Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
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20
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Jiang W, He Y, He W, Zhang X, Chen N, Li Y, Zhong W, Wu G, Zhou X, Hua H, Ye F. Metastatic sites and lesion numbers cooperated to predict efficacy of PD-1 inhibitor-based combination therapy for patients with metastatic colorectal cancer. Cancer Med 2023. [PMID: 37081776 DOI: 10.1002/cam4.5959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/22/2023] [Accepted: 04/02/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. METHODS AND RESULTS In our study, we included a total of 97 patients with mCRC, who each received programmed death-1 (PD-1) inhibitor-based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression-free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non-hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non-hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion-based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand-1 (PD-L1) expression responded, and positive PD-L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non-hypermutated mCRC with liver metastasis (CRLMs). CONCLUSION Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non-hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD-L1 potentially cooperated to guide the immunotherapy of CRLMs.
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Affiliation(s)
- Weiqin Jiang
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yinjun He
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenguang He
- Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiang Zhang
- First Clinical Medical College of Lanzhou University Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Nan Chen
- Departments of Colorectal Surgery, Yuyao Hospital of Traditional Chinese Medicine, Yuyao, China
| | - Yandong Li
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixiang Zhong
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guosheng Wu
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xile Zhou
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanju Hua
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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Fakih M, Raghav KPS, Chang DZ, Larson T, Cohn AL, Huyck TK, Cosgrove D, Fiorillo JA, Tam R, D'Adamo D, Sharma N, Brennan BJ, Wang YA, Coppieters S, Zebger-Gong H, Weispfenning A, Seidel H, Ploeger BA, Mueller U, Oliveira CSVD, Paulson AS. Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study. EClinicalMedicine 2023; 58:101917. [PMID: 37090438 PMCID: PMC10119887 DOI: 10.1016/j.eclinm.2023.101917] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 04/25/2023] Open
Abstract
Background Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding Bayer/Bristol Myers Squibb.
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Affiliation(s)
- Marwan Fakih
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Corresponding author. City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
| | - Kanwal Pratap Singh Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Tim Larson
- Minnesota Oncology/The US Oncology Network, Minneapolis, MN, USA
| | | | | | - David Cosgrove
- Division of Medical Oncology, Vancouver Cancer Center, Compass Oncology, Vancouver, WA, USA
| | | | - Rachel Tam
- Bristol Myers Squibb, Lawrenceville, NJ, USA
| | | | | | | | - Ying A. Wang
- Bayer HealthCare Pharmaceuticals, Cambridge, MA, USA
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22
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Lou E. Immunotherapy Success for Microsatellite Stable Colorectal Cancers-Searching for the Horizon. JAMA Oncol 2023; 9:615-617. [PMID: 36892823 DOI: 10.1001/jamaoncol.2022.7786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Affiliation(s)
- Emil Lou
- Division of Hematology, Oncology and Transplantation, University of Minnesota Twin Cities, Minneapolis
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23
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Saeed A, Park R, Dai J, Al-Rajabi R, Kasi A, Baranda J, Williamson S, Saeed A, Ripp J, Collins Z, Mulvaney K, Shugrue M, Firth-Braun J, Godwin AK, Madan R, Phadnis M, Sun W. Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. Cell Rep Med 2023; 4:100916. [PMID: 36702123 PMCID: PMC9975105 DOI: 10.1016/j.xcrm.2023.100916] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/27/2022] [Accepted: 01/03/2023] [Indexed: 01/27/2023]
Abstract
This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.
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Affiliation(s)
- Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA; Department of Medicine, Division of Hematology and Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Robin Park
- Division of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Junqiang Dai
- Department of Biostatistics, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Raed Al-Rajabi
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA
| | - Anup Kasi
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA
| | - Joaquina Baranda
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA
| | - Stephen Williamson
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA
| | - Azhar Saeed
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jacob Ripp
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Zachary Collins
- Department of Radiology, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Kelly Mulvaney
- Kansas University Cancer Center, Kansas City, KS 66205, USA
| | - Molly Shugrue
- Kansas University Cancer Center, Kansas City, KS 66205, USA
| | | | - Andrew K Godwin
- Kansas University Cancer Center, Kansas City, KS 66205, USA; Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Rashna Madan
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Milind Phadnis
- Department of Biostatistics, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Weijing Sun
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66160, USA; Kansas University Cancer Center, Kansas City, KS 66205, USA
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24
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Wang Q, Shen X, Chen G, Du J. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation. Int J Cancer 2023. [PMID: 36752642 DOI: 10.1002/ijc.34464] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 01/14/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023]
Abstract
Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.
