The 1-year progression-free survival rate was more than tripled with the combination of nivolumab and ipilimumab versus chemotherapy in treatment-naïve patients with non–small cell lung cancer with high tumor mutation burden, according to initial findings from the phase III CheckMate-227 trial.
Matthew D. Hellmann, MD
The 1-year progression-free survival (PFS) rate was more than tripled with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus chemotherapy in treatment-naïve patients with nonsmall cell lung cancer (NSCLC) with high tumor mutation burden (TMB), according to initial findings from the phase III CheckMate-227 trial. The trial results were presented at the 2018 AACR Annual Meeting and published online in theNew England Journal of Medicine(NEJM).1,2
The 1-year PFS rate was 43% for patients with high TMB (≥10 mutations/megabase) 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.
“In this study of TMB-high nonsmall cell lung cancer, we found that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy,” lead author Matthew D. Hellman, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center, said at an AACR press conference.
“The breadth, duration, and depth of response were all substantially improved, with a more than tripling of the 1-year PFS with the immunotherapy combination. This benefit was independent of PD-L1 as well as histology,” added Hellman.
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).
“At this point, more than 50% of the data points are censored. Nearly all data points beyond 14 months are censored and still, there’s a clear trend in improvement in survival with nivolumab plus ipilimumab,” said.
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.
“This result highlights that TMB and PD-L1 are independent biomarkers, that TMB is predictive of benefit with nivolumab plus ipilimumab irrespective of PD-L1, and that TMB-high represents a distinct subgroup of nonsmall cell lung cancer,” Hellman said.
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.