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Jiménez-Labaig P, Mohamed F, Tan NJI, Sanna I, El Bairi K, Khan SZ, Akhade A, Amaral T, Trapani D, Patel A, Harrington KJ. Expanding access to cancer immunotherapy: A systematic review of low-dose PD-(L)1 inhibitor strategies. Eur J Cancer 2025; 225:115564. [PMID: 40513286 DOI: 10.1016/j.ejca.2025.115564] [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: 03/26/2025] [Revised: 05/12/2025] [Accepted: 05/30/2025] [Indexed: 06/16/2025]
Abstract
BACKGROUND Anti-PD-(L)1 inhibitors have transformed cancer treatment. However, their high costs severely restrict their accessibility, especially in low- and middle-income countries (LMIC). Low-dose regimens, inferior to weigh-based or flat dosings, may help address this barrier. Our aim is to evaluate their dosing strategies, clinical outcomes, and potential cost savings. METHODS WebOfScience, ASCO and ESMO conference databases were systematically searched until January 31st, 2025, for post- commercialization use of anti-PD-(L)1 agents at reduced doses compared to FDA- and/or EMA- approved weight-based regimens. RESULTS Five clinical trials and 27 observational studies, including 2055 patients, met the review criteria. Two studies had non-inferiority designs, and 26 grouped patients across various treatment lines in the metastatic setting among them. Most studies originated from LMIC (53 %), focusing on head and neck (30 %) and lung cancers (15 %). Low-dose anti-PD-(L)1 use reported radiological responses in 16 (ranging 5-100 %), observing similar responses than pivotal trials in refractory Hodgkin lymphoma, lung and kidney cancers. Risk of bias was serious in 56 % of the studies, while rest was moderate. Nivolumab was the anti-PD-(L)1 most frequently investigated (k = 27). Nivo40mg Q2W (k = 8) and Nivo20mg Q3W (k = 6) were the most assessed doses. More than two-thirds of the studies achieved estimated savings of ≥ 80 % compared to list prices. CONCLUSION Low-dose anti-PD-(L)1 regimens show promising radiological responses, including as monotherapy, especially in lymphoma, lung and kidney cancers. However, the high risk of bias in available studies limits definitive conclusions. Prudent use may be considered in resource-limited settings. Ongoing non-inferiority trials or near-equivalence are essential to confirm clinical validity.
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Affiliation(s)
- Pablo Jiménez-Labaig
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom; Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Failah Mohamed
- Department of Medical Oncology, Cruces University Hospital, Barakaldo, Spain
| | - Nur Jihan Irwan Tan
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Ilves Sanna
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Khalid El Bairi
- Faculty of Medical Sciences, UM6P Hospitals, Mohammed VI Polytechnic University, Benguerir 43150, Morocco; National Community Oncology Dispensing Association, Cazenovia, NY 13035, United States
| | - Shah Zeb Khan
- Department of Clinical Oncology, BINOR Cancer Hospital, Bannu, Pakistan
| | - Amol Akhade
- Department of Medical Oncology, Nair Hospital and Topiwala National Medical College Mumbai, Mumbai, India; Suyog Cancer Clinics, Mumbai, India
| | - Teresa Amaral
- Center for Dermato-oncology, Department of Dermatology, Eberhard Karls University of Tübingen, Tübingen 72076, Germany; Cluster of Excellence iFIT (EXC 2180), Image-Guided and Functionally Instructed Tumor Therapies, Tübingen, Germany
| | - Dario Trapani
- Department of Oncology and Haematology, University of Milan, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy
| | - Amol Patel
- Department of Medicine, Oncology Centre, Indian Naval Hospital Ship, Mumbai, India
| | - Kevin J Harrington
- Head and Neck Unit. The Royal Marsden NHS Foundation Trust, London, United Kingdom; The Institute of Cancer Research, Division of Radiotherapy and Imaging, London, United Kingdom
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Shah M, Noronha V, Rajamanickam Kulandaivel S, Poladia B, Niyogi D, Menon N, Kaushal R, Shetty O, Pai T, Tibdewal A, Vora M, Shah D, Vora D, Shah S, Goud S, Shah A, Maske K, Shetake A, Prabhash K. Neoadjuvant Chemotherapy and Low Dose Immunotherapy in Resectable Non-small Cell Lung Cancer: A Multi-center Retrospective Cohort Analysis. Clin Oncol (R Coll Radiol) 2025; 41:103795. [PMID: 40073678 DOI: 10.1016/j.clon.2025.103795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025]
Affiliation(s)
- M Shah
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - V Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - S Rajamanickam Kulandaivel
- Department of Surgical Oncology, Thangam Cancer Center and Research Institute, Namakkal, Tamil Nadu, India
| | - B Poladia
- Department of Medical Oncology, Thangam Cancer Center and Research Institute, Namakkal, Tamil Nadu, India
| | - D Niyogi
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - N Menon
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - R Kaushal
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - O Shetty
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - T Pai
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - A Tibdewal
- Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - M Vora
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - D Shah
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - D Vora
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - S Shah
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - S Goud
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - A Shah
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - K Maske
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - A Shetake
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
| | - K Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai 400012, Maharashtra, India
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Remon J, Bortolot M, Bironzo P, Cortiula F, Menis J, Brandao M, Naidoo J, van Geel R, Reguart N, Arrieta O, Mountzios G, Hendriks LEL, Besse B. De-Escalation Strategies With Immune Checkpoint Blockers in Non-Small Cell Lung Cancer: Do We Already Have Enough Evidence? J Clin Oncol 2025; 43:1148-1156. [PMID: 39836933 DOI: 10.1200/jco-24-02347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/05/2024] [Accepted: 11/27/2024] [Indexed: 01/23/2025] Open
Abstract
Immune checkpoint blockers (ICBs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). Currently, one-dose-fits-all maximalist regimens have been considered the standard of care, with ICBs administered at flat doses regardless of patients' weight. Treatment duration with ICBs is often arbitrary across stages, ranging from a fixed time point to until disease progression or unacceptable toxicity. However, the pharmacokinetic and pharmacodynamic properties of ICBs differ significantly from those of traditional cytotoxic drugs and the approved and selected doses on the basis of the maximum tolerated dose are often overestimated as there is limited evidence supporting a direct relationship between therapeutic intensity and outcomes. This can lead to overtreatment of patients, resulting in an increased risk of toxicity without enhanced efficacy. In addition, the use of these drugs is associated with significant costs that burden the global health care system and exacerbate disparities in access to care. De-escalating treatment by reducing the dose, duration, and frequency of administration of ICBs could optimize treatment efficacy, reduce toxicities, improve patients' quality of life, and even decrease costs. Ultimately, de-escalation strategies may help to reduce treatment inequalities and to improve drug access worldwide. The aim of this review is to summarize and discuss the main issues and challenges regarding the de-escalation of ICBs in patients with NSCLC, focusing on dose-intensity reduction and treatment duration selection. Moreover, we assess the economic impact of implementing de-escalation approaches.
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Affiliation(s)
- Jordi Remon
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - Martina Bortolot
- Department of Pulmonary Diseases, Maastricht University Medical Centre+, GROW Research Institute for Oncology and Reproduction, Maastricht, the Netherlands
- Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Paolo Bironzo
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
- Department of Oncology, University of Turin, Turin, Italy
| | - Francesco Cortiula
- Department of Radiation Oncology (Maastro), Maastricht University Medical Centre (+), GROW Research Institute for Oncology and Reproduction, Maastricht, the Netherlands
- University Hospital of Udine, Department of Oncology, Udine, Italy
| | - Jessica Menis
- Medical Oncology Department, University and Hospital Trust of Verona, Verona, Italy
| | - Mariana Brandao
- Institute Jules Bordet-Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Jarushka Naidoo
- Beaumont Hospital and RCSI University of Health Sciences, Dublin, Ireland
| | - Robin van Geel
- Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre+, Maastricht, the Netherlands
- CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, the Netherlands
| | - Noemi Reguart
- Department of Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Oscar Arrieta
- Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Giannis Mountzios
- Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece
| | - Lizza E L Hendriks
- Department of Pulmonary Diseases, Maastricht University Medical Centre+, GROW Research Institute for Oncology and Reproduction, Maastricht, the Netherlands
| | - Benjamin Besse
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
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Hoyek C, Zheng-Lin B, Bauernfeind JJ, Al-Ahmad OH, Bekaii-Saab T, Chakrabarti S, Rashdan S, Sonbol MB. Overcoming Financial and Access Barriers in Global Cancer Care With Low-Dose Immunotherapy: A Systematic Review. JCO Glob Oncol 2025; 11:e2400409. [PMID: 40127379 DOI: 10.1200/go-24-00409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/19/2024] [Accepted: 01/31/2025] [Indexed: 03/26/2025] Open
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non-small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.
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Affiliation(s)
- Celine Hoyek
- Department of Hematology and Oncology, Mayo Clinic, Arizona, AZ
| | | | | | | | | | | | - Sawsan Rashdan
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
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Marimuthu PK, Georgy JT, Philip DSJ, John AO, Joel A, Thumaty DB, Chacko RT, Jambunathan P, Thomas Z, Harikrishna K, Isiah R, Pavamani SP, Sasidharan B, Mathew M, Alex Kodiatte T, Irodi A, Thangakunam B, Isaac BTJ, Gupta R, Rani J, Singh A. Real-World Outcomes of Induction Chemotherapy With or Without Low-Dose Nivolumab for Stage III Non-Small Cell Lung Cancer Ineligible for Up-Front Local Therapy: A Propensity Score-Matched Analysis. JCO Glob Oncol 2025; 11:e2400256. [PMID: 40127380 DOI: 10.1200/go-24-00256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 11/08/2024] [Accepted: 02/13/2025] [Indexed: 03/26/2025] Open
Abstract
PURPOSE There is a lack of literature on treating stage III non-oncogene-driven non-small cell lung cancer (NSCLC) with low-dose immunotherapy in combination with chemotherapy for patients who are not candidates for local therapy up front. MATERIALS AND METHODS We performed an institutional retrospective analysis of patients with stage III non-oncogene-driven NSCLC deemed ineligible for up-front local therapy. The NACT + I/O group comprised those who received induction chemotherapy in combination with low-dose nivolumab, and the NACT-alone group comprised those who received chemotherapy alone. Propensity score matching was performed based on stage, histology, and respiratory comorbid status. The primary end point was objective response rate (ORR). Secondary end points were conversion rates to local therapy, progression-free survival (PFS), overall survival (OS), and Grade ≥3 adverse events. RESULTS Eighty-two patients were equally divided into the NACT + I/O and NACT-alone groups. The most common histology was squamous cell (60%), followed by adenocarcinoma (34%) and mixed (5%). Majority (85%) had stage IIIB or IIIC disease. The ORR to induction was 73.1% (complete response 1, partial response [PR] 29, stable disease [SD] 10, progressive disease [PD] 1) in the NACT + I/O group versus 39% (PR-16, SD-13, PD-12) in the NACT-alone group (P = .002). The NACT + I/O group had a higher proportion of patients undergoing sequential local therapy (66% v 46.3%, P = .075), a better median PFS (not reached [NR] v 11 months, P = .0014), and median OS (NR v 28 months, P = .22) compared with the NACT-alone group at a median follow-up of 13.5 months. There were no new safety signals identified. CONCLUSION Adding low-dose immunotherapy to chemotherapy improved ORRs, conversion rates to local therapy, and PFS in patients with stage III non-oncogene-driven NSCLC, who were ineligible for up-front local therapy.
