The FDA has approved single-agent nivolumab for the treatment of patients with small cell lung cancer with disease progression following 2 or more lines of therapy.
The FDA has granted an accelerated approval to single-agent nivolumab (Opdivo) for the treatment of patients with small cell lung cancer (SCLC) with disease progression following platinum-based chemotherapy and 1 other line of therapy.
The approval is based on the durability of responses in the 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, according to the new label. 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, according to the FDA.
“While Immuno-Oncology innovations have dramatically changed how oncologists approach certain cancers, we have had limited progress for patients with small cell lung cancer,” Leora Horn, MD, MSc, associate professor of medicine, Ingram associate professor of cancer research, director of the thoracic oncology program and assistant vice chairman for faculty development, Vanderbilt University Medical Center, said in a statement. “Today’s approval of nivolumab is particularly exciting considering it is the first checkpoint inhibitor approved for these specific patients, and now we can finally treat this devastating disease from a different angle.”
The open-label phase I/II CheckMate-032 trial 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 treatment or the combination at one of two doses. The primary endpoint of the study was ORR. Secondary outcome measures focused on overall survival (OS), progression-free survival (PFS), DOR, and the occurrence of treatment-related adverse events (AEs) leading to treatment discontinuation.
In findings published in the Lancet Oncology,1,2 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.
In the single-agent arm, the median age was 63 years and 9% were ≥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.
Single-agent nivolumab 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 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. All-grade AEs were experienced by 53% of those in the monotherapy arm, with 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.
“At Bristol-Myers Squibb, we recognize the critical need to provide patients with cancer therapies that may offer more durable responses — particularly for those living with hard-to-treat, aggressive diseases like small cell lung cancer,” Sabine Maier, MD, development lead, thoracic cancers, Bristol-Myers Squibb, said in a statement. “This approval builds on our heritage of bringing Immuno-Oncology therapies to patients with other types of thoracic cancers. It also reinforces our commitment to bringing transformative treatments to patients in urgent need of effective new options.”
The approval, which is the first for SCLC in nearly 20 years, is contingent on findings from a confirmatory study.
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. 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. Across arms, both platinum-sensitive and -resistant patients responded to treatment.