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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Sashankh PV, Dorairaj DP, Chen JY, Chang YL, Chand K, Karvembu R, Chien CM, Hsu SC. Synthesis, in silico and in vitro studies of piperazinyl thiourea derivatives as apoptosis inducer for the treatment of colorectal carcinoma. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Pharmacological Treatments Available for Immune-Checkpoint-Inhibitor-Induced Colitis. Biomedicines 2022; 10:biomedicines10061334. [PMID: 35740355 PMCID: PMC9219666 DOI: 10.3390/biomedicines10061334] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitor treatment has shown revolutionary therapeutic effects in various carcinomas. However, immune-related adverse events (irAE) following this treatment can sometimes lead to treatment discontinuation. One such frequently encountered adverse event is immune-related colitis (irAE colitis). Corticosteroids (CS) are the first-line treatment for irAE colitis, but we often encounter CS-refractory or -resistant cases. The application of multiple biologics has been proposed as a therapy to be administered after CS treatment; however, the efficacy and safety of biologics for patients with irAE colitis who do not respond to CS have not been established. This review summarizes the treatment regimens available for irAE colitis, focusing on the mechanism of action of corticosteroids, infliximab, vedolizumab, and other drugs.
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Ma C, MacDonald JK, Nguyen TM, Vande Casteele N, Linggi B, Lefevre P, Wang Y, Feagan BG, Jairath V. Pharmacological Interventions for the Prevention and Treatment of Immune Checkpoint Inhibitor-Associated Enterocolitis: A Systematic Review. Dig Dis Sci 2022; 67:1128-1155. [PMID: 33770330 DOI: 10.1007/s10620-021-06948-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment. AIMS We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence. RESULTS A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies. CONCLUSIONS Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies.
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Affiliation(s)
- Christopher Ma
- Division of Gastroenterology and Hepatology, Departments of Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada.
| | - John K MacDonald
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Tran M Nguyen
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Niels Vande Casteele
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Division of Gastroenterology, University of California San Diego, 4350 Executive Drive, Suite 210, La Jolla, San Diego, CA, 92121, USA
| | - Bryan Linggi
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Pavine Lefevre
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Brian G Feagan
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Departments of Medicine, Epidemiology, and Biostatistics, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada
| | - Vipul Jairath
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Departments of Medicine, Epidemiology, and Biostatistics, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada
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Abstract
INTRODUCTION Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury. OBJECTIVE We aimed to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration, and the likelihood that an enteritis vs colitis or enterocolitis is seen. PATIENTS AND METHODS We searched MEDLINE, EMBASE, CENTRAL, the World Health Organization International Clinical Trials Registry, and conference proceedings. We included: (1) randomized controlled trials comparing ipilimumab administration with placebo/standard care/other active chemotherapy regimens and (2) prospective observational studies. Separate meta-analyses were performed for randomized controlled trials and observational studies. RESULTS Of 4760 records, we included ten unique randomized controlled trials (n = 5814 subjects) and 34 unique prospective observational studies (n = 3699 subjects). In randomized controlled trials, the pooled relative risk of ≥ grade 3 enterocolitis or ≥ grade 3 diarrhea associated with ipilimumab was 13.31 (95% confidence interval 6.01-29.48, I2 = 0%, ten trials) and 6.72 (95% confidence interval 3.30-13.65, I2 = 63%, ten trials), respectively. In observational studies, the 3-monthly risk of developing grade 3 or higher enteritis, colitis, or enterocolitis was 4% (95% confidence interval 3-7, I2 = 77.40%, 25 studies). Randomized controlled trials and observational studies did not distinguish between acute and chronic enterocolitis. Of the included observational studies, the pooled risk of incurring small bowel involvement associated with ipilimumab was 1% (95% CI 0-4, I2 = 0%, four studies) per every 3-month time period. CONCLUSIONS Insufficient data exist to quantify or distinguish the risk of acute vs chronic enterocolitis following ipilmumab use. Because of the serious impact of chronic enterocolitis on quality of life and further cancer treatment, future trials evaluating the safety of immunotherapy should report gastrointestinal events in greater detail.
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Ueno S, Uenomachi M, Kusaba H, Ito M, Suzuki K, Ohmura H, Tsuchihashi K, Ariyama H, Akashi K, Baba E. Improvement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report. Mol Clin Oncol 2021; 15:221. [PMID: 34476105 PMCID: PMC8408681 DOI: 10.3892/mco.2021.2379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 07/16/2021] [Indexed: 12/24/2022] Open
Abstract
Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.
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Affiliation(s)
- Shohei Ueno
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masato Uenomachi
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hitoshi Kusaba
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Mamoru Ito
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kunihiro Suzuki
- Department of Respiratory Medicine, Kyushu University Hospital, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hirofumi Ohmura
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kenji Tsuchihashi
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hiroshi Ariyama
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka 812-8582, Japan
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Wang M, Zhai X, Li J, Guan J, Xu S, Li Y, Zhu H. The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors. Front Immunol 2021; 12:670391. [PMID: 34367136 PMCID: PMC8339552 DOI: 10.3389/fimmu.2021.670391] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022] Open
Abstract
Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.
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Affiliation(s)
- Min Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaoyang Zhai
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ji Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jingyuan Guan
- Department of Cardiology, Qilu Hospital Affiliated to Shandong University, Jinan, China
| | - Shuhui Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - YuYing Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Hui Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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Chhabra N, Kennedy J. A Review of Cancer Immunotherapy Toxicity: Immune Checkpoint Inhibitors. J Med Toxicol 2021; 17:411-424. [PMID: 33826117 DOI: 10.1007/s13181-021-00833-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/08/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer immunotherapy, which leverages features of the immune system to target neoplastic cells, has revolutionized the treatment of cancer. The use of these therapies has rapidly expanded in the past two decades. Immune checkpoint inhibitors represent one drug class within immunotherapy with its first agent FDA-approved in 2011. Immune checkpoint inhibitors act by disrupting inhibitory signals from neoplastic cells to immune effector cells, allowing activated T-cells to target these neoplastic cells. Unique adverse effects associated with immune checkpoint inhibitors are termed immune-related adverse effects (irAEs) and are usually immunostimulatory in nature. Almost all organ systems may be affected by irAEs including the dermatologic, gastrointestinal, pulmonary, endocrine, and cardiovascular systems. These effects range from mild to life-threatening, and their onset can be delayed several weeks or months. For mild irAEs, symptomatic care is usually sufficient. For higher grade irAEs, discontinuation of therapy and initiation of immunosuppressive therapy may be necessary. The management of patients with irAEs involves multidisciplinary care coordination with respect to the long-term goals the individual patient. Clinicians must be aware of the unique and sometimes fatal toxicologic profiles associated with immunotherapies to ensure prompt diagnosis and appropriate management.