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Affiliation(s)
- Qianyu Wang
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Chen
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Junfeng Du
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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25
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Ros J, Balconi F, Baraibar I, Saoudi Gonzalez N, Salva F, Tabernero J, Elez E. Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer. Front Oncol 2023; 13:1112276. [PMID: 36816981 PMCID: PMC9932591 DOI: 10.3389/fonc.2023.1112276] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Francesca Balconi
- Medical Oncology, University Hospital and University of Cagliari, Cagliari, Italy
| | - Iosune Baraibar
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Francesc Salva
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,*Correspondence: Elena Elez,
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San-Román-Gil M, Torres-Jiménez J, Pozas J, Esteban-Villarrubia J, Albarrán-Fernández V, Álvarez-Ballesteros P, Chamorro-Pérez J, Rosero-Rodríguez D, Orejana-Martín I, Martínez-Delfrade Í, Reguera-Puertas P, Fuentes-Mateos R, Ferreiro-Monteagudo R. Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma. Cancers (Basel) 2023; 15:863. [PMID: 36765821 PMCID: PMC9913409 DOI: 10.3390/cancers15030863] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
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Affiliation(s)
- María San-Román-Gil
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | - Javier Torres-Jiménez
- Medical Oncology Department, Clínico San Carlos University Hospital, 28040 Madrid, Spain
| | - Javier Pozas
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | | | | | | | - Jesús Chamorro-Pérez
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
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Gandini A, Puglisi S, Pirrone C, Martelli V, Catalano F, Nardin S, Seeber A, Puccini A, Sciallero S. The role of immunotherapy in microsatellites stable metastatic colorectal cancer: state of the art and future perspectives. Front Oncol 2023; 13:1161048. [PMID: 37207140 PMCID: PMC10189007 DOI: 10.3389/fonc.2023.1161048] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/21/2023] [Indexed: 05/21/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator.
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Affiliation(s)
- Annalice Gandini
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Silvia Puglisi
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Valentino Martelli
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Fabio Catalano
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Simone Nardin
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Andreas Seeber
- Department of Haematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alberto Puccini
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Haematology Unit, Rozzano, Milan, Italy
| | - Stefania Sciallero
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
- *Correspondence: Stefania Sciallero,
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Liu X, Ma X, Ou K, Wang Q, Gao L, Yang L. Real-World Results of Raltitrexed Combined with S-1 and Bevacizumab in Heavily Pretreated Metastatic Colorectal Cancer. Cancer Manag Res 2023; 15:277-289. [PMID: 36969545 PMCID: PMC10038009 DOI: 10.2147/cmar.s398539] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/14/2023] [Indexed: 03/29/2023] Open
Abstract
Purpose Treatment options for refractory metastatic colorectal cancer (CRC) are scarce. This retrospective study aimed to evaluate the efficacy and safety of raltitrexed combined with S-1 and bevacizumab in patients with heavily pretreated metastatic CRC in a clinical real-world setting. Patients and Methods Records of patients with metastatic CRC refractory to standard therapies who initiated raltitrexed plus S-1 and bevacizumab from October 2017 to December 2021 were retrospectively reviewed at our institution. The study endpoints included median overall survival (OS), overall response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and adverse events (AEs). Results Forty-four patients with metastatic CRC, who had previously undergone standard chemotherapy received the regimen comprising raltitrexed plus S-1 and bevacizumab. As of March 2022, the median follow-up was 23.2 months (95% confidence interval 15.8-30.6). The median OS and median PFS were 13.5 (95% CI 9.9-17.1) and 4.7 months (95% CI 3.6-5.8), respectively, with a 16-week PFS rate of 60.9%. Among 43 patients with measurable lesions, the ORR and DCR were 7.0% (3/43) and 65.1% (28/43), respectively. Patients without peritoneal metastases (P = 0.003, hazard ratio 0.160, 95% CI 0.048-0.531), lower carcinoembryonic antigen level (≤42.8 ng/mL) (P = 0.039, HR 0.382, 95% CI 0.153-0.952), and no previous treatment with both vascular endothelial growth factor inhibitors (VEGF) and S-1 (P = 0.020, HR 0.215, 95% CI 0.059-0.785) had better OS. The incidence of any grade of treatment-related AEs was 88.6%, most of which were mild to moderate, and no treatment-related deaths occurred. Conclusion Raltitrexed combined with S-1 and bevacizumab shows promising antitumor activity and safety and could be an alternative for patients with metastatic CRC who are refractory or intolerant to standard therapy.
