Durable Responses Elicited with Nivolumab Plus Ipilimumab in Advanced NSCLC

Suresh S. Ramalingam, MD, FASCO

Frontline treatment with the combination of with nivolumab (Opdivo) plus ipilimumab (Yervoy) induced durable and long-term efficacy benefits in patients with advanced non-small cell lung cancer (NSCLC) and tumor PD-L1 expression of at least 1% or less than 1%, according to updated results from part 1 of the phase 3 Checkmate 227 trial presented at the 2020 ASCO Virtual Scientific Program.

"Based on these results, we note that the combination of nivolumab and ipilimumab, which is now approved by the United States FDA, is a novel chemotherapy-sparing first-line treatment approach for advanced-stage non-small-cell lung cancer," Suresh S. Ramalingam, MD, FASCO, deputy director, Winship Cancer Institute of Emory University, said during his presentation.

After a median follow-up of 43.1 months, patients with PD-L1 ≥ 1% had a 21% and 10%, respectively, reduced risk for death when treated with nivolumab plus ipilimumab, compared with chemotherapy (HR, 0.79; 95% CI, 0.67–0.93) and nivolumab monotherapy (HR, 0.90; 95% CI, 0.77-1.06).

Median overall survival (OS) was 17.1 months in the nivolumab plus ipilimumab arm, compared with 15.7 months in the nivolumab monotherapy arm and 14.9 months in the chemotherapy arm. The 3-year OS rates were 33% with nivolumab plus ipilimumab, 29% with nivolumab monotherapy, and 22% with chemotherapy.

At 3 years of follow-up, 18% of those with PD-L1 ≥ 1% remained progression-free on treatment with nivolumab plus ipilimumab, compared with 12% of those who received nivolumab alone and just 4% who were given chemotherapy.

Among patients with a confirmed response, 38% in the nivolumab plus ipilimumab, 32% in the nivolumab monotherapy arm, and 4% in the chemotherapy arm remained in response at 3 years. Those with a complete or partial response at 6 months experienced longer subsequent OS with nivolumab plus ipilimumab, compared with chemotherapy. Moreover, those with stable or progressive disease at 6 months had generally similar subsequent OS between treatments.

During the same time period, patients with PD-L1 < 1% had a 36% and 18%, respectively, reduced risk for death when treated with nivolumab plus ipilimumab, compared with chemotherapy (HR, 0.64; 95% CI, 0.51–0.81) and nivolumab monotherapy (HR, 0.82; 95% CI, 0.66-1.03). The 3-year OS rates were 34% with nivolumab plus ipilimumab, 20% with nivolumab monotherapy, and 15% with chemotherapy.

At 3 years of follow-up, 13% of those with PD-L1 < 1% remained progression-free on treatment with nivolumab plus ipilimumab, compared with 8% of those who received nivolumab alone and just 2% who were given chemotherapy.

Among patients with a confirmed response, 34% in the nivolumab plus ipilimumab, 15% in the nivolumab monotherapy arm, and 0% in the chemotherapy arm remained in response at 3 years.

Compared with 5.6 months with chemotherapy, patients with PD-L1 ≥ 1% demonstrated a median PFS of 5.1 months with nivolumab plus ipilimumab (HR, 0.81; 95% CI, 0.69-0.96) and 4.2 months with nivolumab monotherapy (HR, 0.97; 95% CI, 0.83-1.15). Compared with 4.7 months with chemotherapy, patients with PD-L1 < 1% showed a median PFS of 5.1 months with nivolumab plus ipilimumab (HR, 0.75; 95% CI, 0.59-0.95) and 5.6 months with nivolumab plus chemotherapy (HR, 0.73; 95% CI, 0.58-0.92).

Three-year PFS was 18% with nivolumab plus ipilimumab, 12% with nivolumab monotherapy, and 4% with chemotherapy in patients with PD-L1 ≥ 1%. Three-year PFS was 13% with nivolumab plus ipilimumab, 8% with nivolumab plus chemotherapy, and 2% with chemotherapy in patients with PD-L1 < 1%.