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Affiliation(s)
| | - Josh Thomas Georgy
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | | | - Ajoy Oommen John
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | - Anjana Joel
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | - Divya Bala Thumaty
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | - Raju Titus Chacko
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | | | - Zachariah Thomas
- Department of Medical Oncology, Christian Medical College, Vellore, India
| | | | - Rajesh Isiah
- Department of Radiation Oncology-Unit II, Christian Medical College, Vellore, India
| | | | | | - Manu Mathew
- Department of Radiation Oncology-Unit II, Christian Medical College, Vellore, India
| | | | - Aparna Irodi
- Department of Radiology, Christian Medical College, Vellore, India
| | | | - Barney T J Isaac
- Department of Pulmonary Medicine, Christian Medical College, Vellore, India
| | - Richa Gupta
- Department of Respiratory Medicine, Christian Medical College, Vellore, India
| | - Jansi Rani
- Department of Biostatistics, Christian Medical College, Vellore, India
| | - Ashish Singh
- Department of Medical Oncology, Christian Medical College, Vellore, India
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Smeenk MM, van der Noort V, Hendrikx JMA, Abedian Kalkhoran H, Smit EF, Theelen WSME. Pembrolizumab hybrid dosing is non-inferior to flat dosing in advanced non-small cell lung cancer: a real-world, retrospective bicenter cohort study. J Immunother Cancer 2025; 13:e010065. [PMID: 39915262 PMCID: PMC11804207 DOI: 10.1136/jitc-2024-010065] [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: 07/11/2024] [Accepted: 12/27/2024] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but come with high costs. Alternative ICI dosing strategies could reduce costs without losing efficacy. However, clinical efficacy data are lacking. METHODS In this retrospective cohort trial, consecutive patients with advanced non-small cell lung cancer (NSCLC) who received ≥1 cycle pembrolizumab±chemotherapy at two tertiary institutions were included. Hybrid dosed patients received either 100, 150 or 200 mg pembrolizumab every 3 weeks or double every 6 weeks depending on their weight: <65 kg, 65-90 kg or >90 kg, respectively. Standard-of-care flat dosed patients received 200 mg every 3 weeks or 400 mg every 6 weeks. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier estimation, compared by log-rank test and HRs were calculated with the Cox proportional hazards model in both unweighted and inverse probability of treatment weighted (IPTW) cohorts. Non-inferiority margin was set at an HR of 1.15. RESULTS In total, 375 patients and 391 patients were included and median follow-up was 43.1 and 61.0 months in the hybrid and flat dose cohort, respectively. OS was non-inferior in the hybrid dose cohort compared with the flat dose cohort: median 17.7 months (95% CI 14.9 to 20.9) vs 11.8 months (95% CI 9.3 to 13.8, HR 0.76, 95% CI 0.65 to 0.90, p<0.0001 for non-inferiority). After correcting for confounders by IPTW, OS remained non-inferior (HR 0.76, 95% CI 0.63 to 0.91, p<0.0001 for non-inferiority). PFS in the hybrid cohort was also non-inferior to the flat dose cohort with a median of 6.4 months (95% CI 5.7 to 7.7) vs 4.6 months (95% CI 3.9 to 5.5, HR 0.82, 95% CI 0.70 to 0.96, p<0.0001 for non-inferiority). In total, 26.2% (or 52.5 mg per cycle, p<0.0001) pembrolizumab was saved in the hybrid dose cohort accounting to US$36 331.36 per patient. CONCLUSIONS In this retrospective analysis of a large cohort of advanced NSCLC patients treated with pembrolizumab±chemotherapy, OS of hybrid dosed patients was non-inferior to flat dosed patients. OS remained non-inferior after correcting for possible confounding factors. This hybrid regimen resulted in significant savings of pembrolizumab and costs.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/administration & dosage
- Male
- Female
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Retrospective Studies
- Aged
- Middle Aged
- Aged, 80 and over
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/pharmacology
- Adult
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Affiliation(s)
- Michiel M Smeenk
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Jeroen M A Hendrikx
- Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hanieh Abedian Kalkhoran
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Pharmacy, Haga Teaching Hospital, The Hague, The Netherlands
| | - Egbert F Smit
- Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, The Netherlands
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7
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Kumar A, Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Janu A, Mahajan A, Rajendra A, Agarawal A, Khaddar S, Rajpurohit A, Kashyap L, Srikant A, Panda G, Kota KK, Talreja V, Prabhash K. Efficacy and Safety of Low-Dose Nivolumab in Treatment of Advanced Solid Tumors: A Retrospective Audit from Resource-Constrained Settings. South Asian J Cancer 2025; 14:70-76. [PMID: 40124158 PMCID: PMC11925618 DOI: 10.1055/s-0044-1788649] [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: 08/01/2023] [Accepted: 07/02/2024] [Indexed: 03/25/2025] Open
Abstract
Background Immunotherapy has improved outcomes in many advanced solid tumors. In resource-constrained settings, less than 2% of patients can afford standard dose immunotherapy. A recent phase II study showed the efficacy of low-dose immunotherapy in this setting. We used low-dose immunotherapy on a compassionate basis in patients who had progressed on available standard treatment options and standard dose immunotherapy was not feasible. Patients and Methods We retrospectively collected data from the medical oncology department for consecutive patients who had initially received standard lines of therapy followed by low-dose immunotherapy (nivolumab 40 mg) on a compassionate basis. The demographic details, histology, prior treatment, clinical and radiological response, date of disease progression, date of death, and toxicity data were collected. Results A total of 54 consecutive patients, who received low-dose immunotherapy with nivolumab from January 1, 2018 to February 14, 2020, were included in this analysis; 4 patients were not radiologically evaluable. The median age was 50.4 years (range 35-74 years), male:female ratio was 6:1. The most common comorbidities were hypertension and diabetes seen in 12 (22.2%) and 6 (11.1%) patients, respectively. The majority of the patients (70.4%) were of head and neck cancer. The median follow-up was 4.5 months (range 0.5-11.7). Clinical benefit was observed in 18 (33.3%) patients. Partial response and stable disease were achieved in 9 (16.7%) and 5 (9.3%) patients, respectively. Median survival was not reached for these patients. Six months progression-free survival and overall survival were 100 versus 8.7% (hazard ratio [HR] 0.05, 95% confidence interval [CI]: 0.01-0.36; p = 0.003) and 100 versus 29.7% (HR 0.03, 95% CI: 0.00-0.95; p = 0.047), respectively, for responders and nonresponders. The side effects were manageable. Conclusion In resource-constrained settings, low-dose immunotherapy with nivolumab seems to be an effective treatment option. Further studies are warranted to evaluate this approach.
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Affiliation(s)
- Amit Kumar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Akhil Kapoor
- Department of Medical Oncology, Mahamana Pandit Madan Mohan Malaviya Cancer Centre and Homi Bhabha Cancer Hospital, Tata Memorial Centre, Varanasi, Uttar Pradesh, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Vijay M. Patil
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Amit Janu
- Department of Radiodiagnosis, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Abhishek Mahajan
- Department of Radiodiagnosis, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Akhil Rajendra
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Amit Agarawal
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Satvik Khaddar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Anu Rajpurohit
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Lakhan Kashyap
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Anne Srikant
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Gautam Panda
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Kishore Kumar Kota
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Vikas Talreja
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
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8
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Fernandes Q. Precision meets repurposing: Innovative approaches in human papillomavirus and Epstein-Barr virus-driven cancer therapy. Cancer Lett 2024; 607:217318. [PMID: 39522710 DOI: 10.1016/j.canlet.2024.217318] [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: 09/03/2023] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Viral malignancies represent a distinct entity among cancers. Oncoviruses like the Human Papilloma Virus (HPV) and the Epstein Barr Virus (EBV) are highly potent inducers of oncogenic transformation leading to tumor development. HPV and EBV are known to be increasingly involved in the pathogenesis of various classes of cancers like cervical, head and neck, colorectal, breast, oral and anogenitial. Therapeutic vaccines directed at such oncoviruses, often fail to unleash the desired immune response against the tumor. This is largely due to the immunosuppressive microenvironment of the virus-induced tumors. Consequently, metronomic chemotherapies administered in conjunction with therapeutic viral vaccines have considerably enhanced the antitumor activity of these vaccines. Moreover, given the unique attributes of HPV and EBV-associated cancers, therapeutic agents directly targeting the oncoproteins of these viruses are still obscure. In this light, an increasing number of reports have evidenced the repurposing of drugs for therapeutic benefits in such cancers. This work delineates the significance and implications of metronomic chemotherapy and drug repurposing in HPV and EBV-associated cancers.
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Affiliation(s)
- Queenie Fernandes
- Translational Cancer Research Facility, National Centre for Cancer Care and Research, Hamad Medical Corporation P.O. Box 3050, Doha, Qatar; College of Medicine, Qatar University, P.O. Box 2713, Doha, Qatar.
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9
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Duerinck J, Lescrauwaet L, Dirven I, Del’haye J, Stevens L, Geeraerts X, Vaeyens F, Geens W, Brock S, Vanbinst AM, Everaert H, Caljon B, Bruneau M, Lebrun L, Salmon I, Kockx M, Tuyaerts S, Neyns B. Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma. Neuro Oncol 2024; 26:2208-2221. [PMID: 39406392 PMCID: PMC11630548 DOI: 10.1093/neuonc/noae177] [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] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG. MATERIALS AND METHODS Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles. RESULTS 42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015). CONCLUSION Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.
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Affiliation(s)
- Johnny Duerinck
- Department of Neurosurgery, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Louise Lescrauwaet
- Department of Neurosurgery, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Iris Dirven
- Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Laboratory for Medical and Molecular Oncology (LMMO), Translational Oncology Research Center (TORC), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Jacomi Del’haye
- Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Latoya Stevens
- Laboratory for Medical and Molecular Oncology (LMMO), Translational Oncology Research Center (TORC), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Xenia Geeraerts
- Laboratory for Medical and Molecular Oncology (LMMO), Translational Oncology Research Center (TORC), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Freya Vaeyens
- Department of Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Wietse Geens
- Department of Neurosurgery, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Stefanie Brock
- Department of Pathology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Anne-Marie Vanbinst
- Department of Radiology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Hendrik Everaert
- Department of Nuclear Medicine, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Ben Caljon
- Department of Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Michaël Bruneau
- Department of Neurosurgery, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Laetitia Lebrun
- Department of Pathology, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), CUB Hôpital Erasme, Erasme University Hospital, Brussels, Belgium
| | - Isabelle Salmon
- Department of Pathology, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), CUB Hôpital Erasme, Erasme University Hospital, Brussels, Belgium
| | | | - Sandra Tuyaerts
- Laboratory for Medical and Molecular Oncology (LMMO), Translational Oncology Research Center (TORC), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Bart Neyns
- Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Laboratory for Medical and Molecular Oncology (LMMO), Translational Oncology Research Center (TORC), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
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10
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Huang WK, Tang YJ, Wu CE, Hou MM, Hsu HC, Su PJ, Chiang NJ, Chen SC, Yeh CN, Chen JS, Chen MH, Hsieh CH, Chou WC. Real-world effectiveness and prognostic factors of durvalumab plus chemotherapy in a multicentric cohort with advanced biliary tract cancer. Oncologist 2024:oyae306. [PMID: 39566070 DOI: 10.1093/oncolo/oyae306] [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: 05/01/2024] [Accepted: 10/02/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Biliary tract cancer (BTC) is an aggressive biliary tract cancer, arising from the bile ducts and gallbladder, with a poor prognosis. The TOPAZ-1 trial of durvalumab plus first-line chemotherapy (gemcitabine plus cisplatin) showed improved survival vs chemotherapy alone. This real-world study aimed to confirm the effectiveness of this regimen. METHODS This retrospective, multicenter study included patients with advanced BTC treated with first-line durvalumab plus platinum chemotherapy at the Linkou, Taoyuan, and Tucheng branches of Chang Gung Memorial Hospital as well as at Taipei Veterans General Hospital between August 2021 and June 2023. RESULTS Among the 45 patients with advanced biliary tree cancer treated with durvalumab plus cisplatin and gemcitabine as first-line treatment, the objective response rate was 31.1% (14 partial responses). An additional 40% (18 patients) had stable disease. The median progression-free survival was 5.6 months (95%CI, 4.4-6.9) and median overall survival was 15.8 months (95%CI, 7.9-23.8). Responders had significantly longer survival than non-responders (15.8 vs 3.3 months). Although higher durvalumab doses (1000-1500 mg) appeared to have improved efficacy compared to lower doses (<1000 mg), the difference was not statistically significant. On multivariate analysis, poor ECOG performance status (≥2) and a high neutrophil-lymphocyte ratio were independent prognostic factors for shorter overall survival. CONCLUSION This real-world study demonstrated the comparable efficacy of durvalumab plus chemotherapy to the TOPAZ-1 trial for patients with advanced BTC and identified prognostic factors. There was a trend toward improved efficacy with higher durvalumab dosing (1000-1500 mg) vs lower dosing, though further research is needed to confirm this relationship.
