CM214 - Biomarker Analysis From the Phase 3 CheckMate 214 Trial of Nivolumab Plus Ipilimumab (N+I) or Sunitinib (S) in Advanced Renal Cell Carcinoma (aRCC)
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PROVIDER: EGAS00001005501 | EGA |
REPOSITORIES: EGA
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Project description:Background: Adjuvant therapy for high-risk resected melanoma with PD-1 blockade results in median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of nivolumab (NIVO) in Checkmate-915, did not result in increased RFS. A pilot phase II adjuvant study of either standard or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative studies. Methods: Patients (pts) with resected stages IIIB/IIIC/IV melanoma received either IPI 3mg/kg and NIVO 1mg/kg (cohort 4) or IPI 1mg/kg and NIVO 3mg/kg (cohorts 5 and 6) induction therapy every three weeks for 12 weeks, followed by maintenance NIVO. Peripheral blood samples at baseline and on-treatment were assessed by flow cytometry for potential biomarkers. Peripheral CD8+ T-cells were assessed by RNA-Seq. Results: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of patients in cohorts 4, 5 and 6 respectively. At a median of 63.9 months of follow up, 16/56 pts (29%) relapsed. For all patients, at five-years, RFS was 71% (95% CI: 60, 84), and overall survival was 94% (95% CI: 88, 100). Expansion of CD3+CD4+CD38+CD127-GARP- T-cells, an on-treatment increase in CD39 expression in CD8+ T-cells, and T-cell expression of phosphorylated STAT2 and STAT5 were associated with relapse. Conclusions: Adjuvant IPI/NIVO at the induction doses used resulted in excellent relapse-free survival, albeit with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T-cells and STAT signaling pathways with relapse.
2022-12-02 | GSE219251 | GEO
Project description:BackgroundIn patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.MethodsWe administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.ResultsA total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.ConclusionsConcurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
| S-EPMC5698004 | biostudies-literature
Project description:Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .
| S-EPMC11293616 | biostudies-literature
Project description:CM214 - Biomarker Analysis From the Phase 3 CheckMate 214 Trial of Nivolumab Plus Ipilimumab (N+I) or Sunitinib (S) in Advanced Renal Cell Carcinoma (aRCC)
| EGAD00001007938 | EGA
Project description:PurposeIn the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.Patients and methodsPatients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.ResultsMedian OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.ConclusionThese 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
| S-EPMC8718224 | biostudies-literature
Project description:BackgroundNivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.MethodsWe randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk.ResultsA total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.ConclusionsOverall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).
| S-EPMC5972549 | biostudies-literature
Project description:Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aimed at investigating safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy ADI-PEG 20. 9 patients were enrolled in this pilot study. The combination therapy was safe and tolerable with absence of immune related adverse events (irAE) of special interest but with 4 of 9 patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at baseline in metastases.
2022-05-13 | GSE202687 | GEO
Project description:ImportanceAlthough the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.ObjectiveTo examine whether the addition of ipilimumab to standard-dose nivolumab safely improves clinical outcomes in patients with advanced cancers other than melanoma.Data sourcesElectronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) were systematically searched for studies of standard-dose nivolumab plus ipilimumab vs nivolumab alone in the treatment of advanced cancers other than melanoma published from database inception to October 31, 2022.Study selectionEight studies (total patients, 1727; nivolumab plus ipilimumab group, 854; nivolumab monotherapy group, 873) met the selection criteria. Patients had squamous cell lung cancer, non-small cell lung cancer with programmed death ligand 1 level of 1% or higher, small cell lung cancer, pleural mesothelioma, urothelial carcinoma, esophagogastric carcinoma, sarcoma, or glioblastoma multiforme.Data extraction and synthesisFor comparison of overall survival (OS) and progression-free survival (PFS) outcomes, estimation of log(hazard ratios [HRs]) and SEs was initially performed for OS and PFS of each included study based on summary statistics extracted from individual Kaplan-Meier curves. Inverse-variance weighting was then used to compute pooled HRs (95% CIs). For comparison of dichotomous data (treatment-related grade 3 to 4 adverse events and discontinuations), odds ratios (ORs) were used, and the Mantel-Haenszel method was used to estimate pooled ORs (95% CIs).ResultsTreatment with nivolumab plus ipilimumab was not associated with improvement in OS over treatment with nivolumab alone (pooled HR, 0.95; 95% CI, 0.85-1.06; P = .36), with 4 of the 8 studies having numerically lower median OS with the combination. Nivolumab plus ipilimumab combination therapy was associated with marginal, but not clinically meaningful, improvement in PFS over nivolumab alone (pooled HR, 0.88; 95% CI, 0.79-0.98; P = .02). The combination was associated with substantially higher treatment-related grade 3 to 4 adverse events (pooled OR, 1.84; 95% CI, 1.47-2.31; P < .001) and treatment-related discontinuations (pooled OR, 1.96; 95% CI, 1.44-2.65; P < .001). This finding was recapitulated in meta-analyses of individual grade 3 to 4 adverse events of hepatotoxicity, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, dermatitis, fatigue.Conclusions and relevanceIn this meta-analysis of 8 advanced cancers other than melanoma, the differences detected in OS and PFS between nivolumab plus ipilimumab and nivolumab were not clinically meaningful (even though statistical significance was detected in PFS). Treatment-related higher-grade toxicity and discontinuations were substantially higher with the combination therapy. The data indicate that investigations of anti-programmed death 1 (PD1) plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies in any nonmelanoma advanced cancer should be conducted along with anti-PD1 monotherapy to ensure that the net effect of the addition of anti-CTLA-4 to anti-PD1 can be clearly established for that cancer and setting and that unnecessary CTLA-4 inhibition with related toxic effects (both clinical and financial) can be avoided.
