Frontline Nivolumab/Ipilimumab Shows Trend Toward Improved Intracranial PFS in Advanced NSCLC

Martin Reck, MD, PhD

Frontline nivolumab (Opdivo) plus ipilimumab (Yervoy) showcased improved overall survival (OS) over chemotherapy and a trend toward improved intracranial progression-free survival (PFS) and duration of response (DOR) in patients with advanced non–small cell lung cancer (NSCLC), according to data from a post-hoc analysis of part 1 of the CheckMate-227 trial (NCT02477826).¹

Results, which were shared during the 2021 ESMO Immuno-Oncology Congress, showed that the doublet (n = 68) resulted in a median OS of 17.4 months in patients with baseline brain metastases vs 13.7 months with chemotherapy (n = 66; HR, 0.63; 95% CI, 0.43-0.92). In those without brain metastases, the median OS in the investigative (n = 515) and control (n = 517) arms was 17.1 months and 13.9 months, respectively (HR, 0.75; 95% CI, 0.65-0.86).

Among the subset of patients with PD-L1 expression of 1% or higher and baseline brain metastases, nivolumab plus ipilimumab (n = 49) still showcased a longer median OS vs chemotherapy (n = 48), at 20.6 months and 13.7 months, respectively (HR, 0.62; 95% CI, 0.39-0.97). Among those without brain metastases and a PD-L1 of at least 1%, the median OS with the immunotherapy combination (n = 347) was 16.7 months vs 15.0 months with chemotherapy (n = 349; HR, 0.80; 95% CI, 0.68-0.95).

“With a 4-year minimum follow-up, first-line nivolumab plus ipilimumab for advanced NSCLC continued to provide durable and long-term efficacy benefit vs chemotherapy in this post-hoc analysis in patients with or without baseline brain metastases,” Martin Reck, MD, PhD, Airway Research Center North, German Center for Lung Research, LungenClinic, said in a presentation on the data. “Among patients with baseline brain metastases, a trend toward improved intracranial PFS and DOR was observed with nivolumab plus ipilimumab vs chemotherapy.”

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 findings from CheckMate-227.

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. For those with brain metastases, they must have been adequately treated and asymptomatic for 2 weeks or longer before the first treatment dose.

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.

Among those with brain metastases at baseline, 68 received the dual immunotherapy combination and 66 received chemotherapy. In those without brain metastases at baseline, 515 received nivolumab plus ipilimumab and 517 received chemotherapy.

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

The primary objectives of the post-hoc analysis were systemic safety and efficacy in patients with or without brain metastases at baseline, and intracranial efficacy in those with brain metastases at baseline.

Among those with baseline brain metastases, the median age in those who received nivolumab plus ipilimumab was 60 years (range, 31-77) vs 61 years (range, 31-76) in those who received chemotherapy; 37% and 39% of patients, respectively, were female. Most patients across the treatment arms had an ECOG performance status of 1, were current or former smokers, and had nonsquamous disease.

Among those who received nivolumab plus ipilimumab, 16% and 31% of patients had liver and bone metastases, respectively; these rates were 29% and 32%, respectively, in those who received chemotherapy. Regarding PD-L1 expression in those who received the immunotherapy regimen, 28% had an expression of less than 1% and 72% had an expression of at least 1%. In those who received chemotherapy, 27% had an expression of less than 1% and 73% had an expression of 1% or higher.

Additional data showed that in patients with baseline brain metastases, the median PFS was 5.4 months with nivolumab plus ipilimumab (n = 68) vs 5.8 months with chemotherapy (n = 66; HR, 0.77; 95% CI, 0.52-1.16). Among those without baseline brain metastases, the median PFS with the immunotherapy regimen (n = 515) was 4.9 months vs 5.4 months with chemotherapy (n = 517; HR, 0.80; 95% CI, 0.69-0.92).

Among those with baseline brain metastases, nivolumab plus ipilimumab elicited an objective response rate (ORR) of 32.4% vs 25.8% with chemotherapy. The median DOR was 24.9 months in the investigative arm vs 8.4 months in the control arm. In those without baseline brain metastases, the dual immunotherapy regimen induced an ORR of 33.6% vs 28.0% with chemotherapy. The median DORs in the investigative and control arms were 20.7 months and 5.8 months, respectively.

In the population of patients with a PD-L1 expression of 1% or higher, the systemic PFS and response were comparable in patients with or without brain metastases.

Moreover, the median intracranial PFS with nivolumab plus ipilimumab was 8.6 months vs 8.7 months with chemotherapy (HR, 0.80; 95% CI, 0.50-1.27). The 12-month intracranial PFS rates in the investigative and control arms were 46% and 33%, respectively; at 24 months, 36 months, and 48 months, these rates were 36% and 24%, respectively, 31% and 15%, respectively, and 28% and 7%, respectively.

Among patients with baseline brain metastases, nivolumab plus ipilimumab and chemotherapy both elicited an intracranial ORR of 29%. The disease control rates for both arms were 65%. In the investigative arm, the median time to response was 2.9 months (range, 1.2-11.8); this was 2.8 months (range, 1.2-20.7). The median DOR with the dual immunotherapy combination was 45.5 months (95% CI, 27.1-52.4) vs 32.0 months (95% CI, 5.1-44.2) with chemotherapy.

“Fewer patients developed new brain lesions with nivolumab plus ipilimumab; however, interpretation is limited by small sample size,” Reck said.

The median treatment duration with the immunotherapy combination compared with chemotherapy in those with baseline brain metastases was 4.2 months (range, 0.0-24.4) and 3.6 months (range, 0.0-49.4). In those without baseline brain metastases, the median treatment duration with nivolumab plus ipilimumab was 4.2 months (range, 0.0-25.5) vs 2.6 months (range, 0.0-49.1) with chemotherapy.

No new safety signals were observed in patients with baseline brain metastases. Any-grade treatment-related adverse effects (TRAEs) were reported in 77% and 76% of those in the investigative and control arms, respectively; these effects were grade 3 or 4 in 30% and 27% of patients, respectively.

Any-grade treatment-related nervous system disorders such as headache (5%), paresthesia (3%), somnolence (3%), and taste disorder (3%) were reported in patients who received the dual immunotherapy regimen. Among those who received nivolumab plus ipilimumab, 19% experienced any-grade treatment-related serious toxicities; 14% had grade 3 or 4 treatment-related serious effects. No treatment-related deaths occurred.

“These data further support nivolumab plus ipilimumab as an efficacious first-line treatment option in patients with advanced NSCLC and brain metastases,” Reck concluded.

Reference

Reck M, Ciuleanu T-E, Pluzanski A, et al. Nivolumab + ipilimumab as first-line treatment for patients with advanced NSCLC and baseline brain metastases: intracranial and systemic outcomes from CheckMate 227 part 1. Presented at: 2021 ESMO Immuno-Oncology Congress; December 9, 2021; virtual. Abstract 122MO.