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Affiliation(s)
- Wen-Kuan Huang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yan-Jei Tang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chiao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ming-Mo Hou
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hung-Chih Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Po-Jung Su
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Nai-Jung Chiang
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - San-Chi Chen
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Nan Yeh
- Department of General Surgery, GIST Team, and Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Chang Gung University, Taoyuan, Taiwan
| | - Jen-Shi Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Hsun Hsieh
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan
| | - Wen-Chi Chou
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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11
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Gandhi KA, Shirsat A, Hj SK, Chavan A, Dicholkar P, Shah S, Menon N, Noronha V, Joshi A, Prabhash K, Patil V, Gota V. Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer. Cancer Chemother Pharmacol 2024; 94:659-668. [PMID: 39060628 PMCID: PMC11470857 DOI: 10.1007/s00280-024-04697-x] [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: 12/29/2023] [Accepted: 07/05/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses. METHODS Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity. RESULTS Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group. CONCLUSION Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.
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Affiliation(s)
- Khushboo A Gandhi
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Aditi Shirsat
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Sharat Kumar Hj
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Ashish Chavan
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Parnika Dicholkar
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Saniya Shah
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
- Homi bhabha National Institute, Mumbai, 400094, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
- Homi bhabha National Institute, Mumbai, 400094, India
| | - Amit Joshi
- Homi bhabha National Institute, Mumbai, 400094, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410210, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
- Homi bhabha National Institute, Mumbai, 400094, India
| | - Vijay Patil
- Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
| | - Vikram Gota
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC) Sector- 22, Kharghar, Navi Mumbai, 410210, India.
- Homi bhabha National Institute, Mumbai, 400094, India.
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12
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Dhanawat A, Trikha M, Vora M, Gujarathi H, Ostwal V, Bhargava P, Kaushal R, Ramaswamy A. The use of immune checkpoint inhibitors in advanced gastric/gastroesophageal adenocarcinomas - real-world evidence and the use of alternative dosing. Ecancermedicalscience 2024; 18:1741. [PMID: 39421166 PMCID: PMC11484652 DOI: 10.3332/ecancer.2024.1741] [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: 05/20/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Immune check point inhibitors (ICIs) have an established role in Microsatellite-Instability-High (MSI-H) and Combined Positive Score (CPS) high advanced gastric/gastroesophageal (G/GE) adenocarcinomas, but there is limited real world data with regard to practice patterns, and efficacy of standard doses (SD-ICIs) and alternative lower doses (LD-ICIs). METHODS A retrospective study of patients with advanced G/GE adenocarcinomas receiving ICIs was conducted. The primary endpoint of the study was 12-month overall survival (OS), which was computed by Kaplan-Meier method. RESULTS A total of 91 patients were available for analysis during the study period. Seventy-four patients (81%) received nivolumab, while the remaining received pembrolizumab. Fifteen patients (16%) had MSI-H status and had a 12-month OS of 60% and median OS of 15 months (median follow-up - 38.3 months). In the Microsatellite-Stable (MSS) cohort (84%; n = 76), ICIs (combined with chemotherapy) were used predominantly in pre-treated patients (54%; n = 41). Patients with CPS ≥5 (72%; n = 55) had improved survival compared to patients with CPS <5 (28%; n = 21) (12-month OS: 52% vs. 26%; Median OS: 12.8 months vs. 3.2 months; p = 0.005). There was no difference in survival between patients who received SD-ICIs (54%; n = 41) and LD-ICIs (46%; n = 35) (12-month OS: 42% vs. 48%; Median OS: 8.7 months vs. 11 months; p = 0.44). CONCLUSIONS Patients with advanced G/GEJ adenocarcinomas in the real world predominantly received ICIs during later lines of therapy as opposed to first line therapy. Using a CPS cutoff of ≥5 as opposed to CPS <5 predicts for improved survivals in MSS patients and patients receiving low dose ICIs have similar survival outcomes to patients receiving standard dose ICIs within the confines of a heterogenous study cohort.
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Affiliation(s)
- Aditya Dhanawat
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Mehak Trikha
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Manan Vora
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Himanshu Gujarathi
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Rajiv Kaushal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Dr E Borges Road, Parel, Mumbai 400 012, India
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13
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Trikha M, Sarkar L, Dhanawat A, Syed N, Gujarathi H, Vora M, Sivakumar Raja AS, Bhargava P, Ramaswamy A, Mandavkar S, Saklani A, Kaushal RK, Bal M, Shetty O, Yadav S, Ostwal V. Performance of Low-Dose Immunotherapy and Standard-Dose Immunotherapy in Microsatellite Instability-High Metastatic Colorectal Cancer: Real-World Data (CLouD-High Study). JCO Glob Oncol 2024; 10:e2400141. [PMID: 39159410 DOI: 10.1200/go.24.00141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/29/2024] [Accepted: 05/30/2024] [Indexed: 08/21/2024] Open
Abstract
PURPOSE Standard-dose immune checkpoint inhibitors (SD-ICIs) are the standard of care as initial therapy in microsatellite instable-high (MSI-H) advanced/metastatic colorectal adenocarcinomas (mCRC), but there are preclinical data to suggest that low-dose ICIs (LD-ICI) might also have similar efficacy. MATERIALS AND METHODS A retrospective study of patients with MSI-H mCRC receiving ICIs between June 2017 and January 2023 was conducted. The primary end point of the study was 12-month progression-free survival (PFS), which was computed using the Kaplan-Meier method. RESULTS A total of 65 patients were available for analysis during the study period. Sixty patients (92%) received nivolumab, whereas the remaining received pembrolizumab. First-line ICIs were received by 18 patients (28%), whereas 47 patients (72%) received ICIs during later lines. Thirty patients (47%) received LD-ICIs (all received nivolumab), with the remaining receiving SD-ICIs (53%). At a median follow-up of 16.5 (95% CI, 11.8 to 21.2) months, median PFS was not reached in the entire cohort. The 12-month PFS rate in the LD-ICI cohort was 90%, whereas it was 75.8% in the SD-ICI cohort. There were no statistical differences in patients receiving ICIs as first-line therapy (12 months PFS-94.4%) or during later lines of therapy (12-month PFS-77.9%; P = .56). CONCLUSION ICIs in the current study show survivals which are similar to those seen in seminal trials in patients with MSI-H mCRC. Low-dose ICIs appear to work in MSI-H mCRC and should be explored prospectively in clinical trials. Patients with MSI-H status should be exposed to ICIs, whether initially or later during treatment, whenever feasible.
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Affiliation(s)
- Mehak Trikha
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Laboni Sarkar
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Aditya Dhanawat
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Noorzia Syed
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Himanshu Gujarathi
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Manan Vora
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - A Sree Sivakumar Raja
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Sarika Mandavkar
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
| | - Avanish Saklani
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute HBNI, Mumbai, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute HBNI, Mumbai, India
| | - Munita Bal
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute HBNI, Mumbai, India
| | - Omshree Shetty
- Department of Molecular Pathology, Tata Memorial Centre, Homi Bhabha National Institute HBNI, Mumbai, India
| | - Subhash Yadav
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute HBNI, Mumbai, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Parel, Mumbai, India
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14
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Puszkiel A, Bianconi G, Pasquiers B, Balakirouchenane D, Arrondeau J, Boudou-Rouquette P, Bretagne MC, Salem JE, Declèves X, Vidal M, Kramkimel N, Guegan S, Aractingi S, Huillard O, Alexandre J, Wislez M, Goldwasser F, Blanchet B. Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients. Br J Cancer 2024; 130:1866-1874. [PMID: 38532102 PMCID: PMC11130267 DOI: 10.1038/s41416-024-02659-x] [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: 10/03/2023] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France). CONCLUSIONS Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.
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Affiliation(s)
- Alicja Puszkiel
- Université Paris Cité, Faculté de Pharmacie de Paris, INSERM UMR-S1144, Paris, France.
- Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP, Paris, France.
| | - Guillaume Bianconi
- Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP, Paris, France
| | - Blaise Pasquiers
- Université Paris Cité, Faculté de Pharmacie de Paris, INSERM UMR-S1144, Paris, France
- PhinC Development, Massy, France
| | | | - Jennifer Arrondeau
- Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Pascaline Boudou-Rouquette
- Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Marie-Claire Bretagne
- Department of Pharmacology, Pharmacovigilance Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Joe-Elie Salem
- Department of Pharmacology, Pharmacovigilance Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
- INSERM, CIC-1901, Sorbonne Université, Paris, France
| | - Xavier Declèves
- Université Paris Cité, Faculté de Pharmacie de Paris, INSERM UMR-S1144, Paris, France
- Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP, Paris, France
| | - Michel Vidal
- Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP, Paris, France
- Université Paris Cité, Faculté de Pharmacie de Paris, UMR8038 CNRS CiTCoM, U1268 INSERM, CARPEM, Paris, France
| | - Nora Kramkimel
- Department of Dermatology, Cochin University Hospital, AP-HP, Paris, France
| | - Sarah Guegan
- Department of Dermatology, Cochin University Hospital, AP-HP, Paris, France
| | - Selim Aractingi
- Department of Dermatology, Cochin University Hospital, AP-HP, Paris, France
| | - Olivier Huillard
- Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Jérôme Alexandre
- Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France
- Université Paris Cité, INSERM, Centre de Recherche des Cordeliers, Équipe labélisée Ligue Contre le Cancer, CNRS SNC 5096, Sorbonne Université, Paris, France
| | - Marie Wislez
- Department of Pneumology, Cochin University Hospital, AP-HP, Paris, France
| | - François Goldwasser
- Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France
- Université Paris Cité, Faculté de Médecine, INSERM, U1016, Institut Cochin, Paris, France
| | - Benoit Blanchet
- Biologie du Médicament - Toxicologie, Cochin University Hospital, AP-HP, Paris, France
- Université Paris Cité, Faculté de Pharmacie de Paris, UMR8038 CNRS CiTCoM, U1268 INSERM, CARPEM, Paris, France
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15
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Patel A, Hande V, Mr K, Dange H, Das AK, Murugesan V, Bhatt T, Shankaran R. Effectiveness of Immune Checkpoint Inhibitors in Various Tumor Types Treated by Low, Per-Weight, and Conventional Doses at a Tertiary Care Center in Mumbai. JCO Glob Oncol 2024; 10:e2300312. [PMID: 38181308 DOI: 10.1200/go.23.00312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/17/2023] [Accepted: 10/31/2023] [Indexed: 01/07/2024] Open
Abstract
PURPOSE The cost of immune checkpoint inhibitors (ICIs) limits their accessibility to a small number of patients with cancer in low- and middle-income countries. Early-phase clinical trials have shown target inhibition and high activity at doses lower than those registered and evaluated in clinical trials. Here, we report everyday experience of using ICIs in 100 Indian patients, many of whom received lower doses of ICIs. METHODS Consecutive patients who received at least one dose of an ICI irrespective of tumor type at a tertiary care hospital in Mumbai, India, that was able to access ICIs for its patients were enrolled. The objectives were to study the doses used over a 3-year time period, and the effectiveness of therapy, assessed primarily by the overall response rate (ORR), overall survival (OS), and progression-free survival were secondary end points. RESULTS Twenty-five patients were treated with conventional doses of ICIs, 29 patients received lower doses per body weight, and 46 patients received low-dose treatment. The median number of cycles received was 5 (range, 1-28). Seventy-eight patients received ICIs in a palliative setting. The median follow-up time was 10.2, 9.8, and 3.9 months for those receiving fixed approved dosing, per body weight dosing, and low-dose treatment, respectively. There was a trend with time to prescribe lower doses. Response evaluation was available for 92 patients. Twenty-one (five-adjuvant and 16-palliative) patients received ICIs only. The ORR did not differ statistically among different dosing groups, but comparisons are confounded by inclusion of different ICIs, different tumor sites, and concurrent treatments. The median OS was 6.8 (range, 4.6-9.0) months. CONCLUSION Adoption of per-body weight and lower dosing of ICIs appears to give acceptable outcomes. Lower dosing can improve access and timely delivery of ICIs in low- and middle-income countries.