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Affiliation(s)
- Neeraj Chhabra
- Cook County Health, Department of Emergency Medicine, Division of Medical Toxicology, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA. .,Toxikon Consortium, Chicago, IL, USA.
| | - Joseph Kennedy
- Cook County Health, Department of Emergency Medicine, Division of Medical Toxicology, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA.,Toxikon Consortium, Chicago, IL, USA
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Kadokawa Y, Takagi M, Yoshida T, Tatsumi A, Fujita K, Inoue T, Ohe S, Nakai Y, Yamamoto S, Otsuka T, Ishihara R, Isei T, Kumagai T, Nishimura K, Imamura F. Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: A retrospective study. Mol Clin Oncol 2021; 14:65. [PMID: 33680456 PMCID: PMC7890436 DOI: 10.3892/mco.2021.2227] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 01/12/2021] [Indexed: 12/19/2022] Open
Abstract
The present study investigated outcomes of infliximab (IFX) treatment among 8 Japanese patients with various types of cancer (4 with malignant melanoma, 3 with lung cancer and 1 with renal cancer) who developed severe steroid-resistant immune-related adverse events (irAEs) in association with immune checkpoint inhibitors (ICIs) to determine its efficacy and safety. Information, including patient background, treatment progress, examination data and imaging data, was collected retrospectively from electronic medical records. Adverse reactions were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Specific ICIs used were anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibody preparations in 7, 2 and 5 patients, respectively. Specific irAEs included grade 3 diarrhea/colitis in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. The median duration between systemic steroid and IFX treatments was 9 (range, 2-39) days. A total of 3 patients responded to IFX, 1 of whom responded after one dose and 2 responded after two doses. Respective diseases improved to grade 0 after a median of 18 (range, 9-32) days. No AEs were attributable to IFX. Additionally, anti-cytomegalovirus (CMV) and antibacterial agents were administered in parallel given the presence of CMV and Clostridium difficile (CD) infections in all patients, except in 1 exhibiting a marked IFX response after one dose. The combination of highly immunosuppressive IFX and high-dose systemic steroid administration over a long period presumably predisposed the patients to opportunistic enteric infections. Accordingly, early initiation of IFX treatment in conjunction with systemic steroid therapy should be considered for severe diarrhea/colitis and other irAEs. However, the possibility for CMV and CD infections should be recognized, and for these the treatment strategy may need to be modified at an early stage.
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Affiliation(s)
- Yukio Kadokawa
- Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Mari Takagi
- Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Tomoe Yoshida
- Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Akitoshi Tatsumi
- Education and Research Center for Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Hyogo 658-8558, Japan
| | - Keiko Fujita
- Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Takako Inoue
- Department of Respiratory Medicine, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Shuichi Ohe
- Department of Dermatologic Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Yasutomo Nakai
- Department of Urology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Sachiko Yamamoto
- Department of Gastroenterology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Tomoyuki Otsuka
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Ryu Ishihara
- Department of Gastroenterology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Taiki Isei
- Department of Dermatologic Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Toru Kumagai
- Department of Respiratory Medicine, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Kazuo Nishimura
- Department of Urology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
| | - Fumio Imamura
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541-8567, Japan
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Balaji A, Hsu M, Lin CT, Feliciano J, Marrone K, Brahmer JR, Forde PM, Hann C, Zheng L, Lee V, Illei PB, Danoff SK, Suresh K, Naidoo J. Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes. J Immunother Cancer 2021; 9:e001731. [PMID: 33414264 PMCID: PMC7797270 DOI: 10.1136/jitc-2020-001731] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis. METHODS Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression. RESULTS Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone. CONCLUSIONS Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
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Affiliation(s)
- Aanika Balaji
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Melinda Hsu
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Cheng Ting Lin
- Radiology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Josephine Feliciano
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kristen Marrone
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Julie R Brahmer
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Patrick M Forde
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Christine Hann
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Lei Zheng
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Valerie Lee
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Peter B Illei
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- Division of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Sonye K Danoff
- Pulmonology and Critical Care Medicine, Johns Hopkins Medicine School of Medicine, Baltimore, Maryland, USA
| | - Karthik Suresh
- Pulmonology and Critical Care Medicine, Johns Hopkins Medicine School of Medicine, Baltimore, Maryland, USA
| | - Jarushka Naidoo
- Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
- The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
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Abstract
Immune checkpoint inhibitors (ICIs) have shown significant benefit in cancer patients. Their success, however, is associated with immune-related adverse events (irAEs), which commonly affect the gastrointestinal tract, resulting in diarrhea and colitis. IrAEs range from mild self-limiting to severe life-threatening diseases and potentially limit the use of these medications. Diagnosis of ICI-induced enterocolitis is based on clinical symptoms, physical examination, stool tests, endoscopic and histologic evaluation, and/or imaging. Current management strategy is mainly anti-diarrheal agents for mild symptoms and immunosuppressants (e.g., corticosteroids, and infliximab or vedolizumab) for more severe diseases.
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12
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Singh BP, Marshall JL, He AR. Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors. Oncologist 2020; 25:197-202. [PMID: 32162824 PMCID: PMC7066712 DOI: 10.1634/theoncologist.2018-0304] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/19/2019] [Indexed: 12/14/2022] Open
Abstract
As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side-effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune-mediated toxicities need special attention. One of the most common is immune-mediated colitis. Workup and management of immune-mediated colitis can be challenging and is the purpose of this review. KEY POINTS: Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune-mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.
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Affiliation(s)
- Bhavana Pendurthi Singh
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - John L. Marshall
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - Aiwu Ruth He
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
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13
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Abstract
Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early endoscopic evaluation to establish the diagnosis and prompt initiation of corticosteroids. Response to first-line therapy should be assessed early to determine the need of escalation to biologic agents. With treatment, most patients will experience full resolution of symptoms, and subsequent rechallenge with anti-programmed cell death protein 1 or anti-programmed death-ligand 1 inhibitors can be considered.
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14
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Balaji A, Zhang J, Wills B, Marrone KA, Elmariah H, Yarchoan M, Zimmerman JW, Hajjir K, Venkatraman D, Armstrong DK, Laheru DA, Mehra R, Ho WJ, Reuss JE, Heng J, Vellanki P, Donehower RC, Holdhoff M, Naidoo J. Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes. J Oncol Pract 2019; 15:e825-e834. [PMID: 31386608 DOI: 10.1200/jop.18.00703] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described. METHODS We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined. RESULTS Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2). CONCLUSION A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.
