The FDA has granted a priority review to a supplemental biologics license application (sBLA) for nivolumab (Opdivo) for the treatment of patients with small cell lung cancer (SCLC) with disease progression following 2 or more lines of therapy, according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.UPDATE 8/17/2018: FDA Approves Nivolumab for Small Cell Lung Cancer >>>
The sBLA is based on data from the phase I/II CheckMate-032 trial, in which single-agent nivolumab led to a median overall survival (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.1,2
Under the priority review, the FDA is scheduled to make its decision by August 16, 2018.
“Small cell lung cancer is a highly aggressive disease, one where most patients experience relapse within a year of diagnosis. The overall prognosis for this cancer remains poor, and there have been no new treatment advances in nearly 20 years. We are pleased with this important step forward in the FDA’s consideration to expand the use of Opdivo to patients with small cell lung cancer who have received 2 or more lines of previous treatment,” Sabine Maier, development lead, thoracic cancers, BMS, said in a statement.
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 objective response rate (ORR). Secondary outcome measures focused on OS, progression-free survival (PFS), duration of response (DOR), and the occurrence of treatment-related adverse events (AEs) leading to treatment discontinuation.
In the monotherapy arm, 98 patients received nivolumab at 3 mg/kg every 2 weeks. 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.
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.
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. 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.
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.