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Affiliation(s)
- Amol Patel
- Department of Medical Oncology, Indian Naval Hospital Ship, Asvini, Mumbai, India
| | - Vivek Hande
- Department of Medicine, Indian Naval Hospital Ship, Asvini, Mumbai, India
| | - Kaushik Mr
- Department of Medical Oncology, Indian Naval Hospital Ship, Asvini, Mumbai, India
| | - Hemendra Dange
- Medical Stores, Indian Naval Hospital Ship, Asvini, Mumbai, India
| | - Amit Kumar Das
- Department of Pathology, Indian Naval Hospital Ship, Asvini, Mumbai, India
| | | | - Trilok Bhatt
- Department of Radiology, Indian Naval Hospital Ship, Asvini, Mumbai, India
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16
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Kuah CY, Monfries R, Quartagno M, Seckl MJ, Ghorani E. What is the optimal duration, dose and frequency for anti-PD1 therapy of non-small cell lung cancer? Ther Adv Med Oncol 2023; 15:17588359231210271. [PMID: 37954230 PMCID: PMC10638879 DOI: 10.1177/17588359231210271] [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: 03/02/2023] [Accepted: 10/09/2023] [Indexed: 11/14/2023] Open
Abstract
Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the management of multiple malignancies including lung cancer. However, the optimal use of these agents in terms of duration, dose and administration frequency remains unknown. Focusing on anti-PD1 agents nivolumab and pembrolizumab in the context of non-small cell lung cancer, we argue that several lines of evidence suggest current administration regimens of these drugs may result in overtreatment with potentially important implications for cost, quality of life and toxicity. This review summarizes evidence for the scope to optimize anti-PD1 regimens, the limitations of existing data and potential approaches to solve these problems including with a novel multi-arm clinical trial design implemented in the recently opened REFINE-Lung study.
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Affiliation(s)
- Chii Yang Kuah
- Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, UK
| | - Robert Monfries
- Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, UK
| | - Matteo Quartagno
- Institute for Clinical Trials and Methodology, University College London, London, UK
| | - Michael J. Seckl
- Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College London W6 8RF, UK
| | - Ehsan Ghorani
- Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College London W6 8RF, UK
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17
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Thomas Z, Jambunathan P, Jibi A, John AO, Singh A. Low-dose nivolumab and cabozantinib in recurrent intestinal-type papillary adenocarcinoma of the sinonasal region. BMJ Case Rep 2023; 16:e255021. [PMID: 37923331 PMCID: PMC10626912 DOI: 10.1136/bcr-2023-255021] [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] [Indexed: 11/07/2023] Open
Abstract
Intestinal-type sinonasal adenocarcinoma is a rare epithelial malignancy primarily treated with surgery and chemoradiation. The combination of low-dose immunotherapy and a tyrosine kinase inhibitor in recurrent disease has not been previously studied.A man in his 20s with papillary adenocarcinoma of the sinonasal region, following surgical resection, was treated with six cycles of concurrent chemoradiotherapy, followed by four cycles of docetaxel, cisplatin and capecitabine. While on treatment, he was found to have extensive residual disease and he was started on low-dose nivolumab and cabozantinib. Repeat imaging after ten months of treatment revealed a significant reduction in lesions.Non-squamous head and neck cancers are often excluded from major trials, and the effect of immunotherapy in these histologies is poorly understood. The response seen with low-dose immunotherapy underscores the need for further research in this setting.
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Affiliation(s)
- Zachariah Thomas
- Department of Medical Oncology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
| | - Prashant Jambunathan
- Department of Medical Oncology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
| | - Anjali Jibi
- Department of General Pathology, Christian Medical College Vellore, Vellore, Tamil Nadu, India
| | - Ajoy Oommen John
- Department of Medical Oncology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
| | - Ashish Singh
- Department of Medical Oncology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
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18
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Wesevich A, Goldstein DA, Paydary K, Peer CJ, Figg WD, Ratain MJ. Interventional pharmacoeconomics for immune checkpoint inhibitors through alternative dosing strategies. Br J Cancer 2023; 129:1389-1396. [PMID: 37542109 PMCID: PMC10628132 DOI: 10.1038/s41416-023-02367-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/05/2023] [Accepted: 07/12/2023] [Indexed: 08/06/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are approved for the treatment of a variety of cancer types. The doses of these drugs, though approved by the Food and Drug Administration (FDA), have never been optimised, likely leading to significantly higher doses than required for optimal efficacy. Dose optimisation would hypothetically decrease the risk, severity, and duration of immune-related adverse events, as well as provide an opportunity to reduce costs through interventional pharmacoeconomic strategies such as off-label dose reductions or less frequent dosing. We summarise existing evidence for ICI dose optimisation to advocate for the role of interventional pharmacoeconomics.
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Affiliation(s)
- Austin Wesevich
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Daniel A Goldstein
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
- Clalit Health Service, Tel Aviv, Israel
- Optimal Cancer Care Alliance, Chicago, IL, USA
| | - Koosha Paydary
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Cody J Peer
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - William D Figg
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mark J Ratain
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
- Optimal Cancer Care Alliance, Chicago, IL, USA.
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19
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Choudhary N, Bawari S, Burcher JT, Sinha D, Tewari D, Bishayee A. Targeting Cell Signaling Pathways in Lung Cancer by Bioactive Phytocompounds. Cancers (Basel) 2023; 15:3980. [PMID: 37568796 PMCID: PMC10417502 DOI: 10.3390/cancers15153980] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Lung cancer is a heterogeneous group of malignancies with high incidence worldwide. It is the most frequently occurring cancer in men and the second most common in women. Due to its frequent diagnosis and variable response to treatment, lung cancer was reported as the top cause of cancer-related deaths worldwide in 2020. Many aberrant signaling cascades are implicated in the pathogenesis of lung cancer, including those involved in apoptosis (B cell lymphoma protein, Bcl-2-associated X protein, first apoptosis signal ligand), growth inhibition (tumor suppressor protein or gene and serine/threonine kinase 11), and growth promotion (epidermal growth factor receptor/proto-oncogenes/phosphatidylinositol-3 kinase). Accordingly, these pathways and their signaling molecules have become promising targets for chemopreventive and chemotherapeutic agents. Recent research provides compelling evidence for the use of plant-based compounds, known collectively as phytochemicals, as anticancer agents. This review discusses major contributing signaling pathways involved in the pathophysiology of lung cancer, as well as currently available treatments and prospective drug candidates. The anticancer potential of naturally occurring bioactive compounds in the context of lung cancer is also discussed, with critical analysis of their mechanistic actions presented by preclinical and clinical studies.
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Affiliation(s)
- Neeraj Choudhary
- Department of Pharmacognosy, GNA School of Pharmacy, GNA University, Phagwara 144 401, India
| | - Sweta Bawari
- Amity Institute of Pharmacy, Amity University, Noida 201 301, India
| | - Jack T. Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Dona Sinha
- Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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20
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Ghorani E, Quartagno M, Blackhall F, Gilbert DC, O'Brien M, Ottensmeier C, Pizzo E, Spicer J, Williams A, Badman P, Parmar MKB, Seckl MJ. REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment. Lancet Oncol 2023; 24:e219-e227. [PMID: 37142383 PMCID: PMC7617361 DOI: 10.1016/s1470-2045(23)00095-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 05/06/2023]
Abstract
Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.
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Affiliation(s)
- Ehsan Ghorani
- Department of Medical Oncology, Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, London, UK
| | - Matteo Quartagno
- Institute for Clinical Trials and Methodology, University College London, London, UK
| | - Fiona Blackhall
- Christie National Health Service Foundation Trust, Manchester, UK
| | - Duncan C Gilbert
- Institute for Clinical Trials and Methodology, University College London, London, UK
| | - Mary O'Brien
- Royal Marsden Hospital, Imperial College London, London, UK
| | - Christian Ottensmeier
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, UK
| | - Elena Pizzo
- Department of Applied Health Research, University College London, London, UK
| | - James Spicer
- King's College London, Guy's Hospital, London, UK
| | - Alex Williams
- Imperial College Trials Unit-Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Philip Badman
- Imperial College Trials Unit-Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mahesh K B Parmar
- Institute for Clinical Trials and Methodology, University College London, London, UK.
| | - Michael J Seckl
- Department of Medical Oncology, Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, London, UK.
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21
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Ter Heine R, van den Heuvel MM, Piet B, Deenen MJ, van der Wekken AJ, Hendriks LEL, Croes S, van Geel RMJM, Jansman FGA, Boshuizen RC, Franssen EJF, Smit AAJ, Dumoulin DW, Oude Munnink TH, Smit EF, Derijks HJ, van der Leest CH, Hendrikx JJMA, Moes DJAR, de Rouw N. A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer. Target Oncol 2023; 18:441-450. [PMID: 37081309 DOI: 10.1007/s11523-023-00958-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 04/22/2023]
Abstract
BACKGROUND Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.
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Affiliation(s)
- Rob Ter Heine
- Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands.
| | | | - Berber Piet
- Department of Pulmonology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital Eindhoven, Eindhoven, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Anthonie J van der Wekken
- Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lizza E L Hendriks
- Department of Pulmonary Diseases, GROW-School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Sander Croes
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Disease, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Robin M J M van Geel
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Disease, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Frank G A Jansman
- Department of Clinical Pharmacy, Deventer Hospital, Deventer, The Netherlands
- Unit of PharmacoTherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands
| | | | - Eric J F Franssen
- Department of Clinical Pharmacy, Onze Lieve Vrouwe Gasthuis Hospital AC, Amsterdam, The Netherlands
| | - Arthur A J Smit
- Department of Pulmonology, Onze Lieve Vrouwe Gasthuis Hospital AC, Amsterdam, The Netherlands
| | - Daphne W Dumoulin
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Thijs H Oude Munnink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Egbert F Smit
- Department of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Hieronymus J Derijks
- Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands
- Department of Pharmacy, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
| | | | - Jeroen J M A Hendrikx
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute (NKI-AVL), Amsterdam, The Netherlands
| | - Dirk J A R Moes
- Department of Clinical Pharmacology and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Nikki de Rouw
- Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, Geert Grooteplein Zuid 10, 6525GA, Nijmegen, The Netherlands
- Department of Clinical Pharmacy, Amphia Hospital, Breda, The Netherlands
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22
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Meriggi F, Zaniboni A, Zaltieri A. Low-Dose Immunotherapy: Is It Just an Illusion? Biomedicines 2023; 11:biomedicines11041032. [PMID: 37189650 DOI: 10.3390/biomedicines11041032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
The development and use of immunotherapy in the last decade have led to a drastic improvement in results in the onco-haematological field. This has implied, on the one hand, the need for clinicians to manage a new type of adverse event and, on the other hand, a significant increase in costs. However, emerging scientific evidence suggests that, as with other drugs in the recent past, the registry dosage can be drastically reduced for immunotherapies without penalizing their effectiveness. This would also lead to an important reduction in costs, expanding the audience of cancer patients who could access immunotherapy-based treatments. In this “Commentary”, we analyze the available evidence of pharmacokinetics and pharmacodynamics and the most recent literature in favor of low-dose immunotherapy.