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Affiliation(s)
- Xiu Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Xiaoting Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Kai Ou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Qi Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Medical Oncology, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing, People’s Republic of China
| | - Lizhen Gao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Medical Oncology, Beijing Chaoyang Huanxing Cancer Hospital, Beijing, People’s Republic of China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Correspondence: Lin Yang, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiyuanninli, Beijing, 10021, People’s Republic of China, Tel +86-10-87788118, Email
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Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology 2022; 11:2120676. [PMID: 36117524 PMCID: PMC9481153 DOI: 10.1080/2162402x.2022.2120676] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy.
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Affiliation(s)
- Robby Barnestein
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
| | - Loïck Galland
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
| | - Laura Kalfeist
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - François Ghiringhelli
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Sylvain Ladoire
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Emeric Limagne
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
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Chen B, Zhao H, Huang J, Lv H, Xu W, Nie C, Wang J, Zhao J, He Y, Wang S, Chen X. Efficacy of regorafenib combined with PD-1 inhibitors in elderly patients with advanced metastatic colorectal cancer. BMC Geriatr 2022; 22:987. [PMID: 36539696 PMCID: PMC9769053 DOI: 10.1186/s12877-022-03637-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 11/18/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE This is the first clinical study that wants to investigate the treatment patterns, clinical outcomes, and prognostic factors of regorafenib plus PD-1 inhibitors therapy in Chinese elderly patients with advanced colorectal cancer. METHODS A cohort of metastatic colorectal cancer patients 60 years or older who received treatment with regorafenib combined with PD-1 inhibitors was included in our analysis. The endpoints included overall survival (OS), progression-free survival (PFS), and prognostic factors. RESULTS In total, 24 patients were enrolled with the median age of 68 years, and 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. The objective response rate was 8.3%, and the disease control rate was 70.8%. Patients previously treated with regorafenib had a longer median PFS than those without (6.3 versus 2.8 months). In terms of final daily doses, it showed a trend toward better PFS (median PFS was 10.0 months) in high-dose group (daily dose above 80 mg of regorafenib) compared to low-dose group (daily dose no more than 80 mg of regorafenib) (median PFS was 3.5 months). CONCLUSIONS This real-world evidence confirms that Chinese elderly patients with advanced colorectal cancer may benefit from the treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age patients.
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Affiliation(s)
- Beibei Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Huichen Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Jinxi Huang
- Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
| | - Huifang Lv
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Weifeng Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Caiyun Nie
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Jianzheng Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Jing Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Yunduan He
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Saiqi Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China
| | - Xiaobing Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, China.
- Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, 450008, Henan Province, China.