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Affiliation(s)
- Aanika Balaji
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD
| | - Jiajia Zhang
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Beatriz Wills
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Kristen A Marrone
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Hany Elmariah
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Jacquelyn W Zimmerman
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Khalid Hajjir
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | | | - Deborah K Armstrong
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Daniel A Laheru
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Ranee Mehra
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Joshua E Reuss
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD
| | - Joseph Heng
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Paz Vellanki
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Ross C Donehower
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Matthias Holdhoff
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Jarushka Naidoo
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
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Abstract
Immunotherapy has dramatically improved the prognosis for patients with melanoma and has become the cornerstone of treatment for those with advanced disease. The role of immunotherapy continues to expand with multiple new agents approved in the adjuvant as well as metastatic setting, as first-line therapy and beyond. We review the currently approved drugs for the treatment of melanoma, along with clinical trial data, adverse side effects, response assessment and future directions.
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Affiliation(s)
- Emily Feld
- UDepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tara C Mitchell
- UDepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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16
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Zhang HC, Luo W, Wang Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J Immunother Cancer 2019; 7:47. [PMID: 30777137 PMCID: PMC6380028 DOI: 10.1186/s40425-019-0532-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 02/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background Immune checkpoint inhibitors (ICPIs), used to treat different advanced malignancies, are associated with a wide range of immune-related adverse reactions (irAEs) that deserve close monitoring of patients. Gastrointestinal reactions and hepatotoxicity may occur, which warrant careful evaluation to confirm the etiology and attribution to ICPIs as these events could affect future management. Case presentation We describe a case of a patient with prostate adenocarcinoma, treated with dual ICPIs comprised of ipilimumab and nivolumab, who developed elevated liver enzymes in the context of infliximab therapy prescribed to treat gastrointestinal irAE from his ICPIs. The patient’s grade 3 colitis became steroid-refractory, requiring a one-time infusion of infliximab, a biologic agent used commonly in inflammatory bowel disease, as a rescue therapy, to which he responded. The patient subsequently developed liver injury. This presented a diagnostic dilemma involving differential diagnoses of hepatotoxicity due to ICPI or infliximab exposure. A careful review of the clinical history, evaluation of the chronology of events, and exclusion of other causes of acute hepatitis were employed to make the final diagnosis of this event as infliximab-associated hepatotoxicity. Conclusion ICPIs such as CTLA-4 and PD-1 inhibitors have the potential to cause both gastrointestinal reactions and hepatotoxicity. An additional confounding factor in our patient’s case was the exposure to infliximab used to manage an established irAE that developed after the last exposure to ICPIs. The clinical history and data supported infliximab-associated hepatotoxicity, rather than an irAE. With the increasing application of ICPIs for different cancers, in conjunction with potential risks for irAE, the liver profile should be closely monitored during treatment with ICPI as well as with anti-TNF-α agents in this patient population.
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Affiliation(s)
- Hao Chi Zhang
- Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Wenyi Luo
- Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA.
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17
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Nassri AB, Muenyi V, AlKhasawneh A, Ribeiro BDS, Scolapio JS, Malespin M, de Melo Jr SW. Ipilimumab and Nivolumab induced steroid-refractory colitis treated with infliximab: A case report. World J Gastrointest Pharmacol Ther 2019; 10:29-34. [PMID: 30697447 PMCID: PMC6347649 DOI: 10.4292/wjgpt.v10.i1.29] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/06/2018] [Accepted: 01/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A variety of immune-modulating drugs are becoming increasingly used for various cancers. Despite increasing indications and improved efficacy, they are often associated with a wide variety of immune mediated adverse events including colitis that may be refractory to conventional therapy. Although these drugs are being more commonly used by Hematologists and Oncologists, there are still many gastroenterologists who are not familiar with the incidence and natural history of gastrointestinal immune-mediated side effects, as well as the role of infliximab in the management of this condition.
CASE SUMMARY We report a case of a 63-year-old male with a history of metastatic renal cell carcinoma who presented to our hospital with severe diarrhea. The patient had received his third combination infusion of the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab and developed severe watery non-bloody diarrhea the same day. He presented to the hospital where he was found to be severely dehydrated and in acute renal failure. An extensive workup was negative for infectious etiologies and he was initiated on high dose intravenous steroids. However, he continued to worsen. A colonoscopy was performed and revealed no endoscopic evidence of inflammation. Random biopsies for histology were obtained which showed mild colitis, and were negative for Cytomegalovirus and Herpes Simplex Virus. He was diagnosed with severe steroid-refractory colitis induced by Ipilimumab and Nivolumab and was initiated on Infliximab. He responded promptly to it and his diarrhea resolved the next day with progressive resolution of his renal impairment. On follow up his gastrointestinal side symptoms did not recur.
CONCLUSION Given the increasing use of immune therapy in a variety of cancers, it is important for gastroenterologists to be familiar with their gastrointestinal side effects and comfortable with their management, including prescribing infliximab.
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Affiliation(s)
- Ammar B Nassri
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida at Jacksonville, Jacksonville, FL 32207, United States
| | - Valery Muenyi
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida at Jacksonville, Jacksonville, FL 32207, United States
| | - Ahmad AlKhasawneh
- Department of Pathology and Laboratory Medicine, University of Florida at Jacksonville, Jacksonville, FL 32209, United States
| | - Bruno De Souza Ribeiro
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida at Jacksonville, Jacksonville, FL 32207, United States
| | - James S Scolapio
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida at Jacksonville, Jacksonville, FL 32207, United States
| | - Miguel Malespin
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida at Jacksonville, Jacksonville, FL 32207, United States
| | - Silvio W de Melo Jr
- Division of Gastroenterology, Oregon Health and Science University, Portland, OR 97239, United States
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18
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Patel K, Siraj S, Smith C, Nair M, Vishwanatha JK, Basha R. Pancreatic Cancer: An Emphasis on Current Perspectives in Immunotherapy. Crit Rev Oncog 2019; 24:105-118. [PMID: 31679206 PMCID: PMC8038975 DOI: 10.1615/critrevoncog.2019031417] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Pancreatic cancer affects both male and female individuals with higher incidences and death rates among the male population. Detection of this malignancy is delayed due to the lack of symptoms in the early-stage cancer, which makes it extremely difficult to treat. Identifying effective strategies has been a challenge for improving the survival rates in pancreatic cancer patients. Resistance to chemotherapy is often developed in pancreatic cancer treatment. Although many strategies are under clinical trials to target certain markers associated with cancer, immunotherapeutic approaches are currently gaining importance. Immunotherapy for pancreatic cancer is in the limelight after preclinical research showed some promise. Immunotherapy approaches were tested along with other treatment options to enhance the treatment effect. Adoptive cell transfer and immune checkpoint inhibitors are currently in clinical trials. The Food and Drug Administration approved pembrolizumab in a fast-tracked review for advanced pancreatic cancer patients. Pembrolizumab blocks the checkpoint protein, programmed cell death protein 1 (PD-1), on T cells to boost the response of the immune system against cancer cells, thereby shrinking tumors. The recent developments in immunotherapy and the early success in other cancers are encouraging to further test immunotherapy in pancreatic cancer. The combination of pembrolizumab and pelareorep, an isolate of human reovirus, is in phase II clinical study in metastatic disease. Depending on the results of current clinical trials and testing, the strategies in the pipeline are expected to increase the use of immunotherapy in the clinical testing setting. Success in immunotherapy is urgently needed to address the side-effects, treating patients with advanced disease and reducing metastasis for increasing the survival rate in pancreatic cancer patients.