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23
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Wang N, Zheng L, Li M, Hou X, Zhang B, Chen J, Li S, Chen L. Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial. Lung Cancer 2023; 178:183-190. [PMID: 36868179 DOI: 10.1016/j.lungcan.2023.02.009] [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: 08/22/2022] [Revised: 11/24/2022] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
INTRODUCTION Pembrolizumab is recommended with a fixed dose of 200 mg 3-weekly. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced non-small cell lung cancer (NSCLC). METHODS In this prospective exploratory study, we enrolled advanced NSCLC patients in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200 mg 3-weekly with or without chemotherapy for four cycles, then for patients without progressive disease (PD), pembrolizumab was administrated in new dose-intervals according to steady state plasma-concentration (Css) of pembrolizumab until PD. We set the effective concentration (Ce) at 15 μg/ml and new dose-intervals (T) was calculated according to Css of pembrolizumab using following equation: Css × 21D = Ce (15 μg/ml) × T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR) and safety. Besides, advanced NSCLC patients received pembrolizumab 200 mg 3-weekly and more than four cycles in our center were defined as the history-controlled cohort. Patients with Css of pembrolizumab underwent genetic polymorphism analysis of variable number of tandem repeats (VNTR) region in neonatal Fc receptor (FcRn). The study was registered at ClinicalTrials.gov, NCT05226728. RESULTS A total 33 patients received pembrolizumab in new adjusted dose-intervals. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20 d). In PK-guided cohort, the median PFS was 15.1 months and ORR 57.6 %, whereas in history-controlled cohort was 7.7 months and ORR 48.2 %. The immune-related adverse events were 15.2 % and 17.9 % between two cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 (p = 0.005). CONCLUSIONS PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity. Meanwhile less frequent dosing of pembrolizumab by PK-guided could reduce financial toxicity potentially. This provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC.
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Affiliation(s)
- Na Wang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Lie Zheng
- Department of Medical Imaging, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Meichen Li
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Xue Hou
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Baishen Zhang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Jing Chen
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Su Li
- Clinical Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
| | - Likun Chen
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
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24
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Patil VM, Noronha V, Menon N, Rai R, Bhattacharjee A, Singh A, Nawale K, Jogdhankar S, Tambe R, Dhumal S, Sawant R, Alone M, Karla D, Peelay Z, Pathak S, Balaji A, Kumar S, Purandare N, Agarwal A, Puranik A, Mahajan A, Janu A, Kumar Singh G, Mittal N, Yadav S, Banavali S, Prabhash K. Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 2023; 41:222-232. [PMID: 36265101 DOI: 10.1200/jco.22.01015] [Citation(s) in RCA: 96] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
PURPOSE The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS). METHODS This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS. RESULTS One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P = .744). CONCLUSION To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.
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Affiliation(s)
- Vijay Maruti Patil
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rahul Rai
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Atanu Bhattacharjee
- Section of Biostatistics, Center for Cancer Epidemiology, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Ajay Singh
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Kavita Nawale
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shweta Jogdhankar
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rupali Tambe
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sachin Dhumal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Riddhi Sawant
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Mitali Alone
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Devanshi Karla
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Zoya Peelay
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shruti Pathak
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Arun Balaji
- Department of Speech and Therapy, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Suman Kumar
- Department of Radiology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nilendu Purandare
- Department of Nuclear Medicine, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Archi Agarwal
- Department of Nuclear Medicine, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Ameya Puranik
- Department of Nuclear Medicine, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Abhishek Mahajan
- Department of Radiology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Amit Janu
- Department of Radiology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Gunjesh Kumar Singh
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Neha Mittal
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Subhash Yadav
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shripad Banavali
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
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Malmberg R, Zietse M, Dumoulin DW, Hendrikx JJMA, Aerts JGJV, van der Veldt AAM, Koch BCP, Sleijfer S, van Leeuwen RWF. Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab. Lancet Oncol 2022; 23:e552-e561. [DOI: 10.1016/s1470-2045(22)00554-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022]
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Low JL, Huang Y, Sooi K, Chan ZY, Yong WP, Lee SC, Goh BC. Real-world assessment of attenuated dosing anti-PD1 therapy as an alternative dosing strategy in a high-income country (as defined by World Bank). Front Oncol 2022; 12:932212. [PMID: 36465401 PMCID: PMC9714462 DOI: 10.3389/fonc.2022.932212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/17/2022] [Indexed: 09/10/2024] Open
Abstract
The rising cost of oncological drugs poses a global challenge to patients, insurers, and policy makers, with the leading drugs worldwide by revenue from immune checkpoint inhibitors (ICIs). Despite its cost, ICI is marked as a paradigm shift, offering the potential of a long-term cure. To reduce cost, an attenuated dose of ICI based on pharmacological principles can be used while maintaining efficacy. This real-world study aims to examine the prescribing patterns, the effect of financial constraints, and the outcomes in non-small cell lung cancer (NSCLC). All patients receiving palliative intent ICI treatment for advanced NSCLC between January 2014 and April 2021 in National University Hospital, Singapore were recruited. Demographics, prescription trends, factors affecting the prescription of attenuated dose ICI (AD ICI) versus standard dose ICI (SD ICI), and the effect of dose on survival outcomes, toxicities, and costs were examined. Two hundred seventy-four received ICI. The majority of them were treated in first-line setting. One hundred sixty-two (59%) of patients received AD ICI, whereas 112 (41%) received SD ICI. Patients who did not have a supplemental private as-charged health insurance plan were more likely to have received AD ICI (OR: 4.53 [2.69-7.61] p < 0.001). There was no difference in progression-free survival (PFS) and overall survival (OS)-adjusted HR 1.07 CI [0.76, 1.50] p = 0.697 and HR 0.95 CI [0.67, 1.34] p = 0.773, respectively, between patients who received AD versus SD ICI. A cost minimization analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of USD 7,939,059 over 7 years. Our study provides evidence for AD-ICI as a promising strategy to maximize the number of patients who can be treated with ICI. This has the potential to make significant economic impact and allow more patients to benefit from novel therapies.
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Affiliation(s)
- Jia Li Low
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
| | - Yiqing Huang
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
| | - Kenneth Sooi
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
| | - Zhi Yao Chan
- Department of Pharmacy, National University Hospital, National University Health System, Singapore, Singapore
| | - Wei Peng Yong
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
- Cancer Science Institute (CSI), National University Singapore, Singapore, Singapore
| | - Soo Chin Lee
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
- Cancer Science Institute (CSI), National University Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Boon Cher Goh
- Department of Hematology-Oncology, National University Cancer Institute (NCIS), Singapore, Singapore
- Cancer Science Institute (CSI), National University Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Chen YH, Wang CC, Chen YY, Wang JH, Hung CH, Kuo YH. Low-dose nivolumab in advanced hepatocellular carcinoma. BMC Cancer 2022; 22:1153. [PMID: 36348292 DOI: 10.1186/s12885-022-10271-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
Abstract
Background
The approved dose of nivolumab is 3 mg/kg or a flat dose of 240 mg for indications. There is no dose-response relationship for nivolumab; therefore, a low-dose regimen may be an option to reduce financial toxicity. This study was designed to investigate the efficacy and safety of low-dose nivolumab in the management of hepatocellular carcinoma (HCC).
Methods
We retrospectively reviewed patients with HCC who received 20 or 100 mg of nivolumab intravenously every 2 weeks. The objective response rate was determined in accordance with the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The Cox regression model and Kaplan–Meier method were used to analyze hazard factors, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Results
In total, 78 patients were enrolled, including 49 with hepatitis B virus (HBV) and 23 with hepatitis C virus (HCV). All patients were staged as Barcelona Clinic Liver Cancer stage C, and 20 patients were classified as having Child–Pugh classification B (7). Nivolumab 20 mg was an independent prognostic factor for better PFS, and albumin-bilirubin grade 1 was the independent prognostic factor for superior OS in the multivariate analyses. Patients with better HBV (HBV DNA < 500 IU/ml) and HCV (HCV RNA undetectable) controls had superior OS. All AEs were grade 1–2 in severity, and all patients tolerated nivolumab without treatment interruption or dose adjustment. Additionally, 31 patients underwent subsequent therapy after nivolumab treatment.
Conclusion
Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC who cannot afford the high cost of immune checkpoint inhibitors in real-world practice.
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Optimizing the dose and schedule of immune checkpoint inhibitors in cancer to allow global access. Nat Med 2022; 28:2236-2237. [PMID: 36202999 DOI: 10.1038/s41591-022-02029-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Jin X, Zhang K, Fang T, Zeng X, Yan X, Tang J, Liang Z, Xie L, Zhao D. Low-dose PD-1 inhibitor combined with lenvatinib for preemptive treatment of recurrence after liver transplantation for hepatocellular carcinoma: Case report and literature review. Front Oncol 2022; 12:951303. [PMID: 36119543 PMCID: PMC9478730 DOI: 10.3389/fonc.2022.951303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022] Open
Abstract
Orthotopic liver transplantation (OLT), as one of the curative methods for the treatment of hepatocellular carcinoma (HCC), has brought hope to patients with HCC. However, treatment options for HCC recurrence and metastasis after liver transplantation are limited. Immune checkpoint inhibitor (ICI), such as programmed cell death protein 1 (PD-1) inhibitor, have been successfully used in advanced or metastatic HCC, but the data on the safety of PD-1 inhibitor after liver transplantation is limited. In this article, we report a 47-year-old patient with acute-on-chronic liver failure and multiple HCC who was successfully treated with liver transplantation. On the 45th day after OLT, the patient’s alpha fetoprotein (AFP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) were increased, and imaging examination showed no residual tumor. The patient had high risk factors for tumor recurrence before operation, so the possibility of tumor recurrence was considered. When the tumor markers showed an upward trend, we immediately treated the patient with lenvatinib 8 mg, after half a month, the AFP and AFP-L3 continued to increase compared with before. Then we used low-dose nivolumab 40mg, the patient’s AFP and AFP-L3 gradually decreased. One month later, a second low-dose nivolumab 40mg was given, and the patient’s tumor markers gradually decreased to normal. No acute rejection and other complications occurred during the treatment. So far, we have followed up this patient for 2 years, and no tumor recurrence was observed. To our knowledge, this is the first reported case using a low dose of nivolumab in combination with lenvatinib to prevent recurrence of HCC after liver transplantation.
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30
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Jiang M, Hu Y, Lin G, Chen C. Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course. Front Oncol 2022; 12:906251. [PMID: 35795044 PMCID: PMC9251517 DOI: 10.3389/fonc.2022.906251] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/24/2022] [Indexed: 12/19/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a revolutionary breakthrough in the field of cancer by modulating patient's own immune system to exert anti-tumor effects. The clinical application of ICIs is still in its infancy, and their dosing regimens need to be continuously adjusted. Pharmacokinetic/pharmacodynamic studies showed a significant plateau in the exposure-response curve, with high receptor occupancy and plasma concentrations achieved at low dose levels. Coupled with concerns about drug toxicity and heavy economic costs, there has been an ongoing quest to reevaluate the current ICI dosing regimens while preserving maximum clinical efficacy. Many clinical data showed remarkable anticancer effects with ICIs at the doses far below the approved regimens, indicating the possibility of dose reduction. Our review attempts to summarize the clinical evidence for ICIs regimens with lower-dose, less-frequency, shorter-course, and provide clues for further ICIs regimen optimization.
