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Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

ABSTRACT: CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ?18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ?75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

SUBMITTER: Hodi FS

PROVIDER: S-EPMC7757740 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

Hodi F Stephen FS Chapman Paul B PB Sznol Mario M Lao Christopher D CD Gonzalez Rene R Smylie Michael M Daniels Gregory A GA Thompson John A JA Kudchadkar Ragini R Sharfman William W Atkins Michael M Spigel David R DR Pavlick Anna A Monzon Jose J Kim Kevin B KB Ernst Scott S Khushalani Nikhil I NI van Dijck Wim W Lobo Maurice M Hogg David D

Melanoma research 20210201 1

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 ...[more]

PMID: 33234846

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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.).

Project description:PurposeMetastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers.Patients and methodsPatients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated.ResultsOf 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively.ConclusionNivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Project description:In the randomized, open-label, phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk) had superior efficacy over sunitinib (50 mg once daily, 4 wk on, 2 wk off) in patients with untreated International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk advanced renal cell carcinoma; the benefits were sustained through extended follow-up. To better characterize the association between outcomes and IMDC risk in CheckMate 214, we completed a post hoc analysis (n = 1051) of efficacy by the number of IMDC risk factors. The investigator-assessed objective response rate (ORR), overall survival (OS), and investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors v1.1 were evaluated. ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with increasing number of risk factors. Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40-44% vs 16-38%), OS (hazard ratio [HR] 0.50-0.72), and PFS (HR 0.44-0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors (p < 0.05 for treatment × no. of risk factors interaction). These results demonstrate the benefit of first-line nivolumab plus ipilimumab over sunitinib across all intermediate-risk and poor-risk groups, regardless of the number of IMDC risk factors. PATIENT SUMMARY: This report from the CheckMate 214 study describes a consistent efficacy benefit with first-line nivolumab plus ipilimumab over first-line sunitinib in all groups of patients with intermediate-risk or poor-risk advanced renal cell carcinoma, regardless of the number of risk factors they had before starting treatment. We conclude that there is a benefit of first-line treatment with nivolumab plus ipilimumab for all intermediate-risk patients, including those with one or two risk factors, and for all poor-risk patients, independent of the number of risk factors.

Project description:PurposeCheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.MethodsPatients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.ResultsSeventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.ConclusionWith longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

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.

Project description:BackgroundCheckpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40-60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma.MethodsWe studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis.ResultsInterestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034-0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS.ConclusionsIn short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response.

Dataset Information

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

Publications

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

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