Nivolumab/Ipilimumab Combo Misses Primary Endpoint in Phase III SCLC Trial

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve overall survival (OS) versus placebo as a maintenance therapy for patients with extensive-stage small cell lung cancer (SCLC) without disease progression following frontline platinum-based chemotherapy, missing the primary endpoint of the phase III CheckMate-451 trial.

Bristol-Myers Squibb, the manufacturer of the PD-1 and CTLA-4 inhibitors, reported in a press release that it will work with study investigators on the future publication of the full findings. The combination, the company added, did not elicit any new safety signals.

The international, double-blind, 3-arm, randomized, phase III CheckMate-451 study (NCT02538666) evaluated single-agent nivolumab at 1 mg/kg and in combination with ipilimumab at 3 mg/kg versus placebo as a maintenance treatment in approximately 810 patients with extensive-stage SCLC who did not progress after first-line platinum-based chemotherapy. The primary endpoint was OS; a secondary endpoint was OS with nivolumab versus placebo.

To be eligible for enrollment, patients must have had histologically or cytologically confirmed extensive-stage disease SCLC, an ongoing response of stable disease or better following 4 cycles of platinum-based first-line chemotherapy, and an ECOG performance status of 0 or 1. Those with central nervous system metastases, autoimmune disease, receiving consolidative chest radiation, or those with outstanding adverse events (AEs) from prior anticancer therapy were excluded from the trial.

The FDA granted an accelerated approval to nivolumab monotherapy as a treatment for patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy in August 2018.

The approval was based on data reported from the open-label phase I/II CheckMate-032 trial, in which the objective response rate (ORR) was 12% (95% CI, 6.5-19.5) for nivolumab after platinum-based chemotherapy and 1 other prior line of therapy in 109 patients.1,2 This response rate comprised partial responses (11%) and a complete response (0.9%). The median duration of response (DOR) was 17.9 months (95% CI, 7.9-42.1), with 62% of patients continuing to respond at 12 months and 39% still responding at 18 months.

CheckMate-032 evaluated nivolumab monotherapy or the combination of nivolumab and ipilimumab in patients with advanced or metastatic solid tumors, including SCLC. In the SCLC cohort, 216 patients with progressive SCLC following ≥1 prior line of therapy were randomized to single-agent nivolumab or the combination at one of two doses. The primary endpoint of the study was ORR; secondary endpoints were OS, progression-free survival (PFS), DOR, and the occurrence of treatment-related AEs that led to treatment discontinuation.

Ninety-eight patients received nivolumab at 3 mg/kg biweekly in the monotherapy arm. In the combination arms, patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks (N1/I3; n = 61) or nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks (N3/I1; n = 54). Following 4 cycles, those in the combination arm received single-agent nivolumab at 3 mg/kg every 2 weeks. The approved dose is for nivolumab at 240 mg every 2 weeks.

Results showed that the median OS with single-agent nivolumab was 4.4 months (95% CI, 3.0-9.3) and the 1-year OS rate was 33% (95% CI, 22-45) in patients with progressive SCLC following ≥1 prior line of therapy. The median OS in the N3/I1 group was 6.0 months (95% CI, 3.6-11.0) and the 1-year OS rate was 35% (95% CI, 22-48). In the N1/I3 arm, the median OS was 7.7 months (95% CI, 3.6-18.0) and the 1-year OS was 43% (95% CI, 30-56).

Moreover, the median PFS was 1.4 months with nivolumab monotherapy (95% CI, 1.4-1.9), 1.4 months (95% CI, 1.3-2.2) with the combination, and 2.6 months (95% CI, 1.4-4.1) in the N3/I1 and N1/I3 arms. At the March 24, 2016, data cutoff, the 1-year PFS rate was 11% (95% CI, 5%-19%) with single-agent nivolumab. Additionally, in the N1/I3 group, the 1-year PFS was 19% (95% CI, 9%-32%). The 1-year PFS rate was not reached in the N3/I1 group.

The ORR with single-agent nivolumab was 10% (95% CI, 5-18), and the ORRs were 23% (95% CI, 13%-36%) and 19% (95% CI, 9%-31%) in the N1/I3 and N3/I1 arms, respectively. Responses generally consisted of partial responses, with 1 complete response seen in the N1/I3 arm. Stable disease rates were 22%, 21%, and 17%, in the single-agent, N1/I3, and N3/I1 arms, respectively. Both platinum-sensitive and -resistant patients responded to treatment across both arms.

The median DOR was not yet reached with single-agent nivolumab. In the N3/I1 arm, the median DOR was 4.4 months (95% CI, 3.7-not reached), and was 7.7 months (95% CI, 4.0-not reached) in the N1/I3 group.

References

1. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016:17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5.