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Affiliation(s)
| | | | | | - Chao Chen
- Department of Radiotherapy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
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31
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Kanabar SS, Tiwari A, Soran V, Balendran P, Price M, Turner AM. Impact of PD1 and PDL1 immunotherapy on non-small cell lung cancer outcomes: a systematic review. Thorax 2022; 77:1163-1174. [PMID: 35688624 DOI: 10.1136/thoraxjnl-2020-215614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Despite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1) may be effective for these patients. However, this therapy's impact on outcomes other than survival, and outcomes of patients not in trials, remains largely unknown. Therefore, we compared the effectiveness of PD1 and PDL1 immunotherapy to chemotherapy and placebo across multiple clinical outcomes. METHODS Six databases were searched on 12-13 October 2019 for randomised controlled trials (RCTs) and observational studies investigating nivolumab, pembrolizumab, atezolizumab or durvalumab. Study selection was performed independently by two reviewers. Data for overall survival, progression-free survival, adverse effects (AEs) and quality of life (QoL) were descriptively and meta-analysed. Factors impacting treatment outcomes, including PDL1 expression, were explored. The similarity between RCT and observational data was assessed. RESULTS From 5423 search results, 139 full texts and abstracts were included. Immunotherapy was associated with a lower risk of death than both comparators. In RCTs, the incidence of treatment-related AEs was approximately 20% lower among patients using immunotherapy compared with chemotherapy. However, no other consistent benefits were observed. Progression-free survival results were inconsistent. Improvements to QoL varied according to the instrument used; however, QoL was not recorded widely. Survival results were similar between study designs; however, AEs incidence was lower in observational studies. DISCUSSION Among patients with aNSCLC, immunotherapy improved overall survival and incidence of treatment-related AEs compared with chemotherapy. Benefits to progression-free survival and QoL were less consistent. PROSPERO REGISTRATION NUMBER CRD42019153345.
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Affiliation(s)
- Shivani Setur Kanabar
- Medical School, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK .,Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Abhinav Tiwari
- Medical School, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Vina Soran
- Medical School, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Prashanthan Balendran
- Medical School, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Malcolm Price
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK.,NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Modified-Dose Pembrolizumab and Prognostic Outcomes among Non-Small Cell Lung Cancer Patients: A Chart Review Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19105999. [PMID: 35627534 PMCID: PMC9141635 DOI: 10.3390/ijerph19105999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023]
Abstract
The modified dose (MD) regimen of pembrolizumab (2 mg/kg or 100 mg every 3 weeks) is an alternative option to reduce the financial burden resulting from the extremely high cost of the standard dose (SD) regimen (200 mg every 3 weeks). However, the clinical effectiveness and prognostic outcomes have not been fully elucidated in real-word clinical practice. Sixty-four consecutive patients in Taiwan receiving pembrolizumab for advanced NSCLC between 2018 and 2020 were recruited in this study. Comparisons of overall survival (OS) and progression-free survival (PFS) were performed using Kaplan−Meier survival curves. Additionally, 12 predictors, including pembrolizumab regimen, dose, neutrophil-to-lymphocyte ratio (NLR), age, sex, histopathology, smoking history, ECOG PS, EGFR mutation, PD-L1 expression, distant metastases and treatment line, were analyzed in multivariable Cox models for predicting OS and PFS. The results showed that the MD group and the SD group had similar OS and PFS, especially in patients beyond first-line treatment or with a pretreatment NLR < 5. The NLR was the only independent factor associated with both OS (adjusted HR = 0.052; p = 0.010) and PFS (adjusted HR = 0.259; p = 0.021). The results of this study assure the clinical effectiveness of MD pembrolizumab and suggest that the pretreatment NLR could highlight patients who may benefit from MD pembrolizumab.
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Navani V, Graves MC, Mandaliya H, Hong M, van der Westhuizen A, Martin J, Bowden NA. Melanoma: An immunotherapy journey from bench to bedside. Cancer Treat Res 2022; 183:49-89. [PMID: 35551656 DOI: 10.1007/978-3-030-96376-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Melanoma gave science a window into the role immune evasion plays in the development of malignancy. The entire spectrum of immune focused anti-cancer therapies has been subjected to clinical trials in this disease, with limited success until the immune checkpoint blockade era. That revolution launched first in melanoma, heralded a landscape change throughout cancer that continues to reverberate today.
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Affiliation(s)
| | - Moira C Graves
- Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, University Dr, Callaghan, NSW, 2308, Australia
| | - Hiren Mandaliya
- Calvary Mater Hospital Newcastle, Edith St, Waratah, NSW, 2298, Australia
| | - Martin Hong
- Calvary Mater Hospital Newcastle, Edith St, Waratah, NSW, 2298, Australia
| | - Andre van der Westhuizen
- Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, University Dr, Callaghan, NSW, 2308, Australia.,Calvary Mater Hospital Newcastle, Edith St, Waratah, NSW, 2298, Australia
| | - Jennifer Martin
- Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, University Dr, Callaghan, NSW, 2308, Australia.,John Hunter Hospital, Newcastle, NSW, Australia
| | - Nikola A Bowden
- Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, University Dr, Callaghan, NSW, 2308, Australia
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Araujo DV, Uchoa B, Soto-Castillo JJ, Furlan LL, Oliva M. When Less May Be Enough: Dose Selection Strategies for Immune Checkpoint Inhibitors Focusing on AntiPD-(L)1 Agents. Target Oncol 2022; 17:253-270. [PMID: 35687223 DOI: 10.1007/s11523-022-00890-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
Abstract
Early clinical trials investigating antiPD(L)-1 agents rarely reached a maximum tolerated dose (MTD), and efficacy signals were observed even at the lowest dose levels. Most extended treatment intervals investigated indicated that these drugs do not follow a direct dose-toxicity or dose-efficacy relationship. Within this context and considering the high cost of antiPD(L)-1 agents, there is a significant debate on whether lower doses or the administration of such agents at an extended interval should be prospectively evaluated in already-approved agents, or at least be considered in novel combination trials involving antiPD(L)-1 drugs. Herein, we review the dosing, overall response rates, and incidence of treatment-related adverse events of antiPD(L)-1 agents in early dose-escalation trials and discuss the appropriateness of recommended Phase 2 dose selection as well as the final regulatory approved doses of such agents. Efficacy and safety data from randomized dose-range Phase 2 trials and real-world data (RWD) on the usage of lower doses and/or non-standard extended treatment intervals are also examined. As the accumulating evidence suggests lower doses or extended dosing intervals of antiPD(L)-1 may achieve a similar clinical benefit in comparison to the currently approved doses, we address the clinical and financial toxicity implications of using potentially higher doses than necessary. Last, we discuss ways to resolve the current dosing conundrum of antiPD-(L)1 agents such as performing near-equivalence studies and propose a framework for future development of immunotherapeutics to find the lowest efficacious dose instead of MTD.
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Affiliation(s)
- Daniel V Araujo
- Department of Medical Oncology, Hospital de Base/HB Onco, FUNFARME/FAMERP, Av. Brigadeiro Faria Lima 5544, São José do Rio Preto, SP, Brazil.
| | - Bruno Uchoa
- Department of Medical Oncology, Hospital de Base/HB Onco, FUNFARME/FAMERP, Av. Brigadeiro Faria Lima 5544, São José do Rio Preto, SP, Brazil
| | - Juan José Soto-Castillo
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Av. Gran Via de L'Hospitalet 199-203, 08908, Barcelona, Spain
| | - Larissa L Furlan
- Department of Medical Oncology, Hospital de Base/HB Onco, FUNFARME/FAMERP, Av. Brigadeiro Faria Lima 5544, São José do Rio Preto, SP, Brazil
| | - Marc Oliva
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Av. Gran Via de L'Hospitalet 199-203, 08908, Barcelona, Spain. .,Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
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Abraham G, Noronha V, Rajappa S, Agarwal A, Batra U, Somani N, Raja T, Patil S, Kaushal AM, Joshi A, Radhakrishnan V, Singh N, Babu G, Tewani R, Baghmar S, Dodagoudar C, Ananthakrishnan R, Haragadde Poppareddy S, Sharma V, Menon N, M Patil V, Joshi A, Gupta S, Prabhash K, Bajpai J. The clinical utility and safety of short-course immune checkpoint inhibitors in multiple tumours-A real-world multicentric study from India. Int J Cancer 2022; 150:1045-1052. [PMID: 34751432 DOI: 10.1002/ijc.33868] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/14/2021] [Accepted: 09/09/2021] [Indexed: 11/10/2022]
Abstract
The real-world data on short course of immune checkpoint inhibitor (ICI) use are sparse and merit exploration. A multicentric observational study on the safety and efficacy of ICI in oncology patients between August 2014 and October 2020 involves 1011 patients across 13 centers in India. The median age was 59 (min 16-max 98) years with male preponderance (77.9%). The predominant cohort received short-course ICI therapy; the median number of cycles was 5 (95% confidence interval [CI] 1-27), and the median duration of therapy was 3 (95% CI 0.5-13) months. ICIs were used commonly in the second and third line setting in our study (66.4%, n = 671). Objective response rate (complete or partial response) was documented in 254 (25.1%) of the patients, 202 (20.0%) had stable disease, and 374 (37.0%) had progressive disease. The clinical benefit rate was present in 456 (45.1%). Among the patients whom ICI was stopped (n = 906), the most common reason for cessation of ICI was disease progression (616, 68.0%) followed by logistic reasons like financial constraints (234, 25.82%). With a median follow-up of 14.1 (95% CI 12.9-15.3) months, there were 616 events of progression and 443 events of death, and the median progression free survival and overall survival were 6.4 (95% CI 5.5-7.3) and 13.6 (95% CI 11.6-15.7) months, respectively, in the overall cohort. Among the immune-related adverse events, autoimmune pneumonitis (29, 3.8%) and thyroiditis (24, 2.4%) were common. Real-world multicentric Indian data predominantly with short-course ICI therapy have comparable efficacy/safety to international literature with standard ICI therapy.
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Affiliation(s)
- George Abraham
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Senthil Rajappa
- Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, India
| | - Amit Agarwal
- Department of Medical Oncology, BLK Superspeciality Hospital, Delhi, India
| | - Ullas Batra
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Naresh Somani
- Department of Medical Oncology, HCG Cancer Centre, Jaipur, India
| | | | - Shekhar Patil
- Department of Medical Oncology, HCG Cancer Centre, Bengaluru, India
| | - Ashish M Kaushal
- Department of Medical Oncology, HCG Cancer Centre, Ahmedabad, India
| | - Ashish Joshi
- Department of Medical Oncology, Mumbai Oncocare Centre, Mumbai, India
| | | | - Navneet Singh
- Department of Medical Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Govind Babu
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, India
| | - Rohan Tewani
- Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, India
| | - Saphalta Baghmar
- Department of Medical Oncology, BLK Superspeciality Hospital, Delhi, India
| | | | | | | | - Vibhor Sharma
- Department of Medical Oncology, Paras Hospitals, Gurgaon, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Vijay M Patil
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Jyoti Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
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Reddy R, Velagapudi RM, Chitikela SD, Barwad A, Shrivastava S, Dhamija E, Shamim SA, Tripathy S, Pandey R, Rastogi S. Indian experience with immunotherapy in sarcoma and gastrointestinal stromal tumors: a retrospective study. Future Sci OA 2022; 8:FSO795. [PMID: 35662745 PMCID: PMC9136636 DOI: 10.2144/fsoa-2021-0117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 03/09/2022] [Indexed: 11/23/2022] Open
Abstract
Aim To study the role of check point inhibitors (CPI) in sarcoma and gastrointestinal stromal tumors. Materials & methods Retrospective data of 15 patients diagnosed with advanced sarcoma or gastrointestinal stromal tumors and treated with CPI. Results 3/14 patients (21.4%) responded to treatment with a disease control rate of 42.8% (6/14). After a median follow-up of 14 months (range: 2-24 months), 11 (73.3%) patients progressed, the median progression-free survival was 4 months (95% CI: 1.7-6.3) and median overall survival was 14 months (95% CI: 2.6-25.7). Only one patient experienced a grade IV adverse event. Conclusion Our data represent the first real-world application of CPI in sarcoma from India. We believe that CPI should be further evaluated in clinical trials.