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Akin Telli T, Bregni G, Vanhooren M, Saude Conde R, Hendlisz A, Sclafani F. Regorafenib in combination with immune checkpoint inhibitors for mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer. Cancer Treat Rev 2022; 110:102460. [DOI: 10.1016/j.ctrv.2022.102460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 11/02/2022]
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Lote H, Starling N, Pihlak R, Gerlinger M. Advances in immunotherapy for MMR proficient colorectal cancer. Cancer Treat Rev 2022; 111:102480. [DOI: 10.1016/j.ctrv.2022.102480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/23/2022] [Accepted: 10/26/2022] [Indexed: 11/02/2022]
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Maiorano BA, Parisi A, Maiello E, Ciardiello D. The Interplay between Anti-Angiogenics and Immunotherapy in Colorectal Cancer. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101552. [PMID: 36294987 PMCID: PMC9604892 DOI: 10.3390/life12101552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/30/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022]
Abstract
Simple Summary Colorectal cancer is a frequent and lethal neoplasm. The tumor often creates new vessels to grow and spread—a process called ‘angiogenesis’. Therefore, drugs blocking angiogenesis are effective against this malignancy. On the other side, immune checkpoint inhibitors, which unleash the immune system to fight against tumors, have limited efficacy in patients carrying instability of DNA regions called microsatellites. However, there is an interaction between angiogenic factors and the immune system. This gives a chance to combine anti-angiogenic agents and immune checkpoint inhibitors to improve the efficacy of treating this malignancy. Abstract Angiogenesis, a hallmark of cancer, plays a fundamental role in colorectal cancer (CRC). Anti-angiogenic drugs and chemotherapy represent a standard of care for treating metastatic disease. Immune checkpoint inhibitors (ICIs) have changed the therapeutic algorithm of many solid tumors. However, the efficacy of ICIs is limited to mCRC patients carrying microsatellite instability (MSI-H), which represent approximately 3–5% of mCRC. Emerging evidence suggests that anti-angiogenic drugs could exhibit immunomodulatory properties. Thus, there is a strong rationale for combining anti-angiogenics and ICIs to improve efficacy in the metastatic setting. Our review summarizes the pre-clinical and clinical evidence regarding the combination of anti-angiogenics and ICIs in mCRC to deepen the possible application in daily clinical practice.
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Affiliation(s)
- Brigida Anna Maiorano
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Correspondence:
| | - Alessandro Parisi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, 60126 Ancona, Italy
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Evaristo Maiello
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Davide Ciardiello
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Medical Oncology Unit, Department of Precision Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy
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Liu J, Tao H, Yuan T, Li J, Li J, Liang H, Huang Z, Zhang E. Immunomodulatory effects of regorafenib: Enhancing the efficacy of anti-PD-1/PD-L1 therapy. Front Immunol 2022; 13:992611. [PMID: 36119072 PMCID: PMC9479218 DOI: 10.3389/fimmu.2022.992611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/18/2022] [Indexed: 11/14/2022] Open
Abstract
Anti-PD-1/PD-L1 therapy has shown significant benefits in the treatment of a variety of malignancies. However, not all cancer patients can benefit from this strategy due to drug resistance. Therefore, there is an urgent need for methods that can effectively improve the efficacy of anti-PD-1/PD-L1 therapy. Combining anti-PD-1/PD-L1 therapy with regorafenib has been demonstrated as an effective method to enhance its therapeutic effect in several clinical studies. In this review, we describe common mechanisms of resistance to anti-PD-1/PD-L1 therapy, including lack of tumor immunogenicity, T cell dysfunction, and abnormal expression of PD-L1. Then, we illustrate the role of regorafenib in modifying the tumor microenvironment (TME) from multiple aspects, which is different from other tyrosine kinase inhibitors. Regorafenib not only has immunomodulatory effects on various immune cells, but can also regulate PD-L1 and MHC-I on tumor cells and promote normalization of abnormal blood vessels. Therefore, studies on the synergetic mechanism of the combination therapy may usher in a new era for cancer treatment and help us identify the most appropriate individuals for more precise treatment.
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Affiliation(s)
- Junjie Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haisu Tao
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Tong Yuan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Erlei Zhang, ; Zhiyong Huang, ; Huifang Liang,
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Erlei Zhang, ; Zhiyong Huang, ; Huifang Liang,
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Erlei Zhang, ; Zhiyong Huang, ; Huifang Liang,
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Liu S, Zhang Y, Lin Y, Wang P, Pan Y. Case report: The MSI-L/p-MMR metastatic rectal cancer patient who failed systemic therapy responds to anti-PD-1 immunotherapy after stereotactic body radiation-therapy. Front Immunol 2022; 13:981527. [PMID: 36119063 PMCID: PMC9479073 DOI: 10.3389/fimmu.2022.981527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/17/2022] [Indexed: 02/03/2023] Open
Abstract
Background Traditionally, patients with microsatellite stability (MSS)/microsatellite instability-Low (MSI-L)/proficient mismatch repair (p-MMR) metastatic colorectal cancer (mCRC) have had poor benefit from immunotherapy. Therefore, how to enhance the response of immunotherapy is still a challenge for MSS/MSI-L/p-MMR CRC patient. Case presentation We report a special case of a rectal cancer patient with programmed death-ligand 1 (PD-L1) negative expression, MSI-L/p-MMR, tumor mutational burden-low (TMB-L) and liver metastases, who partial response (PR) to immunotherapy after systemic therapy failure including chemotherapy, anti-angiogenesis therapy and stereotactic body radiation-therapy (SBRT). The computed tomography (CT) results showed that among three liver metastases had been reduction or disappearance after Tislelizumab treatment for three times. Besides, the carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) decrease and maintained at a low level for 3 months. The progression-free survival (PFS) of patient has exceeded 3 months. Conclusions This case indicates that the patient with MSI-L/p-MMR mCRC can respond to anti-PD-1 immunotherapy after systemic therapy. And the SBRT (targeting liver metastases) may a method for increase-sensitivity of immunotherapy in CRC patients with MSI-L/p-MMR.