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Affiliation(s)
| | | | - Chloe Smith
- Old Dominion University, Norfolk, Virginia 23529
| | - Maya Nair
- Graduate School of Biomedical Sciences, UNT Health Science Center, Fort Worth, Texas 76107
| | - Jamboor K. Vishwanatha
- Graduate School of Biomedical Sciences, UNT Health Science Center, Fort Worth, Texas 76107
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19
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Jeung HC, Oh SE, Kim JH. Immune-related Adverse Events: Overview and Management Strategies for the Use of Immune Checkpoint Inhibitors. JOURNAL OF RHEUMATIC DISEASES 2019. [DOI: 10.4078/jrd.2019.26.4.221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Hei-Cheul Jeung
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Se Eung Oh
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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20
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Chang VA, Simpson DR, Daniels GA, Piccioni DE. Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation. J Immunother Cancer 2018; 6:153. [PMID: 30577851 PMCID: PMC6303890 DOI: 10.1186/s40425-018-0471-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 11/30/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Neurologic toxicities with immune therapy are rare, but can cause devastating and often permanent injury when they occur. Although there is increasing interest in the potential synergism between immune therapy and radiation, it is possible that such combinations may lead to a greater number or increased severity of immune-related adverse events. We present here a case of extensive and progressive transverse myelitis following combined therapy, which did not improve until treatment with infliximab. This case highlights the unmet need for treatment of adverse events that are refractory to consensus recommendations, and may ultimately require further study and incorporation into future published guidelines. CASE PRESENTATION We report a case of a 68-year-old with metastatic melanoma, who developed transverse myelitis in the setting of immune checkpoint blockade and spinal irradiation for vertebral metastases. Despite management according to published consensus guidelines: cessation of immune therapy, high-dose steroids, and plasmapheresis, he continued to deteriorate neurologically, and imaging revealed a progressive and ascending transverse myelitis. The patient was then treated with infliximab, and demonstrated dramatic imaging and modest clinical improvement following the first treatment cycle. CONCLUSIONS This is the first report describing the successful use of infliximab in immune therapy and radiation-related transverse myelitis that was not responding to recommended therapy. Evaluation of additional treatment options such as infliximab for high-grade immune-related neurologic toxicities is warranted, and may be needed earlier in the disease process to prevent significant morbidity. The adverse effects of immune therapy when used in combination with radiation also require further investigation.
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Affiliation(s)
- Victoria A Chang
- School of Medicine, University of California San Diego, La Jolla, California, USA
| | - Daniel R Simpson
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, Moores Cancer Center, La Jolla, California, USA
| | - Gregory A Daniels
- Department of Hematology & Oncology, University of California San Diego, Moores Cancer Center, La Jolla, California, USA
| | - David E Piccioni
- Division of Neuro-Oncology, Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
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21
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Iwamoto N, Yokoyama K, Takanashi M, Yonezawa A, Matsubara K, Shimada T. Verification between Original and Biosimilar Therapeutic Antibody Infliximab Using nSMOL Coupled LC-MS Bioanalysis in Human Serum. Curr Pharm Biotechnol 2018; 19:495-505. [PMID: 29968534 PMCID: PMC6198460 DOI: 10.2174/1389201019666180703093517] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 05/29/2018] [Accepted: 07/02/2018] [Indexed: 12/14/2022]
Abstract
Background: Infliximab (IFX) is a chimeric therapeutic monoclonal antibody targeting tumor necrosis factor alpha (TNFα)-mediated inflammatory immune diseases. However, despite of an initial good clinical response, decrease in response to long-term treatment is a common observation. Objective: Recent studies suggest that IFX level in circulation has a correlation with clinical bioavailabil-ity. Therefore, the management of IFX dosage for individual manifestation by IFX monitoring may be valuable for the improvement of therapeutic response and outcomes. Method: In order to develop a broad IFX therapeutic monitoring in human serum, we have developed the validated IFX bioanalysis for RemicadeTM and its biosimilar product using our nano-surface and molecu-lar-orientation limited proteolysis (nSMOL) technology coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The nSMOL chemistry has a unique property of Fab-selective prote-olysis, and makes it possible a global bioanalysis for many monoclonal antibodies. Results: The quantitation range of IFX in serum was from 0.293 to 300 μg/ml with good linearity. Quan-titation verification at the concentrations of 0.293, 0.879, 14.1 and 240 μg/ml was within 1.56-7.53% of precision and 98.9-111% of accuracy using H-chain signature peptide SINSATHYAESVK. Moreover, cross-verified bioanalysis of Remicade quantitation using biosimilar standard, and its opposite combina-tion, obtained an identical and inter-comparative results. Conclusion: The nSMOL strategy has the potential as a practical therapeutic monitoring technology in IFX therapeutic applications.
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Affiliation(s)
- Noriko Iwamoto
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Kotoko Yokoyama
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Megumi Takanashi
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Atsushi Yonezawa
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuo Matsubara
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Takashi Shimada
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
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22
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Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018; 24:1804-1808. [PMID: 30420754 DOI: 10.1038/s41591-018-0238-9] [Citation(s) in RCA: 533] [Impact Index Per Article: 76.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 09/27/2018] [Indexed: 02/08/2023]
Abstract
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
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23
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Hamamoto Y, Shin N, Hoshino T, Kanai T. Management of challenging immune-related gastrointestinal adverse events associated with immune checkpoint inhibitors. Future Oncol 2018; 14:3187-3198. [PMID: 30188189 DOI: 10.2217/fon-2018-0509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Immune-related gastrointestinal toxicities (irGI) are well-known adverse events (AEs) with immune checkpoint inhibitors. The aim of this review was to present clinical data from 82 cases to provide information to clinicians who face real-world challenges among their patients with irGI AEs. The findings of this review support the use of the current management guidelines. By analyzing the treatment courses and outcomes of all cases identified, our review recommends that recurrent cases be treated carefully regardless of the grade of diarrhea at the onset of events. Earlier gastroenterology consultation and computed tomography/endoscopy diagnosis are essential, especially when an irGI AE recurs or worsens during steroid tapering. We would also suggest earlier decision to add immunosuppressant agents, particularly for recurrent cases.
