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Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

ABSTRACT: INTRODUCTION:Nivolumab has been approved in patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. A pivotal trial compared nivolumab with ipilimumab; however, no head-to-head trial exists comparing nivolumab to observation, a common comparator in the adjuvant setting. Here, we compared the efficacy and cost-effectiveness of nivolumab with observation or ipilimumab as adjuvant therapies in resected stage IIIB/C melanoma. METHODS:Patient data were pooled from the EORTC 18071 and CheckMate 238 trials using propensity score weighting and adjusting for cross-trial differences. Number needed to treat (NNT) and costs per recurrence-free life-month (RFLM) at 12, 16, 18, and 24 months (as data allowed) were estimated. Costs included drug acquisition, administration costs, and direct medical costs. Sensitivity analyses including patients with stage IIIB/C and resected stage IV melanoma were conducted. RESULTS:A total of 1287 patients (278 nivolumab, 365 observation, and 644 ipilimumab) with resected stage IIIB/C melanoma were pooled. NNTs to achieve one additional recurrence-free survivor with nivolumab versus observation were 3.93 at 12 months and 3.42 at 24 months; NNTs for nivolumab versus ipilimumab were 7.97 at 12 months and 6.43 at 24 months. Mean drug costs per RFLM were lower for nivolumab at 12, 18, and 24 months, respectively (nivolumab: $13,447, $9462, and $7370; ipilimumab: $52,734, $40,484, and $33,875). Mean medical costs per RFLM were the lowest for nivolumab versus observation or ipilimumab at 12 months ($449 versus $674 or $1531) and 16 months ($383 versus $808 or $1316). The sensitivity analysis results were consistent with the base case. CONCLUSION:For resected melanoma, adjuvant nivolumab is both clinically effective and cost-effective compared with observation or ipilimumab. Adjuvant nivolumab was associated with a lower drug cost per RFLM compared with ipilimumab, and a lower medical cost compared with observation. Future analyses incorporating long-term follow-up data may help increase understanding of the economic impact of nivolumab in the adjuvant setting. FUNDING:Bristol-Myers Squibb Company.

SUBMITTER: Freeman M

PROVIDER: S-EPMC6822822 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

Freeman Morganna M Betts Keith A KA Jiang Shan S Du Ella X EX Gupte-Singh Komal K Lu Yichen Y Rao Sumati S Shoushtari Alexander N AN

Advances in therapy 20190822 10

<h4>Introduction</h4>Nivolumab has been approved in patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. A pivotal trial compared nivolumab with ipilimumab; however, no head-to-head trial exists comparing nivolumab to observation, a common comparator in the adjuvant setting. Here, we compared the efficacy and cost-effectiveness of nivolumab with observation or ipilimumab as adjuvant therapies in resected stage II ...[more]

PMID: 31440980

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Project description:BACKGROUND:In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS:In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS:Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS:The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).

Project description:Background:Monoclonal antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) (e.g., ipilimumab [IPI]) and the programmed cell death-1 (PD1) receptor (e.g., nivolumab [NIVO]) represent significant breakthroughs in the treatment of advanced melanoma. A combination of the 2 agents has demonstrated efficacy and survival benefits over NIVO or IPI monotherapy in treating advanced melanoma. We compared melanoma-specific costs following treatment with NIVO?+?IPI, NIVO monotherapy, or IPI monotherapy from the UK and German perspectives to ascertain whether these clinical benefits resulted in a cost advantage. Methods:Patient-level resource utilization data for the three treatment cohorts were obtained from the CheckMate 067 trial (NCT01844505). All melanoma-specific resources, including drugs (index, concomitant and subsequent melanoma medications), office visits, emergency room visits, hospitalizations, lab tests, procedures and surgeries, utilized over a 48-month evaluation period after start of index treatment were included. Unit costs specific to each geography were applied from external sources. Mean costs per surviving patients were calculated for each successive 30-day period from treatment start and aggregated over the evaluation period. Results:The total per-patient costs incurred by advanced melanoma patients over the 48-month period following treatment initiation with NIVO?+?IPI were 9% lower than NIVO monotherapy (£226k vs £248k) and 3% lower compared to IPI monotherapy (£226k vs. £233k) in the UK. In Germany, the total costs incurred by NIVO?+?IPI cohort were 5% lower than NIVO monotherapy (€258k vs €271k) and 4% lower compared to IPI monotherapy (€258k vs. €268k). Drug costs accounted for >?85% of total costs. Non-drug costs were slightly higher for NIVO?+?IPI and IPI monotherapy because of higher hospitalization rates. Costs incurred on subsequent drugs post progression were about 45% and 65% lower in NIVO?+?IPI cohort compared with NIVO and IPI monotherapy cohorts respectively. Conclusions:The total costs incurred by a patient over a 48-month period following treatment initiation with NIVO?+?IPI are lower when compared with patients initiating monotherapies; further, the cost advantage is seen to be increasing over time. The clinical benefits offered by the regimen are thus supplemented by a cost advantage, as patients receiving either monotherapy treatment experience faster progression and, consequently, higher subsequent treatment costs. (Note: The cost results reported here are specific to the UK, and Germany, and may not be generalizable to other geographies).

Project description:BACKGROUND:In 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. METHODS:We 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. RESULTS:A 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%. CONCLUSIONS:Concurrent 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:BACKGROUND:Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS:We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS:The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS:Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Dataset Information

Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

Publications

Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

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