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Affiliation(s)
- Shijin Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yujian Lin
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Peize Wang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Ministry of Education (MOE) Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China
- *Correspondence: Yunlong Pan,
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Jin Z, Sinicrope FA. Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade. J Clin Oncol 2022; 40:2735-2750. [PMID: 35649217 PMCID: PMC9390830 DOI: 10.1200/jco.21.02691] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/15/2022] [Accepted: 03/07/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti-programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.
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Affiliation(s)
- Zhaohui Jin
- Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN
| | - Frank A. Sinicrope
- Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN
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37
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Yukami H, Kawazoe A, Lin YT, Koyama S, Fukuoka S, Hara H, Takahashi N, Kojima T, Asayama M, Yoshii T, Bando H, Kotani D, Nakamura Y, Kuboki Y, Mishima S, Wakabayashi M, Kuwata T, Goto M, Higuchi K, Yoshino T, Doi T, Nishikawa H, Shitara K. Updated Efficacy Outcomes of Anti-PD-1 Antibodies plus Multikinase Inhibitors for Patients with Advanced Gastric Cancer with or without Liver Metastases in Clinical Trials. Clin Cancer Res 2022; 28:3480-3488. [PMID: 35679062 PMCID: PMC9662898 DOI: 10.1158/1078-0432.ccr-22-0630] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 05/24/2022] [Accepted: 06/07/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. PATIENTS AND METHODS Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. RESULTS In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors. CONCLUSIONS Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.
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Affiliation(s)
- Hiroki Yukami
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.,The Second Department of Internal Medicine Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.,Corresponding Authors: Akihito Kawazoe, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 2778577, Japan. Phone: 814-7133-1111; Fax: 814-7134-6928; E-mail: ; and Kohei Shitara,
| | - Yi-Tzu Lin
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shota Fukuoka
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masako Asayama
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Takako Yoshii
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masashi Wakabayashi
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Kazuhide Higuchi
- The Second Department of Internal Medicine Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Toshihiko Doi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Corresponding Authors: Akihito Kawazoe, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 2778577, Japan. Phone: 814-7133-1111; Fax: 814-7134-6928; E-mail: ; and Kohei Shitara,
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38
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Martelli V, Pastorino A, Sobrero AF. Prognostic and predictive molecular biomarkers in advanced colorectal cancer. Pharmacol Ther 2022; 236:108239. [PMID: 35780916 DOI: 10.1016/j.pharmthera.2022.108239] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/21/2022] [Accepted: 06/27/2022] [Indexed: 10/17/2022]
Abstract
The revolution of precision medicine has produced unprecedented seismic shifts in the treatment paradigm of advanced cancers. Among the major killers, colorectal cancer (CRC) is far behind the others. In fact, the great successes obtained in breast, NSCLC, melanoma, and genitourinary tract tumors have been observed only in fewer than 5 % metastatic colorectal cancer (mCRC): those with the mismatch repair deficiency (dMMR), a well-known predictive factor for to the outstanding efficacy of checkpoint inhibitors (CPI). The treatment of the remaining vast majority mCRC patients is still based upon only two molecular determinants: the RAS and BRAF mutational status. New promising biomarkers include HER2, tumor mutational burden (TMB) for its possible implications on CPI efficacy, and the extremely rare NTRK fusions. The Consensus Molecular Subtypes classification (CMS) is a good example of the efforts to combine different molecular features of this disease, although its relevance in clinical practice is still under investigation. In this Review, we focus on all these prognostic and predictive biomarkers, analyzing data from the most important clinical trials of the last years. We also try to rank them according to their prognostic and predictive power.
