FDA Accepts Application for Frontline Nivolumab/Ipilimumab in TMB-High NSCLC

The FDA has accepted a supplemental biologics license application (sBLA) for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the frontline treatment of patients with advanced non–small cell lung cancer (NSCLC) with tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb), according to Bristol-Myers Squibb (BMS), the manufacturer of both immune checkpoint inhibitors.

The sBLA is based on findings from the phase III CheckMate-227 trial presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine,1,2 in which the 1-year progression-free survival (PFS) rate was 43% for patients with high TMB (≥10 mut/Mb) assigned to the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy. The median PFS was 7.2 months versus 5.5 months, respectively, representing a 42% reduction in risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).

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. A final decision on the sBLA is expected by February 20, 2019. 

“Lung cancer is a complex disease, and we believe multiple treatment approaches, including those that are biomarker-driven, are needed to help individual patients. We look forward to working with the FDA throughout the review process to bring this important treatment option to patients,” Sabine Maier, MD, development lead, thoracic cancers, BMS, said in a statement.

These data represent part 1 of a 3-part trial in patients with stage IV or recurrent NSCLC who had not received prior treatment. Patients with a PD-L1 expression level ≥1% were stratified into squamous and nonsquamous groups and assigned to 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks (n = 139), 360 mg of nivolumab plus platinum-doublet chemotherapy depending on histologic subtype (n = 71), or 500 m2 of pemetrexed plus 5 or 6 AUC of carboplatin or 75 m2 of cisplatin every 3 weeks for 4 cycles (n = 160).

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.

Overall survival (OS) data are not yet mature, but Hellman said the preliminary results are encouraging. The HR for OS at the cutoff for TMB-high patients was 0.79 (95% CI, 56-1.10).

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 tumor mutational burden (<10 mutations/megabase), 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 assigned to the immunotherapy combination, 24.4% were still on treatment at the January 24, 2018, database lock compared with 3.1% treated with chemotherapy. Of patients 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 mutations/megabase 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 mutations/megabase 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).

Rash, diarrhea, and anemia (1.6% each) were the most common grade 3/4 TRAEs in the combination arm. Twelve percent 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.


  1. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077. 2017;35(suppl 4S; abstr 350).
  2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801946.
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