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Affiliation(s)
- Rohit Reddy
- Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Raja Mounika Velagapudi
- Department of Internal Medicine, Venkateshwara Institute of Medical Sciences, Uttar Pradesh, 244236, India
| | - Sindhura Durga Chitikela
- Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Adarsh Barwad
- Department of Pathology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Shakti Shrivastava
- Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Ekta Dhamija
- Department of Radio diagnosis, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Shamim Ahmed Shamim
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sarthak Tripathy
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rambha Pandey
- Department of Radiation Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sameer Rastogi
- Sarcoma Medical Oncology Clinic, Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
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Luo Y, Teng F, Fu H, Ding GS. Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World J Gastrointest Oncol 2022; 14:163-180. [PMID: 35116109 PMCID: PMC8790424 DOI: 10.4251/wjgo.v14.i1.163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/30/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.
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Affiliation(s)
- Yi Luo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Guo-Shan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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38
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Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer. Drugs 2021; 82:15-32. [PMID: 34894338 DOI: 10.1007/s40265-021-01654-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2021] [Indexed: 12/20/2022]
Abstract
In oncology, and especially in the treatment of non-small-cell lung cancer (NSCLC), dose optimization is often a neglected part of precision medicine. Many drugs are still being administered in "one dose fits all" regimens or based on parameters that are often only minor determinants for systemic exposure. These dosing approaches often introduce additional pharmacokinetic variability and do not add to treatment outcomes. Fortunately, pharmacological knowledge is increasing, providing valuable information regarding the potential of, for example, therapeutic drug monitoring. This article focuses on the evidence for the most promising and easily implemented optimized dosing approaches for the small-molecule inhibitors, chemotherapeutic agents, and monoclonal antibodies as treatment options currently approved for NSCLC. Despite limitations such as investigations having been conducted in oncological diseases other than NSCLC or the retrospective origin of many analyses, an alternative dosing regimen could be beneficial for treatment outcomes, prescriber convenience, or financial burden on healthcare systems. This review of the literature provides recommendations on the implementation of dose optimization and advice regarding promising strategies that deserve further research in NSCLC.
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Affiliation(s)
- Ian F. Tannock
- Division of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada
| | - Amol Patel
- Department of Medicine, Oncology Centre, Indian Naval Hospital Ship, Asvini, Colaba, Mumbai, Maharashtra, India
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40
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Schlicke P, Kuttler C, Schumann C. How mathematical modeling could contribute to the quantification of metastatic tumor burden under therapy: insights in immunotherapeutic treatment of non-small cell lung cancer. Theor Biol Med Model 2021; 18:11. [PMID: 34078405 PMCID: PMC8170801 DOI: 10.1186/s12976-021-00142-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 04/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cancer is one of the leading death causes globally with about 8.2 million deaths per year and an increase in numbers in recent years. About 90% of cancer deaths do not occur due to primary tumors but due to metastases, of which most are not clinically identifiable because of their relatively small size at primary diagnosis and limited technical possibilities. However, therapeutic decisions are formed depending on the existence of metastases and their properties. Therefore non-identified metastases might have huge influence in the treatment outcome. The quantification of clinically visible and invisible metastases is important for the choice of an optimal treatment of the individual patient as it could clarify the burden of non-identifiable tumors as well as the future behavior of the cancerous disease. RESULTS The mathematical model presented in this study gives insights in how this could be achieved, taking into account different treatment possibilities and therefore being able to compare therapy schedules for individual patients with different clinical parameters. The framework was tested on three patients with non-small cell lung cancer, one of the deadliest types of cancer worldwide, and clinical history including platinum-based chemotherapy and PD-L1-targeted immunotherapy. Results yield promising insights into the framework to establish methods to quantify effects of different therapy methods and prognostic features for individual patients already at stage of primary diagnosis.
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Affiliation(s)
- Pirmin Schlicke
- Center of Mathematics, Technical University of Munich, Boltzmannstraße, Garching, Germany.
| | - Christina Kuttler
- Center of Mathematics, Technical University of Munich, Boltzmannstraße, Garching, Germany
| | - Christian Schumann
- Clinic of Pneumology, Thoracic Oncology, Sleep and Respiratory Critical Care, Klinikverbund Allgäu, Robert-Weichsler-Straße, Kempten, Germany
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41
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Petracci F, Ghai C, Pangilinan A, Suarez LA, Uehara R, Ghosn M. Use of real-world evidence for oncology clinical decision making in emerging economies. Future Oncol 2021; 17:2951-2960. [PMID: 34044583 DOI: 10.2217/fon-2021-0425] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Real-world evidence (RWE) can provide insights into patient profiles, disease detection, treatment choice, dosing strategies, treatment sequencing, adverse event management and financial toxicity associated with oncology treatment. However, the full potential of RWE is untapped in emerging economies due to structural and behavioral factors. Structural barriers include lack of regulatory engagement, real-world data availability, quality and integrity. Behavioral barriers include entrenched healthcare professional behaviors that impede rapid RWE understanding and adoption. These barriers can be addressed with close collaboration of healthcare stakeholders; of whom, regulators need to be at the forefront given their ability to facilitate use of RWE in healthcare policy and legislation.
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Affiliation(s)
- Fernando Petracci
- Breast Cancer Department, Instituto Alexander Fleming, Avenida Crámer 1180 Ciudad Autónoma de Buenos Aires. C.P. 1426, Argentina
| | - Chirag Ghai
- IQVIA, Real World Evidence Strategy and Solutions, New York, NY 10282, USA
| | - Andrew Pangilinan
- IQVIA, Real World Evidence Strategy and Solutions, New York, NY 10282, USA
| | | | | | - Marwan Ghosn
- Hematology & Oncology Department, Hotel Dieu de France University Hospital & Saint Joseph University, Beirut, Lebanon
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42
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Săftescu S, Negru Ș, Volovăț S, Popovici D, Chercota V, Stanca S, Feier H, Malita D, Dragomir R, Volovăț C. Predictors of the response to nivolumab immunotherapy in the second or subsequent lines for metastatic non-small cell lung cancers. Exp Ther Med 2021; 21:605. [PMID: 33936262 PMCID: PMC8082661 DOI: 10.3892/etm.2021.10037] [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: 10/30/2020] [Accepted: 12/01/2020] [Indexed: 11/19/2022] Open
Abstract
Checkpoint inhibitors represent the first therapeutic class to replace chemotherapy lines for the treatment of metastatic non-small cell lung cancer (NSCLC), due to improved overall survival and tolerability. Nivolumab, a fully human anti-programmed cell death-1 immunoglobulin G4 monoclonal antibody, is the first immune checkpoint inhibitor approved by the US Food and Drug Administration in 2014 for cases of metastatic melanoma and in 2015 for cases of squamous cell lung cancer and kidney cell cancer. The present study aimed to identify predictive markers (favorable or unfavorable) for time to treatment discontinuation using nivolumab in the second or subsequent line of therapy of metastatic NSCLC cases. Analysis of a group of 78 NSCLC patients treated with nivolumab allowed the identification of negative predictive markers, related to the presence of metastases (adrenal in men under 65 years, liver, brain and the number of metastatic sites) and the hematological profile (neutrophilia at the initiation of treatment and lymphocyte variation at 6 weeks of treatment).
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Affiliation(s)
- Sorin Săftescu
- Department of Oncology, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Șerban Negru
- Department of Oncology, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Simona Volovăț
- Department of Oncology, 'Gr. T. Popa' University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Dorel Popovici
- Department of Oncology, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad Chercota
- Department of Ophthalmology, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Simona Stanca
- Department of Pediatrics, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Horea Feier
- Department of Cardiovascular Surgery, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Daniel Malita
- Department of Radiology and Medical Imaging, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Radu Dragomir
- Department of Obstetrics and Gynecology, 'Victor Babeş' University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Constantin Volovăț
- Department of Oncology, 'Gr. T. Popa' University of Medicine and Pharmacy, 700115 Iasi, Romania
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43
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Nguyen NP, Baumert BG, Oboite E, Motta M, Appalanaido GK, Arenas M, Lara PC, Bonet M, Zamagni A, Vuong T, Popescu T, Karlsson U, Trigo L, Sun Myint A, Thariat J, Vinh-Hung V. Immunotherapy and Radiotherapy for Older Cancer Patients during the COVID-19 Era: Proposed Paradigm by the International Geriatric Radiotherapy Group. Gerontology 2021; 67:379-385. [PMID: 33784693 PMCID: PMC8089416 DOI: 10.1159/000514451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/15/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus. SUMMARY Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.
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Affiliation(s)
- Nam Phong Nguyen
- Department of Radiation Oncology, Howard University, Washington, District of Columbia, USA
| | - Brigitta G. Baumert
- Institute of Radiation Oncology, Cantonal Hospital Graubünden, Chur, Switzerland
| | - Eromosele Oboite
- Department of Radiation Oncology, Howard University, Washington, District of Columbia, USA
| | - Micaela Motta
- Department of Radiation Oncology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | | | - Meritxell Arenas
- Department of Radiation Oncology, Sant Joan de Reus University, University Rovira I Virgili, Tarragona, Spain
| | - Pedro Carlos Lara
- Department of Radiation Oncology, Fernando Pessoa Canarias Las Palmas University, Las Palmas, Spain
| | - Marta Bonet
- Department of Radiation Oncology, Arnau de Villanova University Hospital, Lleida, Spain
| | - Alice Zamagni
- Radiation Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, and Department of Experimental, Diagnostic, and Specialty Medicine, -DIMES, Alma Mater Studiorum Bologna University, Bologna, Italy
| | - Te Vuong
- Department of Radiation Oncology, McGill University, Montreal, Québec, Canada
| | - Tiberiu Popescu
- Department of Radiation Oncology, Amethyst Radiotherapy Center, Cluj, Romania
| | - Ulf Karlsson
- Department of Radiation Oncology, International Geriatric Radiotherapy Group, Washington, District of Columbia, USA
| | - Lurdes Trigo
- Service of Brachytherapy, Instituto Portugues de Oncologia Francisco Martins Porto E.P.E., Porto, Portugal
| | - Arthur Sun Myint
- Department of Radiation Oncology, Clatterbridge Cancer Center, Liverpool, United Kingdom
| | - Juliette Thariat
- Department of Radiation Oncology, Baclesse Cancer Center, Caen, France
| | - Vincent Vinh-Hung
- Department of Radiation Oncology, University Hospital of Martinique, Martinique, France
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Low JL, Huang Y, Sooi K, Ang Y, Chan ZY, Spencer K, Jeyasekharan AD, Sundar R, Goh BC, Soo R, Yong WP. Low-dose pembrolizumab in the treatment of advanced non-small cell lung cancer. Int J Cancer 2021; 149:169-176. [PMID: 33634869 PMCID: PMC9545741 DOI: 10.1002/ijc.33534] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/01/2021] [Accepted: 02/10/2021] [Indexed: 12/24/2022]
Abstract
A dose of 200 mg 3‐weekly of pembrolizumab was approved by the Food and Drug Administration (FDA) as treatment for advanced non‐small cell lung cancer (NSCLC) without oncogenic drivers. This is despite evidence showing no difference in efficacy with 2 mg/kg. Our study aimed to assess the efficacy of a lower fixed dose of 100 mg, which is closer to 2 mg/kg weight‐based dose in an average‐sized Asian patient. All patients receiving pembrolizumab for advanced NSCLC from January 2016 to March 2020 in National University Hospital, Singapore, were included in this retrospective observational study. The effect of pembrolizumab 100 mg (Pem100) vs 200 mg (Pem200) upon survival outcomes, toxicity and cost were examined. One hundred fourteen patients received pembrolizumab. Sixty‐five (57%) and 49 (43%) received Pem100 and Pem200, respectively. There was no difference in progression‐free survival (PFS) and overall survival (OS) between Pem100 vs Pem200 as a single agent (PFS: 6.8 vs 4.2 months, hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.36‐1.46, P = .36; 9 month OS: 58% vs 63%, HR 1.08, 95% CI 0.48‐2.41, P = .86) and when combined with chemotherapy (9‐month PFS: 60% vs 50%, HR0.84, 95% CI 0.34‐2.08, P = .71; 9‐month OS: 85% vs 58%, HR 0.27, 95% CI 0.062‐1.20, P = .09). No significant difference in response rate or ≥G3 immune‐related toxicities between Pem100 and Pem200 was observed. A cost minimisation analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of SGD4,290,912 and cost saving per patient of SGD39,942 in the Pem100 group. A 100 mg of pembrolizumab appears to be effective with reduction in cost. A randomised trial should be done to investigate a lower dose of pembrolizumab.