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Affiliation(s)
- Valentino Martelli
- Medical Oncology Unit 1, Ospedale Policlinico San Martino - IRCCS, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Alessandro Pastorino
- Medical Oncology Unit 1, Ospedale Policlinico San Martino - IRCCS, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Alberto F Sobrero
- Medical Oncology Unit 1, Ospedale Policlinico San Martino - IRCCS, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
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39
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Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, Li X. Exploring immunotherapy in colorectal cancer. J Hematol Oncol 2022; 15:95. [PMID: 35842707 PMCID: PMC9288068 DOI: 10.1186/s13045-022-01294-4] [Citation(s) in RCA: 187] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/18/2022] [Indexed: 02/07/2023] Open
Abstract
Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability-high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.
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Affiliation(s)
- Junyong Weng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Shanbao Li
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Zhonglin Zhu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Qi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Ruoxin Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Yufei Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Xuhui, Shanghai, 200032, China.
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40
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Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin 2022; 72:372-401. [PMID: 35472088 DOI: 10.3322/caac.21728] [Citation(s) in RCA: 290] [Impact Index Per Article: 96.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.
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Affiliation(s)
- Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Davide Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- Division of Medical Oncology, IRCCS Foundation Home for the Relief of Suffering, San Giovanni Rotondo, Italy
| | - Giulia Martini
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Stefania Napolitano
- Division of Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus, Barcelona, Spain
- Institute of Oncology, University of Vic/Central University of Catalonia, Barcelona, Spain
- Oncology Institute of Barcelona-Quironsalud, Biomedical Research Center in Cancer, Barcelona, Spain
| | - Andres Cervantes
- Medical Oncology Department, Instituto de Investigación Sanitaria Valencia Biomedical Research Institute, University of Valencia, Valencia, Spain
- Carlos III Institute of Health, Biomedical Research Center in Cancer, Madrid, Spain
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41
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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42
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Lefler DS, Snook AE, Bashir B. Immune checkpoint inhibitors in luminal gastrointestinal malignancies: going beyond MSI-H/dMMR, TMB and PD-L1. Immunotherapy 2022; 14:885-902. [PMID: 35694998 DOI: 10.2217/imt-2022-0012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review is to characterize luminal gastrointestinal tumors' responses to ICIs considering known predictive biomarkers and discuss emerging therapeutic approaches using ICIs.
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Affiliation(s)
- Daniel S Lefler
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adam E Snook
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.,Department of Microbiology & Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Babar Bashir
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.,Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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43
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Sahin IH, Ciombor KK, Diaz LA, Yu J, Kim R. Immunotherapy for Microsatellite Stable Colorectal Cancers: Challenges and Novel Therapeutic Avenues. Am Soc Clin Oncol Educ Book 2022; 42:1-12. [PMID: 35658496 DOI: 10.1200/edbk_349811] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
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Affiliation(s)
| | | | - Luis A Diaz
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Richard Kim
- H. Lee Moffitt Cancer Center and Research Institute, Tampa FL
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44
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Immunotherapy for Colorectal Cancer. Hematol Oncol Clin North Am 2022; 36:603-626. [DOI: 10.1016/j.hoc.2022.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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45
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Efficacy and safety comparison of regorafenib and fruquintinib in metastatic colorectal cancer-An observational cohort study in the real world. Clin Colorectal Cancer 2022; 21:e152-e161. [DOI: 10.1016/j.clcc.2022.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/13/2022] [Accepted: 01/15/2022] [Indexed: 11/21/2022]
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46
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Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel) 2021; 13:cancers13205216. [PMID: 34680363 PMCID: PMC8533881 DOI: 10.3390/cancers13205216] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.