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Affiliation(s)
- Yasuo Hamamoto
- Keio Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Natalya Shin
- Research and Development Department, Division of Pharmacovigilance, Bristol-Myers Squibb K.K., Shinjuku-ku, Tokyo, Japan
| | - Tomohiro Hoshino
- Safety Strategy 2, Safety management, Division of Pharmacovigilance, Ono Pharmaceutical Co., Ltd, Chuo-ku, Osaka, Japan
| | - Takanori Kanai
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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24
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25
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Adler BL, Pezhouh MK, Kim A, Luan L, Zhu Q, Gani F, Yarchoan M, Chen J, Voltaggio L, Parian A, Lazarev M, Lauwers GY, Pawlik TM, Montgomery EA, Jaffee E, Le DT, Taube JM, Anders RA. Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis. J Intern Med 2018; 283:568-577. [PMID: 29464806 PMCID: PMC5992029 DOI: 10.1111/joim.12744] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. OBJECTIVE We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC and to directly compare these features to ulcerative colitis (UC). METHODS This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3. RESULTS Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi-AC vs. 75% for UC, P = 0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells mm-2 for Ipi-AC vs. 1173.3 ± 1158.2 cells mm-2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. CONCLUSIONS Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.
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Affiliation(s)
- Brittany L. Adler
- Department of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maryam K. Pezhouh
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy Kim
- Department of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lan Luan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Qingfeng Zhu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Faiz Gani
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark Yarchoan
- Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jonathan Chen
- Department of Pathology, H. Lee Moffitt Cancer and Research Institute, Tampa, FL, USA
| | - Lysandra Voltaggio
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alyssa Parian
- Department of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark Lazarev
- Department of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Gregory Y. Lauwers
- Department of Pathology, H. Lee Moffitt Cancer and Research Institute, Tampa, FL, USA
| | - Timothy M. Pawlik
- Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | | | - Elizabeth Jaffee
- Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Dung T. Le
- Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Janis M. Taube
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Robert A. Anders
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
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Marin-Acevedo JA, Harris DM, Burton MC. Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist. J Hosp Med 2018; 13:413-418. [PMID: 29419822 DOI: 10.12788/jhm.2925] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Since their introduction for melanoma treatment, the use of immune checkpoint inhibitors (ICIs) has rapidly expanded. Though their impact on survival is irrefutable, these medications have been associated with autoimmune-like adverse events related to their ability to induce the immune system. One of the most commonly affected organ systems is the gastrointestinal (GI) tract, in which manifestations range from mild diarrhea to severe colitis with intestinal perforation. Because of the increased use of ICIs, hospitalists are caring for an increasing number of patients experiencing their adverse events. We present a case-oriented review of the GI adverse events associated with the use of ICIs to familiarize the hospitalist with their mechanism of action and potential complications and to emphasize the importance of early diagnosis and treatment to decrease morbidity and mortality.
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Affiliation(s)
| | - Dana M Harris
- Division of Community Internal Medicine, Mayo Clinic, Jacksonville, Florida, USA.
| | - M Caroline Burton
- Division of Hospital Internal Medicine, Mayo Clinic, Jacksonville, Florida, USA
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Ferraz LS, Watashi CM, Colturato-Kido C, Pelegrino MT, Paredes-Gamero EJ, Weller RB, Seabra AB, Rodrigues T. Antitumor Potential of S-Nitrosothiol-Containing Polymeric Nanoparticles against Melanoma. Mol Pharm 2018; 15:1160-1168. [DOI: 10.1021/acs.molpharmaceut.7b01001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Letícia S. Ferraz
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
| | - Carolina M. Watashi
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
| | - Carina Colturato-Kido
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
| | - Milena T. Pelegrino
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
| | - Edgar J. Paredes-Gamero
- Interdisciplinary Center for Biochemistry Investigation (CIIB), University of Mogi das Cruzes (UMC), 08780-911 Mogi das Cruzes, São Paulo, Brazil
| | - Richard B. Weller
- Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, EH16 4TJ Edinburgh, U.K
| | - Amedea B. Seabra
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
- Nanomedicine Research Unit (NANOMED), Federal University of ABC (UFABC), Santo André, São Paulo, Brazil
| | - Tiago Rodrigues
- Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), 09210-580 Santo André, São Paulo, Brazil
- Nanomedicine Research Unit (NANOMED), Federal University of ABC (UFABC), Santo André, São Paulo, Brazil
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Abstract
Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab.
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Tian Y, Abu-Sbeih H, Wang Y. Immune Checkpoint Inhibitors-Induced Colitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 995:151-157. [DOI: 10.1007/978-3-030-02505-2_7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Yelehe-Okouma M, Granel-Brocard F, Hudziak H, Schmutz JL, Gillet P. [Severe ipilimumab-induced ulcerative colitis remitting after infliximab therapy and secondary switching with pembrolizumab]. Therapie 2017; 73:291-293. [PMID: 29203065 DOI: 10.1016/j.therap.2017.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 10/16/2017] [Indexed: 02/04/2023]
Affiliation(s)
- Mélissa Yelehe-Okouma
- Centre régional de pharmacovigilance, hôpital central, CHRU de Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 60034, 54035 Nancy, France
| | - Florence Granel-Brocard
- Département de dermatologie et allergologie, site de Brabois, CHRU de Nancy, 545011 Vandœuvre Les Nancy, France
| | - Hervé Hudziak
- Département de gastro-entérologie et hépatologie, hôpital d'adultes, site de Brabois, CHRU de Nancy, 545011 Vandœuvre Les Nancy, France
| | - Jean-Luc Schmutz
- Département de dermatologie et allergologie, site de Brabois, CHRU de Nancy, 545011 Vandœuvre Les Nancy, France
| | - Pierre Gillet
- Centre régional de pharmacovigilance, hôpital central, CHRU de Nancy, 29, avenue du Maréchal-de-Lattre-de-Tassigny, CO 60034, 54035 Nancy, France.