What's new?
Pembrolizumab, a monoclonal antibody directed against the PD‐1 receptor, has received FDA approval for the treatment of lung cancer at a fixed dose of 200 mg every 3 weeks. However, doses above 2 mg/kg show a lack of benefit, calling for further evaluation in Asian populations. This retrospective observational study demonstrates the efficacy of a lower fixed dose of pembrolizumab (100 mg every 3 weeks) compared with standard‐dose pembrolizumab. The results also confirm the clinical activity of pembrolizumab at a lower dose than 2 mg/kg every 3 weeks, which could provide considerable cost savings to patients and the health system.
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Affiliation(s)
- Jia Li Low
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore
| | - Yiqing Huang
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore
| | - Kenneth Sooi
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore
| | - Yvonne Ang
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore
| | - Zhi Yao Chan
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore.,Department of Pharmacy, National University Hospital, National University Health System, Singapore, Singapore
| | - Katie Spencer
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Anand Devaprasath Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore.,Cancer Science Institute, Singapore (CSI), Singapore, Singapore
| | - Raghav Sundar
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore
| | - Boon Cher Goh
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore.,Cancer Science Institute, Singapore (CSI), Singapore, Singapore
| | - Ross Soo
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore.,Cancer Science Institute, Singapore (CSI), Singapore, Singapore
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute Singapore (NCIS), Singapore, Singapore.,Cancer Science Institute, Singapore (CSI), Singapore, Singapore
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Groenland SL, Ratain MJ, Chen LS, Gandhi V. The Right Dose: From Phase I to Clinical Practice. Am Soc Clin Oncol Educ Book 2021; 41:92-106. [PMID: 34010057 DOI: 10.1200/edbk_319567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
To realize the full potential of promising new anticancer drugs, it is of paramount importance to administer them at the right dose. The aim of this educational article is to provide several opportunities to optimize anticancer drug dosing, focusing on oral targeted therapies. First, therapeutic drug monitoring can optimize exposure in individual patients, if the optimal concentration is known. This approach is of particular interest in regard to oral kinase inhibitors with high interindividual pharmacokinetic variability. If exposure is related to response, then therapeutic drug monitoring is potentially feasible, although the clinical utility of this approach has not yet been established. Other approaches to reduce variability include administration of more frequent, smaller doses and administration under optimal prandial conditions. However, for many drugs, the labeled dose has not been demonstrated to be the optimal dose; for such agents, the vast majority of patients may be receiving excessive doses, which results in excessive toxicity. Furthermore, administration of lower off-label doses may reduce both medical and financial toxicity. These strategies should be applied from registration studies to clinical practice, with the goal of better optimizing anticancer treatment.
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Affiliation(s)
- Stefanie L Groenland
- Department of Clinical Pharmacology, Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Mark J Ratain
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
| | - Lisa S Chen
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Varsha Gandhi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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46
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Pramanik R, Sharma A, Kumar A. Combining Immunotherapy with Multikinase Inhibitors: A Cautious New Promise. Indian J Med Paediatr Oncol 2020. [DOI: 10.4103/ijmpo.ijmpo_326_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
AbstractImmune check point inhibitors have made a sea change in oncology practice in current times. These drugs have crossed the conventional boundaries of histology and organ of origin. Tumor agnostic approvals for mismatch repair deficient, microsatellite-instability (MSI)-H and recently tumor mutational burden-high solid tumors have been a giant leap. The Oncology community seems poised to embrace the concept of “immunotherapy for all.” Recent studies have evaluated the manipulation of tumor-associated macrophages using multi-kinase inhibitors, to make even MSI low tumor responsive to checkpoint inhibitors. With accelerated food and drug administration approvals, the promise of this combo is palpable but definitely merits caution.
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Affiliation(s)
- Raja Pramanik
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Sharma
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Akash Kumar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
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47
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Abstract
BACKGROUND Metastatic and unresectable thymoma (T) or thymic carcinoma (TC) have limited treatment options, especially after first line. METHODS Patients with unresectable or recurrent thymic tumors who used minimum one dose of nivolumab at any line of treatment were evaluated retrospectively. Even though nivolumab was administered 3mg/kg dosage in PRIMER study, due to toxicity and financial concerns, we used low dose regimen mostly. RESULTS Among 46 unresectable and recurrent thymic epithelial tumors; 8 patients with TC (n = 3), T (n = 4) and mixt histology (n = 1) were reviewed. Three patients had myasthenia gravis history that had to be controlled before treatment. Four patients showed moderate (n = 2) or severe (n = 2) adverse events with nivolumab treatment. Interestingly, two severe adverse events were occurred at first dose even with 40 mg nivolumab and required cessation of treatment permanently. The median number of nivolumab received was four (range: 1-18). Best response was partial response. Two patients progressed at the 3rd and 5th month of treatment. Best duration of response for one patient with TC and one patient with T-B2 were 9 and 14 months, respectively. Median survival time after nivolumab was 7.4 months (range: 2-22.1). CONCLUSIONS After the results of the previous study could be supported by randomized prospective studies with more number of patients, nivolumab may be considered as an option in patients with thymic epithelial tumors who have received multiple line treatments. However, given the high rate of severe toxicities, there is need to find out a reliable marker to prediction patients who will derive benefit or exhibit toxicity.
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Affiliation(s)
- Naziye Ak
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Adnan Aydiner
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
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48
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A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma. Hemasphere 2020; 4:e480. [PMID: 33062947 PMCID: PMC7523758 DOI: 10.1097/hs9.0000000000000480] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022] Open
Abstract
Supplemental Digital Content is available in the text The introduction of nivolumab has changed the landscape of relapsed/refractory classical Hodgkin lymphoma (r/r cHL) treatment. Despite its clinical importance, this therapy may remain inaccessible for a significant number of patients worldwide, especially in low-income countries, due to its high cost. The results of pharmacokinetic analysis and clinical observations suggest the potential efficacy of low dose nivolumab in r/r cHL patients. The aim of this trial was to assess the efficacy and safety of nivolumab at a fixed dose of 40 mg in patients with r/r cHL. The study included 30 patients with r/r cHL, treated with 40 mg nivolumab every 2 weeks. The median dose of nivolumab per kilogram bodyweight was 0.59 mg/kg (0.4–1 mg/kg). Median follow up was 19.2 months (range 12.7–25.4). The objective response rate was 70%, with 13 (43.3%) patients achieving a complete response. Median PFS was 18.4 months (95% CI, 11.3 to 18.5 months) with 18-month PFS of 53.6% (95% CI, 32%–71%). At the time of analysis, 96.7% of patients were alive with a median OS not reached. Severe (grade 3–5) adverse events were observed in 4 patients (13.3%). Nivolumab in a fixed dose of 40 mg was efficient in patients with r/r cHL, independent from dose per kg bodyweight. The results of this study are in good agreement with previously reported data and create a rationale for further studies aimed to define the optimal dosing regimen of nivolumab for the treatment of r/r cHL. Registered at www.clinicaltrials.gov (NCT03343665)
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Kim YJ, Oremus M, Chen HH, McFarlane T, Shah D, Horton S. Real-world effectiveness of nivolumab in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Future Oncol 2020; 16:2045-2058. [DOI: 10.2217/fon-2020-0248] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: The effectiveness of immunotherapies for non-small-cell lung cancer under real-world clinical settings remains uncertain. Materials & methods: Systematic searches of PubMed, EMBASE and Web of Science were conducted. Random-effects models were used to estimate pooled median overall survival and progression-free survival estimates. Results: 36 studies of nivolumab were included for narrative synthesis and 11 of these studies were included for meta-analysis. Age, sex, histology and prior lines of treatment did not affect survival outcomes, while Eastern Cooperative Oncology Group Performance Status and brain metastasis were inversely associated with survival. In the meta-analysis, nivolumab was associated with 9.6 months (95% CI: 8.4–10.9) of overall survival and 2.6 months (95% CI: 1.6–3.6) of progression-free survival. Conclusion: Very-low-certainty evidence suggested the real-world effectiveness of nivolumab was consistent with those observed in the clinical trials.
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Affiliation(s)
- Yong-Jin Kim
- University of Waterloo, School of Public Health & Health Systems, Waterloo, ON N2L 3G1, Canada
| | - Mark Oremus
- University of Waterloo, School of Public Health & Health Systems, Waterloo, ON N2L 3G1, Canada
| | - Helen H Chen
- University of Waterloo, School of Public Health & Health Systems, Waterloo, ON N2L 3G1, Canada
| | - Thomas McFarlane
- University of Waterloo, School of Pharmacy, Kitchener, ON N2G 1C5, Canada
| | - Devanshi Shah
- University of Waterloo, School of Public Health & Health Systems, Waterloo, ON N2L 3G1, Canada
| | - Susan Horton
- University of Waterloo, School of Public Health & Health Systems, Waterloo, ON N2L 3G1, Canada
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Sehgal K, Costa DB, Rangachari D. Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic? Front Oncol 2020; 10:1193. [PMID: 32714874 PMCID: PMC7344199 DOI: 10.3389/fonc.2020.01193] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 06/12/2020] [Indexed: 12/19/2022] Open
Abstract
Patients with lung cancer are particularly vulnerable to complications from coronavirus disease-2019 (COVID-19). Recurrent hospital visits and hospital admission are potential risk factors for acquiring infection with its causative pathogen, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As immune checkpoint inhibitors (ICIs) constitute the therapeutic backbone for the vast majority of patients with advanced lung cancer in the absence of actionable driver oncogenes, there have been intense discussions within the oncology community regarding risk-benefit of delaying these treatments or use of alternative extended-interval treatment strategies to minimize the risk of viral transmission secondary to unintended nosocomial exposures. In the midst of the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) granted accelerated approval for extended-interval strategy of pembrolizumab at a dose of 400 mg every 6 weeks for all already approved oncologic indications. Herein, we summarize the evidence from the in silico pharmacokinetic modeling/simulation studies supporting extended-interval dosing strategies for the ICIs used in lung cancer. We further review the evolving clinical evidence behind these approaches and predict that they will continue to be used in routine practice even long after the pandemic, particularly for patients with durable disease control.
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Affiliation(s)
- Kartik Sehgal
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Daniel B. Costa
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Deepa Rangachari
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
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