The efficacy of combination immunotherapy with ipilimumab plus nivolumab in metastatic myxofibrosarcoma
Foteini KalofonouAndrea NapolitanoCharlotte BensonAisha MiahShane ZaidiDaniel LindsayKhin ThwayRobin L. Jones
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Abstract:
We present the case of a patient with Myxofibrosarcoma (MFS), a mesenchymal type of soft tissue sarcoma (STS) and the response to combination immunotherapy with anti PD-1 and anti-CTLA-4 therapy, following disease progression after Standard chemotherapy (SACT) and Radiotherapy (RT). We have shown a timeline of treatment and responses, as well as the overall safety profile and the management of immunotherapy related adverse events. This study demonstrates the potential of checkpoint inhibitors as therapeutic agents in the treatment of MFS.Keywords:
Myxofibrosarcoma
For patients with advanced melanoma, the combination of ipilimumab and nivolumab yields better responses than ipilimumab alone. However, the two-drug combination is much more likely to cause side effects than the monotherapy.
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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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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.
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Background In melanoma patients who progress after prior ipilimumab/nivolumab (ipi/nivo) combination immunotherapy, there is no information regarding the risks and benefits of reinduction ipi/nivo. Methods This was a retrospective review of 26 melanoma patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2012 who received reinduction ipi/nivo at least 6 months following completion of an initial course of ipi/nivo. We collected data on demographics, genetics, immune-related adverse events (irAEs), best overall responses (BORs), time to treatment failure (TTF) and overall survival (OS). Results The BOR rate (complete response+partial response) was 74% (95% CI 52% to 90%) after the first course of ipi/nivo but only 23% (95% CI 8% to 45%)) after reinduction. Response to reinduction did not correlate with response to the initial course. Among the 16 patients who had an objective response to the first course, only four (25%) responded to reinduction. Of five patients who did not respond to the first course, one responded to reinduction. For all patients, median TTF was 5.3 months after reinduction; TTF was shorter for reinduction than for the first course in 85% of patients. Median OS from reinduction was 8.4 months; estimated 2-year OS was 18%. Although reinduction was associated with fewer irAEs than the initial course of ipi/nivo (58% of patients vs 85% of patients in the initial course), eight (31%) patients experienced at least one new irAE after the second course. Conclusions BOR rate and TTF were markedly less favorable after reinduction with ipi/nivo than after the initial course of ipi/nivo. Reinduction ipi/nivo was associated with frequent irAEs although less frequent than for the initial course.
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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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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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Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma.Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma.Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab–ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511).In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.
Combination therapy
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Abstract Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment response in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME, using bioinformatics of The Cancer Genome Atlas (TCGA) cohort. Adaptive immune response was activated in the TNFSF9 -high expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8 + T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. These suggest that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 -high expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.
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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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