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Li E, Lobaina E. Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations. J Manag Care Spec Pharm 2017; 23:1227-1232. [PMID: 29172978 PMCID: PMC10398124 DOI: 10.18553/jmcp.2017.23.12.1227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND The FDA's extrapolation framework allows for a biosimilar to obtain licensure for indications that were not explicitly studied in the context of a clinical trial by extending conclusions from studies in 1 population to make inferences in other populations. Within routine clinical care, drugs and biologics are routinely used for medically accepted off-label indications. The appropriateness of these products for off-label indications are typically curated by compendia and guidelines, which have established processes and criteria for reviewing and evaluating the evidence to make such determinations. The evidence paradigm for biosimilars is different from originator biologics and is one of comparability to a reference product, not to reestablish clinical benefit. Thus, this paradigm shift can be applied to the exercise of making off-label determinations for biosimilars, and the FDA's framework of extrapolation can be used by clinicians and coverage policy decision makers to determine appropriate off-label indications for biosimilars. OBJECTIVE To highlight how the FDA's biosimilar extrapolation framework can be used to make off-label policy decisions, using to 2 approved biosimilars for filgrastim and infliximab as case studies. METHODS This study describes the FDA extrapolation framework for evaluating whether there are any differences in the mechanism of action, pharmacokinetics/biosdistribution, immunogenicity, and toxicity between on-label and off-label indications. Two case studies are presented that evaluate the biosimilars filgrastim-sndz and infliximab-dyyb for the offlabel indications of treating symptomatic anemia in patients with myelodysplastic syndromes and immune-mediated colitis, respectively. The analytical, nonclinical, and clinical pharmacology, along with clinical studies demonstrating that filgrastim-sndz and infliximab-dyyb are biosimilar to their respective reference products, are reviewed and discussed in context with the extrapolation framework to ascertain whether use of the biosimilar within the off-label indications is scientifically justified. RESULTS The mechanism of action of filgrastim and infliximab between their FDA-approved and off-label indications are the same. In addition, there is a high degree of similarity with the analytical and nonclinical characteristics of filgrastim-sndz and infliximab-dyyb and their respective reference products. There is no expectation of differences in safety and immunogenicity across the patient populations. Thus, some decision makers may determine that filgrastim-sndz and infliximab-dyyb be used for the off-label indications of treating symptomatic anemia in patients with myelodysplasia and immune-mediated colitis, respectively. CONCLUSIONS In some cases, the use of biosimilars for off-label indications can be scientifically justified. Since coverage policy decisions are intimately tied to compendia and guideline listings, it is incumbent upon these groups to conduct formal assessments of biosimilar off-label indications using the FDA extrapolation framework. DISCLOSURES No outside funding supported this study. Li discloses that he has received honoraria and/or paid travel expenses as an advisory board and speaker's bureau participant for Pfizer; for speaking on behalf of Mylan and Apobiologix; and for participating on advisory boards for Eli Lilly and Mylan. Lobaina has nothing to disclose. Li was responsible for study design and manuscript revision. Li took the lead in data collection and interpretation and manuscript preparation, along with Lobaina.
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Affiliation(s)
- Edward Li
- 1 University of New England College of Pharmacy, Portland, Maine
| | - Ernesto Lobaina
- 1 University of New England College of Pharmacy, Portland, Maine
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Knight T, Ahn S, Rice TW, Cooksley T. Acute Oncology Care: A narrative review of the acute management of neutropenic sepsis and immune-related toxicities of checkpoint inhibitors. Eur J Intern Med 2017; 45:59-65. [PMID: 28993098 DOI: 10.1016/j.ejim.2017.09.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/15/2017] [Accepted: 09/23/2017] [Indexed: 12/17/2022]
Abstract
Cancer care has become increasingly specialized and advances in therapy have resulted in a larger number of patients receiving care. There has been a significant increase in the number of patients presenting with cancer related emergencies including treatment toxicities and those directly related to the malignancy. Suspected neutropenic sepsis is an acute medical emergency and empirical antibiotic therapy should be administered immediately. The goal of empirical therapy is to cover the most likely pathogens that will cause life-threatening infections in neutropenic patients. Patients with febrile neutropenia are a heterogeneous group with only a minority of treated patients developing significant medical complications. Outpatient management of low risk febrile neutropenia patients identified by the MASCC score is a safe and effective strategy. Immunotherapy with "checkpoint inhibitors" has significantly improved outcomes for patients with metastatic melanoma and evidence of benefit in a wide range of malignancies is developing. Despite these clinical benefits a number of immune related adverse events have been recognised which can affect virtually all organ systems and are potentially fatal. The timing of the onset of the adverse events is dependent on the organ system affected and unlike anti-neoplastic therapy can be delayed significantly after initiation or completion of therapy. The field of Acute Oncology is changing rapidly. Alongside, the traditional challenge of neutropenic sepsis there are many emerging toxicities. Further research into the optimal management, strategies and pathways of acutely unwell patients with cancer is required.
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Affiliation(s)
- Thomas Knight
- University Hospital of South Manchester, Manchester, UK
| | - Shin Ahn
- Asan Medical Center, Seoul, South Korea
| | - Terry W Rice
- Department of Emergency Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Kubo K, Kato M, Mabe K. Nivolumab-Associated Colitis Mimicking Ulcerative Colitis. Clin Gastroenterol Hepatol 2017; 15:A35-A36. [PMID: 28351793 DOI: 10.1016/j.cgh.2017.03.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 03/03/2017] [Accepted: 03/20/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Kimitoshi Kubo
- Department of Gastroenterology National Hospital Organization Hakodate Hospital, Hakodate, Japan
| | - Mototsugu Kato
- Department of Gastroenterology National Hospital Organization Hakodate Hospital, Hakodate, Japan
| | - Katsuhiro Mabe
- Department of Gastroenterology National Hospital Organization Hakodate Hospital, Hakodate, Japan
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Chang ST, Menias CO, Lubner MG, Mellnick VM, Hara AK, Desser TS. Molecular and Clinical Approach to Intra-abdominal Adverse Effects of Targeted Cancer Therapies. Radiographics 2017; 37:1461-1482. [PMID: 28753381 DOI: 10.1148/rg.2017160162] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Targeted cancer therapies encompass an exponentially growing number of agents that involve a myriad of molecular pathways. To excel within this rapidly changing field of clinical oncology, radiologists must eschew traditional organ system-based approaches of cataloging adverse effects in favor of a conceptual framework that incorporates molecular mechanisms and associated clinical outcomes. Understanding molecular mechanisms that underlie imaging manifestations of adverse effects and known associations with treatment response allows radiologists to more effectively recognize adverse effects and differentiate them from tumor progression. Radiologists can therefore more effectively guide oncologists in the management of adverse effects and treatment decisions regarding continuation or cessation of drug therapy. Adverse effects from targeted cancer therapies can be classified into four categories: (a) category 1, on-target adverse effects associated with treatment response; (b) category 2, on-target adverse effects without associated treatment response; (c) category 3, off-target adverse effects; and (d) category 4, tumor necrosis-related adverse effects. This review focuses on adverse effects primarily within the abdomen and pelvis classified according to established or hypothesized molecular mechanisms and illustrated with images of classic examples and several potential emerging toxic effects. ©RSNA, 2017.
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Affiliation(s)
- Stephanie T Chang
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
| | - Christine O Menias
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
| | - Meghan G Lubner
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
| | - Vincent M Mellnick
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
| | - Amy K Hara
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
| | - Terry S Desser
- From the Department of Radiology, VA Palo Alto Health Care System, Palo Alto, Calif (S.T.C.); Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307 MC 5621, Stanford, CA 94305 (S.T.C., T.S.D.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., A.K.H.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (M.G.L.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.)
