Frontline Nivolumab/Ipilimumab Improves OS in Advanced NSCLC, Irrespective of Mutational Status

Suresh S. Ramalingam, MD, FACP, FASCO

The dual immunotherapy combination comprised of nivolumab (Opdivo) and ipilimumab (Yervoy) improved overall survival (OS) vs chemotherapy in patients with advanced non–small cell lung cancer (NSCLC), irrespective of KRAS, TP53, or STK11 mutational status, according to data from exploratory analyses of part 1 of the CheckMate-227 trial (NCT02477826).

Results, which were presented during the 2021 ESMO Immuno-Oncology Congress, showed that the immunotherapy regimen (n = 419) resulted in a median OS of 19.2 months vs 15.3 months with chemotherapy (n = 419; HR, 0.77; 95% CI, 0.66-0.90). Among mutation-evaluable patients, the median OS in those who received the investigative (n = 238) and control (n = 237) regimens were 20.2 months and 16.3 months, respectively (HR, 0.75; 95% CI, 0.61-0.93).

Results from exploratory analyses showed that those with KRAS wild-type disease, the median OS with nivolumab/ipilimumab (n = 150) was 20.6 months vs 17.9 months with chemotherapy (n = 162), translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.56-0.95). In those whose tumors harbored KRAS mutations, the median OS with the immunotherapy combination (n = 88) was 17.5 months vs 15.7 months with chemotherapy (n = 75; HR, 0.79; 95% CI, 0.55-1.12).

In those with TP53 wild-type disease, the median OS achieved with nivolumab plus ipilimumab (n = 111) was 20.4 months vs 16.4 months with chemotherapy (n = 106), translating to a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.59-1.08). Those whose tumors harbored TP53 mutations and received the investigative regimen (n = 127) had a median OS of 20.2 months vs 16.3 months in those who received the control regimen (n = 131; HR, 0.72; 95% CI, 0.54-0.96).

Moreover, among patients with STK11 wild-type disease, the median OS with the dual immunotherapy combination (n = 199) was 21.2 months vs 18.5 months with chemotherapy (n = 198; HR, 0.75; 95% CI, 0.59-0.94). In those with STK11-mutated disease, the median OS with nivolumab plus ipilimumab (n = 39) was 10.8 months vs 11.2 months with chemotherapy (n = 39; HR, 0.78; 95% CI, 0.48-1.27).

“In these exploratory analyses in patients with advanced NSCLC in CheckMate-227 part 1, OS benefit with first-line nivolumab plus ipilimumab vs chemotherapy was observed regardless of KRAS, TP53, or STK11 mutation status,” Suresh S. Ramalingam, MD, FACP, FASCO, of Winship Cancer Institute, Emory University, said in a presentation on the data. “Along with previously reported data from CheckMate-227, these results support the use of nivolumab plus ipilimumab as a first-line treatment option for patients with advanced NSCLC, including those [with these] mutations.”

In May 2020, the FDA approved nivolumab plus ipilimumab for use in the frontline treatment of patients with metastatic NSCLC that does not have EGFR or ALK genomic tumor aberrations, and whose tumors express a PD-L1 level of 1% or higher.2 The decision was based on earlier data from CheckMate-227. In some countries, the combination is also approved for use in those with both a PD-L1 level of 1% or higher and those with a level of less than 1%.

The multi-part, open-label, phase 3 trial enrolled patients with stage IV or recurrent NSCLC who had an ECOG performance status of 0 or 1. Patients could not have disease with sensitizing EGFR mutations or known ALK alterations. They could have previously received systemic therapy, nor could they have untreated central nervous system (CNS) metastases.

A total of 1189 patients with PD-L1 expression of 1% or higher were enrolled to part 1a of the trial. These patients were randomized 1:1:1 to receive nivolumab plus ipilimumab (n = 396), chemotherapy (n = 397), or nivolumab monotherapy (n = 396). Part 1b enrolled 550 patients with a PD-L1 expression of less than 1%. Here, patients were randomized 1:1:1 to receive nivolumab plus ipilimumab (n = 187), chemotherapy (n = 186), and nivolumab plus chemotherapy (n = 177). The all-randomized population comprised 583 patients who received the dual immunotherapy combination and 583 patients who received chemotherapy.