| S-EPMC10472261 | biostudies-literature
Project description:BackgroundThe combination of nivolumab and ipilimumab is approved in several jurisdictions (United States, European Union, Canada) for the first-line treatment of patients with advanced melanoma. CheckMate 218 is a North American expanded-access program (eap) of nivolumab plus ipilimumab in patients with advanced melanoma. Here, we report safety and survival outcomes for the Canadian cohort in the eap.MethodsEligible patients were those 18 years of age or older with unresectable stage iii or iv melanoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior anti-PD-1 or anti-ctla-4 therapy. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction phase); they then continued with nivolumab 3 mg/kg every 2 weeks (maintenance phase) until progression, unacceptable toxicity, or a maximum of 48 weeks, whichever occurred first. Safety and overall survival (os) data were collected.ResultsOf 194 patients enrolled, 174 were treated, and 51% continued on nivolumab maintenance. Median follow-up was 12.9 months. All-grade and grades 3-4 treatment-related adverse events were reported in 98% and 60% of patients respectively and led to treatment discontinuation in 40% and 28% of patients. Two treatment-related deaths were reported. The 12- and 18-month os rates were 80% [95% confidence interval (ci): 73% to 86%] and 76% (95% ci: 67% to 82%) respectively.ConclusionsIn this Canadian population, nivolumab plus ipilimumab demonstrated a safety profile and survival outcomes consistent with phase ii and iii clinical trial data.
| S-EPMC7467793 | biostudies-literature
Project description:BackgroundEstablishing alternatives to lifelong chemotherapy for patients with advanced pancreatic cancer has been proposed to address chemotherapy resistance and cumulative toxicity. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in this setting, and concurrent immune checkpoint blockade could offer synergistic tumour control. The aim of this study was to test the safety and antitumour activity of maintenance with PARP inhibition combined with immune checkpoint blockade in patients with advanced pancreatic cancer who had a stable response to platinum-based chemotherapy.MethodsWe conducted an open-label, randomised, phase 1b/2 study of niraparib plus anti-PD-1 (nivolumab) or anti-CTLA-4 (ipilimumab) therapy for patients with advanced pancreatic cancer whose cancer had not progressed after at least 16 weeks of platinum-based therapy. Patients were randomly assigned (1:1) via permuted block randomisation (block sizes 2 and 4) to niraparib 200 mg orally per day plus either nivolumab 240 mg intravenously every 2 weeks (later changed to 480 mg intravenously every 4 weeks based on manufacturer update) or ipilimumab 3 mg/kg intravenously every 4 weeks for four doses. The primary endpoints were safety and progression-free survival at 6 months. Treatment groups were not compared for activity, which was assessed in each group against a clinically meaningful progression-free survival at 6 months of 44% (null hypothesis). Superiority of a treatment regimen could be declared if 6-month progression-free survival was 60%, and inferiority if 6-month progression-free survival was 27%. All patients who received at least one dose of study treatment and had at least one post-treatment assessment of response according to Response Evaluation Criteria in Solid Tumours version 1.1 were included in the efficacy population. The safety population consisted of all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03404960, and enrolment is completed and follow-up is ongoing.Findings91 patients were enrolled between Feb 7, 2018, and Oct 5, 2021 and were randomly assigned to niraparib plus nivolumab (n=46) or niraparib plus ipilimumab (n=45). Of these patients, 84 were evaluable for the progression-free survival endpoint (niraparib plus nivolumab=44; niraparib plus ipilimumab=40). Median follow-up was 23·0 months (IQR 15·0-31·5). 6-month progression-free survival was 20·6% (95% CI 8·3-32·9; p=0·0002 vs the null hypothesis of 44%) in the niraparib plus nivolumab group; and 59·6% (44·3-74·9; p=0·045) in the niraparib plus ipilimumab group. Ten (22%) of 46 patients in the niraparib plus nivolumab group and 23 (50%) of 45 patients in the niraparib plus ipilimumab group had a grade 3 or worse treatment-related adverse event. The most common grade 3 or worse adverse events in the niraparib plus nivolumab group were hypertension (in four [8%] patients), anaemia (two [4%]), and thrombocytopenia (two [4%]) whereas in the niraparib plus ipilimumab group these were fatigue (in six [14%]), anaemia (five [11%]), and hypertension (four [9%]). There were no treatment-related deaths.InterpretationThe primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer.FundingBristol Myers Squibb, GlaxoSmithKline, the Basser Center Young Leadership Council, The Konner Foundation, The Pearl and Philip Basser Innovation Research Award, the Anonymous Foundation, and the US National Institutes of Health.
| S-EPMC9339497 | biostudies-literature