Nivolumab Misses OS Endpoint in SCLC Study

Single-agent nivolumab (Opdivo) did not improve overall survival (OS) compared with standard topotecan or amrubicin, where approved, in patients with small cell lung cancer (SCLC) who relapsed following platinum-based chemotherapy, according to topline findings from the phase III CheckMate-331 trial.

Safety data were consistent with previously reported findings with single-agent nivolumab in patients with SCLC, according to Bristol-Myers Squibb (BMS), the developer of the PD-1 inhibitor.

“Small cell lung cancer is a highly aggressive disease in which significant unmet need remains,” Sabine Maier, MD, development lead, thoracic cancers for BMS, said in a press release. “We are focused on researching innovative oncology therapies to improve outcomes for patients with lung cancer. We thank the patients, their families, and the physicians involved in the CheckMate-331 study.”

The open-label, randomized phase III CheckMate-331 evaluated nivolumab monotherapy versus chemotherapy in patients with relapsed SCLC following platinum-based chemotherapy (NCT02481830). Patients were randomized to receive nivolumab or either topotecan or amrubicin upon investigator’s choice. The primary endpoint was OS, with secondary endpoints of progression-free survival (PFS) and objective response rate (ORR).

The FDA granted an accelerated approval to nivolumab for the treatment of patients with metastatic SCLC who have progressed on platinum-based chemotherapy and at least one other line of therapy in August 2018.

The accelerated approval is based on the durability of responses in the phase I/II CheckMate-032 trial, which showed an ORR of 12% (95% CI, 6.5-19.5) for nivolumab after platinum-based chemotherapy and one other prior line of therapy in 109 patients. This response rate consisted of 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 investigated single-agent nivolumab or the combination of nivolumab and ipilimumab (Yervoy) 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 treatment or the combination at one of two doses. The primary endpoint of the study was ORR. Secondary outcome measures focused on OS, PFS, DOR, and the occurrence of treatment-related adverse events (AEs) leading to treatment discontinuation.

In results published in the Lancet Oncology, 98 patients received nivolumab at 3 mg/kg every 2 weeks 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). After 4 cycles, those in the combination arm went on to receive nivolumab monotherapy at 3 mg/kg every 2 weeks. The approved dose is for nivolumab at 240 mg every 2 weeks.^1,2

In the single-agent arm, the median age was 63 years and 9% were aged ≥75 years. Thirty-one percent had platinum-resistant SCLC, and the majority had received 2 to 3 prior lines of therapy (56%). In the N1/I3 and N3/I1 arms, the median ages were 66 and 61 years and 11% and 0% were ≥75 years, respectively. Thirty-eight percent and 52% of patients had received 2 to 3 prior regimens and 38% and 39% were platinum-resistant, for the N1/I3 and N3/I1 arms, respectively.

Nivolumab monotherapy led to a median OS of 4.4 months (95% CI, 3.0-9.3) and a 1-year OS rate of 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, median OS was 7.7 months (95% CI, 3.6-18.0) and the 1-year OS was 43% (95% CI, 30-56).

The median PFS was 1.4 months in the single-agent nivolumab arm (95% CI, 1.4-1.9). In the combination groups, the median PFS was 1.4 months (95% CI, 1.3-2.2) and 2.6 months (95% CI, 1.4-4.1), in the N3/I1 and N1/I3 arms, respectively. At the March 24, 2016, data cutoff, the 1-year PFS rate was 11% (95% CI, 5-19) with single-agent nivolumab. 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 in the single-agent nivolumab arm 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. There was 1 complete response in the N1/I3 arm, but most responses were partial responses, with. Stable disease rates were 22%, 21%, and 17%, in the single-agent, N1/I3, and N3/I1 arms, respectively. Across arms, both platinum-sensitive and -resistant patients responded to treatment.

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

Overall, 69% of patients were evaluable for PD-L1 expression at baseline, with 17% expressing the ligand on ≥1% of cells. Responses were seen regardless of PD-L1 expression. Sixteen patients experienced a DOR of more than 6 months, 50% of which were in the N1/I3 group.

AEs were more common in the combination arms versus the single-agent. Fifty-three percent of patients assigned to monotherapy experienced all-grade AEswith a grade 3/4 AE rate of 13%. In the N3/I1 and N1/I3 arms, 74% and 79% of patients experienced AEs of any grade, respectively. Grade 3/4 AEs occurred in 19% and 30% of patients, in the N3/I1 and N1/I3 groups, respectively.

AEs led to treatment discontinuation for 6%, 7%, and 11% of patients in the monotherapy, N3/I1, and N1/I3 arms, respectively. Two treatment-related deaths occurred in the N1/I3 arm from myasthenia gravis and renal failure and 1 death was seen in the N3/I1 arm from pneumonitis. Treatment-related limbic encephalitis occurred in 2 patients and resolved in 1.

BMS has a development program in thoracic malignancies, including SCLC, non-small cell lung cancer, and malignant pleural mesothelioma. As part of this program, BMS is evaluating the combination of nivolumab/ipilimumab and single-agent nivolumab versus placebo in the frontline setting as a maintenance therapy for patients with SCLC who do not progress on frontline chemotherapy.

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 [published online June 4, 2016]. Lancet Oncol. doi: 10.1016/S1470-2045(16)30098-5.