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Feld E, Horn L. Emerging role of nivolumab in the management of patients with non-small-cell lung cancer: current data and future perspectives. Onco Targets Ther 2017; 10:3697-3708. [PMID: 28769573 PMCID: PMC5533488 DOI: 10.2147/ott.s97903] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Immune-checkpoint inhibitors have become valuable therapies in the treatment of patients with non-small-cell lung cancer (NSCLC). Recent clinical trials have shown promising results with regard to efficacy and toxicity profiles of these agents compared to cytotoxic chemotherapy. Nivolumab was one of the first immune-checkpoint inhibitors to demonstrate clinical activity in patients with NSCLC, and is currently approved in the US for treatment of patients with advanced squamous and nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy. This review provides an update on nivolumab's pharmacology, safety, and efficacy, as established by the CheckMate trials. We also discuss specific applications and strategies for the use of nivolumab in NSCLC patients, as well as predictive biomarkers and their role in treatment selection.
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Affiliation(s)
- Emily Feld
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Leora Horn
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Jain A, Lipson EJ, Sharfman WH, Brant SR, Lazarev MG. Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis. World J Gastroenterol 2017; 23:2023-2028. [PMID: 28373768 PMCID: PMC5360643 DOI: 10.3748/wjg.v23.i11.2023] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/06/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy.
METHODS We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used.
RESULTS A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported.
CONCLUSION In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.
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Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol 2017; 8:49. [PMID: 28228726 PMCID: PMC5296331 DOI: 10.3389/fphar.2017.00049] [Citation(s) in RCA: 426] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 01/23/2017] [Indexed: 12/18/2022] Open
Abstract
The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.
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Affiliation(s)
- Vivek Kumar
- Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA
| | - Neha Chaudhary
- Department of Pediatrics, Maimonides Medical Center Brooklyn, NY, USA
| | - Mohit Garg
- Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA
| | | | - Parita Soni
- Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA
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Abstract
Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4 and anti programmed cell death 1/programmed cell death 1 ligand antibodies) have shown impressive clinical activity in multiple cancer types. Despite achieving great clinical success, challenges and limitations of these drugs as monotherapy or various combinational strategies include the development of a unique set of immune-related adverse events (irAEs) that can be severe and even fatal. Therefore, identification of patients at risk, prevention, consistent communication between patients and medical team, rapid recognition, and treatment of irAEs are critical in optimizing treatment outcomes. This review focuses on the description of more common irAEs and provides a suggested approach for management of specific irAEs.
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Hillock NT, Heard S, Kichenadasse G, Hill CL, Andrews J. Infliximab for ipilimumab-induced colitis: A series of 13 patients. Asia Pac J Clin Oncol 2016; 13:e284-e290. [DOI: 10.1111/ajco.12651] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 09/29/2016] [Accepted: 10/23/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Nadine T Hillock
- South Australian Medicines Evaluation Panel; SA Health; Adelaide South Australia Australia
| | - Sharryn Heard
- Royal Adelaide Hospital; Adelaide South Australia Australia
| | | | - Catherine L Hill
- South Australian Medicines Evaluation Panel; Queen Elizabeth Hospital; Adelaide South Australia Australia
| | - Jane Andrews
- Royal Adelaide Hospital; Adelaide South Australia Australia
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Wilson MA, Guld K, Galetta S, Walsh RD, Kharlip J, Tamhankar M, McGettigan S, Schuchter LM, Fecher LA. Acute visual loss after ipilimumab treatment for metastatic melanoma. J Immunother Cancer 2016; 4:66. [PMID: 27777775 PMCID: PMC5067900 DOI: 10.1186/s40425-016-0170-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 09/29/2016] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs). CASE PRESENTATION Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs. CONCLUSIONS This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.
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Affiliation(s)
- Melissa A Wilson
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY USA
| | - Kelly Guld
- Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Department of Cardiology, UCSF Medical Center, San Francisco, CA USA
| | - Steven Galetta
- Department of Neurology, NYU Langone Medical Center, New York, NY USA
| | - Ryan D Walsh
- Departments of Ophthalmology and Neurology, Medical College of Wisconsin, Milwaukee, WI USA
| | - Julia Kharlip
- Division of Endocrinology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Madhura Tamhankar
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Health System, Philadelphia, PA USA
| | - Suzanne McGettigan
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Lynn M Schuchter
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Leslie A Fecher
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C366 MIB 1500 E. Medical Center Drive, SPC5848, Ann Arbor, MI 48109 USA
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Economopoulou P, Psyrri A. Overview and management of toxicities of immune checkpoint-blocking drugs. FORUM OF CLINICAL ONCOLOGY 2016. [DOI: 10.1515/fco-2016-0004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Immunotherapy is considered to be the most important breakthrough in cancer management in the past few years. This success was based on the scientific understanding of immune mechanisms due to improvement in preclinical science and the introduction of new methods of investigation. Immune checkpoint inhibitors (ICIs) are among the most promising drugs in the field of immune-oncology; they represent monoclonal antibodies that modulate the effects of immune checkpoints, such as cytotoxic T lymphocyte Antigen 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), which are co-inhibitory signals responsible for immune suppression. Despite clinical benefits, ICIs are immune activating agents that are associated with a number of important side effects (immune-related adverse events-irAEs), attributed to organ-specific inflammation. Herein, we review the toxicities of ICIs, highlighting the importance of early identification and management.
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Vozy A, Coutzac C. Colite induite par les inhibiteurs de checkpoint immunitaire : anticorps anti-CTLA-4 et anticorps anti-PD-1/PDL-1. ONCOLOGIE 2016. [DOI: 10.1007/s10269-016-2658-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Menis J, Litière S, Tryfonidis K, Golfinopoulos V. The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:267. [PMID: 27563654 DOI: 10.21037/atm.2016.06.19] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cancer immunotherapy has had a major impact on the established paradigms of drug development and clinical trial research. The innovative mechanism of action of these compounds has resulted in new patterns of response and safety profiles, which pose challenges for the classical trial methodology. In this review we report on the search for the maximum tolerated dose, the recommended phase II dose and the appropriate target population in phase I trials. We provide some statistical considerations on the choice of endpoints for phase II and III trials and the limitations of frequently used trial designs in the presence of a delayed treatment effect, which may be induced by the immune modulating effect of the checkpoint inhibitors. We summarize the currently available data on the safety profile of these new compounds, which can guide protocol safety recommendations. Finally, we report on the current evidence of biomarker development.
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Affiliation(s)
- Jessica Menis
- European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - Saskia Litière
- European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - Konstantinos Tryfonidis
- European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
| | - Vassilis Golfinopoulos
- European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
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Abstract
INTRODUCTION The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors. AREAS COVERED We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3-4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.