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Kawazoe A, Itahashi K, Yamamoto N, Kotani D, Kuboki Y, Taniguchi H, Harano K, Naito Y, Suzuki M, Fukutani M, Higuchi T, Ikeno T, Wakabayashi M, Sato A, Koyama S, Nishikawa H, Shitara K. TAS-116 (Pimitespib), an Oral HSP90 Inhibitor, in Combination with Nivolumab in Patients with Colorectal Cancer and Other Solid Tumors: An Open-Label, Dose-Finding, and Expansion Phase Ib Trial (EPOC1704). Clin Cancer Res 2021; 27:6709-6715. [PMID: 34593531 DOI: 10.1158/1078-0432.ccr-21-1929] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/03/2021] [Accepted: 09/24/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors. PATIENTS AND METHODS Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80-160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies. RESULTS A total of 44 patients with colorectal cancer (n = 29), gastric cancer (n = 8), sarcoma (n = 5), non-small cell lung cancer (n = 1), and melanoma (n = 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. CONCLUSIONS TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients.
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Affiliation(s)
- Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kota Itahashi
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Noboru Yamamoto
- Department of Experimental Therapeutics and Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroya Taniguchi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kenichi Harano
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoichi Naito
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Mitsuko Suzuki
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Miki Fukutani
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tsukiko Higuchi
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takashi Ikeno
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masashi Wakabayashi
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Akihiro Sato
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
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48
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Kim CW, Chon HJ, Kim C. Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer. Cancers (Basel) 2021; 13:4906. [PMID: 34638390 PMCID: PMC8507875 DOI: 10.3390/cancers13194906] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/18/2021] [Accepted: 09/26/2021] [Indexed: 12/19/2022] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. (1) They are poorly immunogenic because of their low tumor mutation burden; (2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8+ T cell immunity; (3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and (4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.
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Affiliation(s)
- Chang Woo Kim
- Department of Surgery, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon 16499, Korea;
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea
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Abstract
INTRODUCTION Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent therapeutic advancements are due in part to a shift in trial designs. By examining CRC as a heterogeneous group of various tumor subtypes, researchers have identified molecular distinctions that have led to promising targets. AREAS COVERED Nineteen antineoplastic agents are included in the National Comprehensive Cancer Network guidelines for the palliative management of mCRC. However, not all patients will be candidates for each agent. New therapies for rare mCRC subtypes have emerged. Herein, the authors review these rare mCRC subtypes: microsatellite instability-high/deficient mismatch repair, BRAFV600E-mutant, and human epidermal growth factor receptor 2-positive tumors. Additionally, they provide an overview of unresectable mCRC management and future directions. EXPERT OPINION Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement and remains an unmet need. The authors believe that the key to identifying more breakthroughs in these mCRC patients is to continue to differentiate their tumors molecularly and clinically.
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Affiliation(s)
- Jane E Rogers
- Pharmacy Clinical Programs, The University of Texas Md Anderson Cancer Center, Houston, United States
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas Md Anderson Cancer Center, Houston, USA
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Arrichiello G, Poliero L, Borrelli C, Paragliola F, Nacca V, Napolitano S, Corte CMD, Martini G, Martinelli E. Immunotherapy in colorectal cancer: is the long-awaited revolution finally happening? Cancer Treat Res Commun 2021; 28:100442. [PMID: 34391139 DOI: 10.1016/j.ctarc.2021.100442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/21/2021] [Accepted: 07/25/2021] [Indexed: 12/30/2022]
Abstract
Immunotherapy has recently become a major treatment modality for several types of solid tumours, achieving remarkable and long-lasting remissions. In metastatic colorectal cancer patients (mCRC), immune checkpoint inhibitors (ICIs) were found to be effective as treatment for deficient mismatch repair (dMMR)/ microsatellite instability high (MSI-H) tumours and received regulatory approval for this indication. However, mCRC is a complex disease and dMMR/MSI-H tumours represent a minority of the cases; therefore, new strategies are needed to extend the benefits of immunotherapy to a larger population of patients. This review explores the immunological differences between dMMR/MSI-H and proficient mismatch repair (pMMR)/ microsatellite instability low (MSI-L) tumours, focuses on new proposed biomarkers to predict response to immunotherapy and illustrates results reported from the main clinical trials with immunotherapeutic agents in CRC, addressing the most promising approaches being currently developed.
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Affiliation(s)
- Gianluca Arrichiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Luca Poliero
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Carola Borrelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Fernando Paragliola
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Valeria Nacca
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Stefania Napolitano
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Giulia Martini
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy.
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