Overall response rates were also superior with nivolumab plus ipilimumab (36.4%), compared with nivolumab monotherapy (27.5%) and chemotherapy (30.2%) in patients with PD-L1 ≥ 1%; as well as compared to nivolumab plus chemotherapy and chemotherapy alone (27.3% vs 37.9% vs 23.1%, respectively) in patients with PD-L1 < 1%.

In those with PD-L1 ≥ 1%, treatment with nivolumab plus ipilimumab extended the median duration of response (DOR), compared with nivolumab alone and chemotherapy (23.2 months [95% CI, 15.2-32.2] vs 15.5 months [95% CI, 12.7-23.5] vs 30.2 months [95% CI, 5.6-7.6], respectively). In those with PD-L1 < 1%, DOR was also extended with nivolumab plus ipilimumab, compared with nivolumab plus chemotherapy and chemotherapy alone (18.0 months [95% CI, 12.4-33.2] vs 8.3 months [95% CI, 5.9-9.4] vs 4.8 months [95% CI, 3.7-5.8], respectively).

No new safety signals were identified with nivolumab plus ipilimumab with the extended follow-up.

In part 1a of the phase III Checkmate 227 trial, 1189 patients with stage IV, recurrent NSCLC and PD-L1 ≥ 1% were randomized 1:1:1 to receive either 3 mg/kg nivolumab once every 2 weeks plus 1 mg/kg ipilimumab once every 6 weeks (n = 396); 240 mg nivolumab monotherapy once every 2 weeks (n = 397); or chemotherapy (n = 396). In part 1b, 550 patients with PD-L1 < 1% were randomized 1:1:1 to receive either either 3 mg/kg nivolumab once every 2 weeks plus 1 mg/kg ipilimumab once every 6 weeks (n = 187); 360 mg nivolumab once every 3 weeks plus chemotherapy (n = 186); or chemotherapy (n = 177).

Patients were included in the analysis if they had stage IV or recurrent NSCLC, no prior systemic therapy, no sensitizing EGFR mutations or known ALK alterations, no untreated CNS metastases, and an ECOG score of 0-1.

Data cutoff was February 28, 2020. The primary end point of the study was OS with nivolumab plus ipilimumab compared with chemotherapy in patients with PD-L1 ≥ 1%. In addition, an exploratory analysis of OS in patients by their response status at 6 months was conducted.

"This type of analysis avoids introducing bias due to OS estimation from randomization by subsequently observed response categories during the study – an approach that can overstate the effect of response on survival," Ramalingam said.

In the post-landmark OS in responders at 6 months, 3-year OS was 70% with nivolumab plus ipilimumab, compared with 63% with nivolumab alone and 39% with chemotherapy in those with PD-L1 ≥ 1%. In patients with PD-L1 < 1%, 3-year OS was 82% with nivolumab plus ipilimumab, compared with 43% with nivolumab plus chemotherapy and 25% with chemotherapy alone.

In the post-landmark OS in those with stable disease at 6 months, 3-year OS was 39% with nivolumab plus ipilimumab, compared with 34% with nivolumab alone and 33% with chemotherapy in those with PD-L1 ≥ 1%. In patients with PD-L1 < 1%, 3-year OS was 45% with nivolumab plus ipilimumab, compared with 22% with nivolumab plus chemotherapy and 28% with chemotherapy alone.

In the post-landmark OS in those with progressive disease at 6 months, 3-year OS was 19% with nivolumab plus ipilimumab, compared with 14% with nivolumab alone and 17% with chemotherapy in those with PD-L1 ≥ 1%. In patients with PD-L1 < 1%, 3-year OS was 9% with nivolumab plus ipilimumab, compared with 4% with nivolumab plus chemotherapy and 11% with chemotherapy alone.

_Reference:

_{Ramalingam SS, Eliade Ciuleanu T, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. J Clin Oncol. 2020;38(suppl; abstr 9500). doi: 10.1200/JCO.2020.38.15_suppl.9500}