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Affiliation(s)
- Pol Specenier
- a Oncology , Universitair Ziekenhuis Antwerpen , Edegem , Belgium
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Atrash S, Makhoul I, Mizell JS, Hutchins L, Mahmoud F. Response of metastatic mucosal melanoma to immunotherapy: It can get worse before it gets better. J Oncol Pharm Pract 2016; 23:215-219. [DOI: 10.1177/1078155215627503] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Immune therapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses to immune checkpoint inhibitors are usually delayed. An interim progression on restaging computed tomography scans “pseudo-progression” may be observed before response to treatment occur. In this case, we report a significant interim progression of metastatic mucosal melanoma before meaningful responses to immunotherapy occurred. The patient developed significant immune therapy-related colitis and new onset vitiligo. Further restaging computed tomography scans showed sustained tumor response despite stopping the immune therapy.
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Affiliation(s)
- Shebli Atrash
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Issam Makhoul
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jason S Mizell
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Laura Hutchins
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Fade Mahmoud
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Klair JS, Girotra M, Hutchins LF, Caradine KD, Aduli F, Garcia-Saenz-de-Sicilia M. Ipilimumab-Induced Gastrointestinal Toxicities: A Management Algorithm. Dig Dis Sci 2016; 61:2132-2139. [PMID: 26846115 DOI: 10.1007/s10620-016-4042-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 01/16/2016] [Indexed: 12/17/2022]
Abstract
Ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4-blocking monoclonal antibody, which has shown a significant survival benefit in metastatic melanoma patients. Despite being a promising therapy for a disease with an otherwise rather dismal prognosis, it is associated with several immune-related adverse effects (IRAE) mainly targeted toward the digestive tract, skin, liver, and hypothalamic-pituitary axis. Ipilimumab-induced gastrointestinal toxicity (IGT) include diarrhea (~44 %), colitis (~18 %), bowel perforation (<1 %), and pancreatitis (<1.5 %). Early recognition of IRAE and treatment initiation are critical to decrease the risk of further complications. Management included steroids as initial therapy, followed by infliximab (anti-tumor necrosis factor alpha antibody) and/or surgical option for complications like bowel perforation. We present a series of three patients with metastatic melanoma, who received treatment with ipilimumab, and presented with varying gastrointestinal clinical manifestations and complications. Through this case series, our attempt is to make practicing gastroenterologists cognizant about the wide spectrum of gastrointestinal toxicity of this rather new clinical entity, as well as to discuss management algorithm for IGT.
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Affiliation(s)
- Jagpal S Klair
- Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA.
| | - Mohit Girotra
- Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), 4301 W. Markham Street, Shorey S8/68, Slot # 567, Little Rock, AR, 72205, USA
| | - Laura F Hutchins
- Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Kari D Caradine
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - Farshad Aduli
- Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), 4301 W. Markham Street, Shorey S8/68, Slot # 567, Little Rock, AR, 72205, USA
| | - Mauricio Garcia-Saenz-de-Sicilia
- Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), 4301 W. Markham Street, Shorey S8/68, Slot # 567, Little Rock, AR, 72205, USA
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Verschuren EC, van den Eertwegh AJ, Wonders J, Slangen RM, van Delft F, van Bodegraven A, Neefjes-Borst A, de Boer NK. Clinical, Endoscopic, and Histologic Characteristics of Ipilimumab-Associated Colitis. Clin Gastroenterol Hepatol 2016; 14:836-842. [PMID: 26748223 DOI: 10.1016/j.cgh.2015.12.028] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 12/19/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4, is a treatment for metastatic melanoma that can induce immune-related adverse effects, such as enterocolitis. We aimed to characterize the clinical, endoscopic, and histologic features of ipilimumab-induced colitis and evaluate the efficacy of therapy for this reaction. METHODS We performed a retrospective analysis of 27 consecutive patients who developed colitis after treatment with ipilimumab infusion therapy for castration-resistant prostate cancer or metastatic melanoma, from April 2007 through September 2012. Clinical, endoscopic, and histologic information was collected from the database of the VU University Medical Center, Amsterdam, The Netherlands. Selected cases were ascertained by cross-checking with endoscopy reports. RESULTS All patients had diarrhea (range, 3-20 stools per day); 26% had concurrent rectal blood loss and 30% had abdominal pain. These symptoms usually started after 2 infusions of ipilimumab (range, 1-4) and all patients except for 1 (who received no treatment for colitis) were given corticosteroids. Twelve patients had steroid-refractory colitis, for which they received infliximab (5 mg/kg). Diarrhea resolved in all the patients. Colon erythema was detected by endoscopy in 84% of patients, with an absent vascular pattern in all patients. In histologic analyses, colon biopsy specimens ranged from having normal architecture to severe active inflammation. Intraepithelial neutrophilic leucocytes were detected in 72% of samples, cryptitis in 92%, and crypt abscesses in 60%. Crypt irregularities were found in 40% of colon biopsy specimens, indicating chronic disease. CONCLUSIONS In a retrospective analysis, we associated ipilimumab-associated colitis diarrhea with a variety of endoscopic and histologic features. Treatment with corticosteroids, followed by infliximab in steroid-refractory patients, was successful for all cases.
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Affiliation(s)
| | | | - Janneke Wonders
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Rob Michel Slangen
- Department of Gastroenterology and Hepatology, HagaZiekenhuis Teaching Hospital, The Hague, The Netherlands
| | - Foke van Delft
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Adriaan van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Internal Medicine, Gastroenterology and Geriatrics, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Andra Neefjes-Borst
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Nanne Klaas de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016; 13:473-86. [DOI: 10.1038/nrclinonc.2016.58] [Citation(s) in RCA: 660] [Impact Index Per Article: 73.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Gedye C, van der Westhuizen A, John T. Checkpoint immunotherapy for cancer: superior survival, unaccustomed toxicities. Intern Med J 2016; 45:696-701. [PMID: 25444021 DOI: 10.1111/imj.12653] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 11/26/2014] [Indexed: 12/19/2022]
Abstract
Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments, such as chemotherapy. While there are virtually no immediate toxicities, serious life-threatening autoimmune side-effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side-effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy.
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Affiliation(s)
- C Gedye
- School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.,Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia
| | - A van der Westhuizen
- Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia
| | - T John
- Department of Medical Oncology, Olivia Newton John Cancer and Wellness Centre, Austin Hospital, Melbourne, Victoria, Australia
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Magalhães-Costa P. Severe acute colitis induced by ipilimumab. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:277-279. [PMID: 25888286 DOI: 10.1016/j.gastrohep.2015.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 02/17/2015] [Accepted: 02/23/2015] [Indexed: 06/04/2023]
Affiliation(s)
- Pedro Magalhães-Costa
- Gastroenterology Department, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental, Rua da Junqueira 126, 1349-019 Lisboa, Portugal.
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