Bristol-Myers Squibb has announced its decision to withdraw a supplemental biologics license application currently with the FDA seeking frontline approval for the combination of nivolumab and ipilimumab for patients with advanced non–small cell lung cancer with tumor mutational burden ≥10 mutations per megabase.
Bristol-Myers Squibb (BMS) has announced its decision to withdraw a supplemental biologics license application (sBLA) currently with the FDA seeking frontline approval for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with advanced nonsmall cell lung cancer (NSCLC) with tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb).1The company withdrew its application following recent discussions with the FDA.
The application was initially accepted by the FDA in June 2018, based on data from the phase III CheckMate-227 trial. Findings from the trial showed that the 1-year progression-free survival (PFS) rate was 43% for patients with high TMB assigned to the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy.2,3
In October 2018, BMS submitted an exploratory overall survival (OS) analysis to the FDA from part 1 of the CheckMate-227 trial, which comprised a TMB <10 mut/Mb subgroup of patients with stage IV or recurrent NSCLC who had not received prior treatment.
With these updated data, the FDA extended the review period by 3 months, which made the new action date May 20, 2019.4However, the new data showed no difference in survival outcomes between patients whose tumors had high or low levels of TMB.
The updated OS data that BMS submitted showed that the median OS for the combination in patients with TMB ≥10 mut/Mb was 23.03 months versus 16.72 months for the chemotherapy arm (HR, 0.77; 95% CI, 0.56-1.06). Among patients with TMB <10 mut/Mb, the median OS was 16.20 months versus 12.42 months, respectively (HR, 0.78; 95% CI, 0.61-1.00). The additional data were also submitted to European Union regulatory authorities for an ongoing review of an application for the same indication.
“After recent discussions with the FDA, the company believes further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy on OS in first-line NSCLC patients,” BMS stated in a press release.
The analysis will require availability of the final data from part 1a of the CheckMate-227 studylooking at nivolumab plus low-dose ipilimumab or nivolumab monotherapy versus chemotherapy in patients with PD-L1positive tumors—which the company anticipates will be available in the first half of 2019. Because the final findings will not be available within the review period of the current application, BMS chose to withdraw the sBLA.
In the phase III study, patients were stratified into squamous and nonsquamous groups. Those with a PD-L1 expression level ≥1% were randomly assigned to receive nivolumab (3 mg/kg of body weight every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), platinum doublet chemotherapy based on tumor histologic type every 3 weeks for up to four cycles, or nivolumab (240 mg every 2 weeks). Patients with a PD-L1 expression level <1% were randomly assigned to receive nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), platinum doublet chemotherapy based on tumor histologic type every 3 weeks for up to 4 cycles, or nivolumab (360 mg) plus platinum doublet chemotherapy based on tumor histologic type every 3 weeks for up to 4 cycles.
Of the randomized patients, 139 from the nivolumab/ipilimumab group were included in the TMB coprimary analysis and 160 in the chemotherapy group.
Additional results showed that the median PFS was 7.2 months versus 5.5 months, respectively, which represented a 42% reduction in risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81;P<.001). Regarding safety, the combination was well tolerated and safety was similar to previous results with the therapies. The rate of grade 3/4 treatment-related adverse events (TRAEs) was 31% in the immunotherapy combination arm versus 36% with chemotherapy.
The objective response rate was 45.3% with the immunotherapy combination versus 26.9% with chemotherapy. Among responders, 68% had an ongoing response after 1 year with nivolumab/ipilimumab, versus 25% with chemotherapy.
The median PFS did not favor the combination in the overall population (4.9 vs 5.5 months), though the combination was associated with a higher 1-year PFS rate (30.9% vs 17.0%; HR, 0.83; 95% CI, 0.72-0.96). Among patients with a low TMB, the median PFS was 3.2 months with nivolumab plus ipilimumab versus 5.5 months with chemotherapy (HR, 1.07; 95% CI, 0.84-1.35).
In TMB-high patients who received nivolumab/ipilimumab, 24.4% were still on treatment at the January 24, 2018 database lock compared with 3.1% treated with chemotherapy. Of patients who were initially assigned to chemotherapy, 30% received subsequent immunotherapy.
Subgroup analysis showed that the combination improved PFS among patients with PD-L1 expression ≥1% and <1%. The combination also improved PFS in both the squamous and nonsquamous subtypes.
CheckMate-227 also compared chemotherapy versus nivolumab monotherapy among patients with ≥13 mut/Mb and PD-L1 ≥1%. Median PFS was 4.2 months with nivolumab compared with 5.6 months with chemotherapy (HR, 0.95; 95% CI, 0.61-1.48;P= .78). Among patients with ≥10 mut/Mb and PD-L1 ≥1%, median PFS was 7.1 months with nivolumab plus ipilimumab versus 4.2 months for nivolumab monotherapy (HR, 0.75; 95% CI, 0.53-1.07).
Regarding safety, diarrhea, and anemia (1.6% each) were the most common grade 3/4 TRAEs in the combination arm. Moreover, 12% of patients in the combination arm discontinued due to TRAEs compared with 4.9% in the chemotherapy arm and 6.9% in the nivolumab monotherapy arm.
BMS stated that it will continue to pursue an approval in lung cancer with the combination regimen in patients with PD-L1positive NSCLC, which was evaluated in another cohort of the CheckMate-227 trial.