Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data
Theodoros SoldatosAntonia Dimitrakopoulou‐StraussLionel LarribèreJessica C. HasselChristos Sachpekidis
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Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.Cost utility analyses of oncology treatments are most commonly performed using partitioned survival models, applying health state utilities to progression-free and progressive disease and relative to a specific line of therapy. The objective of this study was to assess utility values across treatments and lines of treatment using data in advanced melanoma for two immuno-oncology agents, nivolumab and ipilimumab. Utility values from 1st line (1L) and 2nd line (2L) advanced melanoma populations treated with nivolumab and ipilimumab were extracted from three randomised controlled clinical trials: CheckMate-067 (1L nivolumab and 1L ipilimumab), CheckMate-037 (2L nivolumab) and MDX010-20 (2L ipilimumab). Visual assessment of QoL over time as well as comparisons of baseline and change from baseline values were performed using summary statistics. Baseline values for 1L and 2L were similar for nivolumab (0.80 vs 0.75, p=0.001) and ipilimumab (0.79 vs 0.81, p=0.123). Across all lines of therapy nivolumab use resulted in improvements in utility whilst patients remained progression free. Ipilimumab treatment regimens showed initial declines in utilities in the first 3 months followed by improvements over the remainder of time on treatment. The change in utility from baseline to 12 months was similar for 1L and 2L nivolumab (0.050 v 0.047, p=0.930). Both these changes were greater than that observed for 1L ipilimumab at 12 months (0.035, p=0.533 v 1L nivolumab and p=0.767 v 2L nivolumab). 2L ipilimumab results were limited to short term follow-up, however utility values were comparable to 1L ipilimumab at 5 months (-0.023 v 0.014, p=0.091). The quality of life of patients on immune-based therapies appears to be independent of therapy line. Furthermore, economic modelling in an immune-oncology setting should reflect that quality of life looks to be a function of time on treatment.
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Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.
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ABSTRACTMetastatic melanoma has less frequency, but considered as the most dreaded cancer. The combination of nivolumab & ipilimumab is proving their mettle in treating metastatic melanoma. The patients when administered with the combination of nivolumab & ipilimumab have shown improved median progression free survival, objective response rate and overall survival rate compared with nivolumab and ipilimumab monotherapy. The combination shrinks the tumor cells by attacking different checkpoints viz. CTLA-4 and PD-L1, respectively. The combination treatment reveals reduced disease progression and suggests nivolumab's non-cross resistant nature. The median progression free survival in "nivolumab plus ipilimumab" group has shown an increase of 66.7% and 296.6% in comparison to nivolumab and ipilimumab monotherapy. The other parameter viz. objective response rate improvement is equivalent to almost 14% and 38.6% when compared to nivolumab and ipilimumab monotherapy, respectively.KEYWORDS: Checkpoint inhibitorsmedian progression free survivalmetastatic melanomametastasizenivolumab AcknowledgementsThis research work was funded by the Institutional Fund projects under grant no. (IFPDP-111-22). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Deanship of Scientific Research, Jeddah, Saudi Arabia.Disclosure statementNo potential conflict of interest was reported by the author(s).Author contributionsConceived and designed the study or experiments: MW RKM AJ AA AHM SH (Steve Harakeh) AH SF RP SHh (Shafiul Haque). Performed the experiments/Collected the data: MW RKM AJ AA. Analyzed the data: MW RKM AJ AA. Contributed reagents/materials/analysis tools: AHM SH AH SF RP SHh. Wrote the paper: MW RKM AJ AA AHM SH AH SF RP SHh. All authors reviewed the manuscript.Additional informationFundingThis research work was funded by the Institutional Fund projects under grant no. (IFPDP-111-22). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Deanship of Scientific Research, Jeddah, Saudi Arabia
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<p>Suppression of T-cell proliferation by MDSC</p>
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Abstract Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab-ipilimumab combination therapy in cancer treatment. Methods: We examined data from PubMed, Web of science, EBSCO and Cochrane library. Eleven articles fulfilled our criteria, which we divided into 3 groups; nivolumab and ipilimumab versus ipilimumab, nivolumab and ipilimumab versus ipilimumab and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR) and TRAEs in any grade and grade 3 or higher. Results: Compared with ipilimumab alone, the combined immunotherapy had better CR (RR: 4.89, p <0.001), PR (RR: 2.75, p <0.001), and ORR (RR: 3.31, p <0.001). The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p <0.001) and PR (RR: 1.50, p <0.001) than nivolumab alone. Finally, N1I3 showed better PR (RR: 1.35, p =0.006) and ORR (RR: 1.21, p =0.03) than N3I1. The incidence of any TRAEs was similar between the both groups (RR: 1.05, p =0.06). However, the incidence of serious adverse events (grade 3 or higher) were lower in group N3I1 than group N1I3 (RR: 1.51, p <0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of ipilimumab or nivolumab monotherapy. In the combination group, N1I3 combination was more effective than N3I1. Although the side effects were slightly increased in group N1I3, the overall safety was acceptable.
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<p>Supplementary Materials and Methods and Supplementary Table 1. This table describes the treatment characteristics of the six cohorts of patients that participated in the study described herein, including what grades of toxicity to prior ipilimumab they might have had.</p>
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Mehta, Anurag; Gupta, Arjun; Hannallah, Franck; Koshy, Thomas; Reimold, Sharon Author Information
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Checkpoint inhibitors are a form of immunotherapy that have revolutionized treatment for malignant melanoma, resulting in longer survival and better disease control. Multiple autoimmune disorders can occur with the use of checkpoint inhibitors, including severe, potentially fatal neurologic complications. Although neurologic complications are uncommon, their early recognition and treatment is required. The purpose of this article is to present information on neurologic complications of ipilimumab and nivolumab to inform nursing practice. Recommendations for evaluation and treatment of neurologic complications are reviewed.
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Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.
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Abstract To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors ( RECIST ) in terms of the overall response rate ( ORR ), progression‐free survival ( PFS ), and disease control rate ( DCR ). Overall survival ( OS ) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events ( CTCAE ). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil‐to‐lymphocyte ratio ( NLR ) and high C‐reactive protein ( CRP ) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.
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