Patients were stratified based on histology (squamous vs nonsquamous).

The independent primary end points of the trial were progression-free survival in the population of patients with high tumor mutational burden (TMB), and OS in the population of patients with a PD-L1 expression of 1% or higher. A key exploratory end point was to examine efficacy by oncogenic driver mutational status.

KRAS, TP53, STK11, and KEAP1 mutations have been linked with variable clinical benefit in patients with advanced NSCLC who are receiving immunotherapy or chemotherapy. At the 2021 ESMO IO Congress, Ramalingam reported findings from exploratory analyses of efficacy outcomes by mutational status at a minimum follow-up of 4 years.

Of the 1166 patients who comprised the all-randomized population, 838 had nonsquamous histology. Of these patients, 475 patients were determined to be mutation evaluable. Sixty-six percent of patients had KRAS wild-type disease, 34% had KRAS mutations, 54% had TP53 mutations, 46% had TP53 wild-type disease, 84% had STK11 wild-type disease, 16% had STK11 mutations, 92% had KEAP1 wild-type disease, and 8% had KEAP1 mutations.

Baseline characteristics were noted to be well balanced between the wild-type and mutant subsets, and between treatment arms for KRAS and TP53. Because the STK11- and KEAP1-mutated subsets were small, the ability to compare characteristics was limited.

Collectively, among mutation-evaluable patients, the median age was 63.5 years (range, 29-87), 57.5% were male, 64% had an ECOG performance status of 1, and 14% were never smokers. Across the treatment arms, 11.5% had bone metastasis, 14.5% had liver metastasis, and 16.5% had CNS metastasis. Regarding PD-L1 status, 30.5% had an expression of less than 1%, 69.5% had an expression of 1% or higher, and 34.5% had an expression of 50% or higher. Regarding TMB status, 42% had a status of 10 mut/Mb or higher and 58% had a status of less than 10 mut/Mb.

Additional data showed that in the mutation-evaluable population, 12-month OS rates with the investigative and control regimens were 65% and 60%, respectively; at 24 months, 36 months, and 48 months, respectively, these rates were 45% and 37%, 38% and 26%, and 32% and 20%.

In patients with KRAS wild-type disease, the 4-year OS rate with nivolumab plus ipilimumab was 34% vs 22% with chemotherapy; in those with KRAS-mutated disease, these rates were 27% and 16%, respectively. In a subset of patients with KRAS G12C mutations, the median OS in those who received the investigative (n = 30) and control (n = 26) regimens were 27.5 months and 21.2 months, respectively (HR, 0.78; 95% CI, 0.42-1.43).

Among those with TP53 wild-type disease, the OS rate at 4 years with the dual immunotherapy combination was 26% vs 19% with chemotherapy; in those with TP53-mutated disease, these rates were 37% and 21%, respectively. In those with STK11 wild-type disease, the 4-year OS rates with the investigative and control regimens were 34% and 23%, respectively; in those with STK11-mutated disease, these rates were 19% and 5%, respectively.

In patients with KEAP1 wild-type disease (n = 437), the median OS with nivolumab plus ipilimumab was 20.1 months vs 16.7 months with chemotherapy (HR, 0.80; 95% CI, 0.65-1.00). The OS rates at 4 years in the investigative and control arms were 31% and 22%, respectively. In those with KEAP-mutated disease (n = 38), the median OS with the dual immunotherapy regimen was 24.4 months vs 8.9 months with chemotherapy (HR, 0.31; 95% CI, 0.14-0.70); in this subset, the 4-year OS rates were 44% and 0%, respectively.

“STK11 mutations had a negative prognostic effect, as observed in various studies,” Ramalingam noted. “[The] KEAP1-mutant subgroup was small, limiting data interpretation.”

Reference

Ramalingam SS, Balli D, Ciuleanu T-E, et al. Nivolumab + ipilimumab versus chemotherapy as first-line treatment for advanced NSCLC in CheckMate 227 part 1: efficacy by KRAS, TP53, STK11, and KEAP1 mutation status. Presented at: 2021 ESMO Immuno-Oncology Congress; December 9, 2021; virtual. Presentation 40.