First-Line Nivolumab/Ipilimumab and 2 Chemo Cycles Provide Superior OS Vs Chemo Alone in Advanced NSCLC

Nivolumab (Opdivo) plus ipilimumab (Yervoy) and 2 cycles of chemotherapy provided superior overall survival (OS) results compared with chemotherapy alone as well as a favorable risk-benefit profile among patients with advanced non–small cell lung cancer (NSCLC), regardless of PD-L1 expression or histology, according to findings from a preplanned interim analysis and exploratory longer-term follow-up analysis from the phase 3 CheckMate 9LA trial (NCT03215706).

Investigators indicated that these data, published in The Lancet Oncology, support the use of this regimen as a new first-line treatment for this patient population. Of note, this study remains active, though it is no longer recruiting patients.

“As the study is still maturing (60% maturity in this report), longer follow-up will provide further characterization of the risk–benefit profile of nivolumab plus ipilimumab combined with chemotherapy in this setting,” wrote the study authors, who were led by Luis Paz-Ares, MD.

In this international, randomized, open-label trial conducted at 103 hospitals in 19 countries, patients were randomized 1:1 to receive either experimental therapy with nivolumab at a dose of 360 mg intravenously every 3 weeks plus ipilimumab at a dose of 1 mg/kg intravenously every 6 weeks combined with histology-based, platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles or control therapy with chemotherapy alone every 3 weeks for 4 cycles.

The study’s primary end point was OS in randomly assigned patients. Between August 24, 2017 and January 30, 2019, a total of 1150 patients were enrolled and 719 (62.5%) were assigned, of whom 361 (50%) received nivolumab plus ipilimumab with 2 cycles of chemotherapy and 358 (50%) received 4 cycles of chemotherapy alone.

At the pre-planned interim analysis, the median follow-up was 9.7 months (interquartile range [IQR], 6.4-12.8). Among all randomly assigned patients, median OS was found to be significantly longer in the experimental arm at 14.1 months (95% CI, 13.2-16.2) versus 10.7 months (95% CI, 9.5-12.4) in the control arm (HR, 0.69; 96.71% CI, 0.55-0.87; P =.00065).

With an additional 3.5 months of follow-up, for a median of 13.2 months (IQR, 6.5-17.0), median OS was 15.6 months (95% CI, 13.9-20.0) among patients in the experimental group compared with 10.9 months (95% CI, 9.5-12.6) in the control group (HR, 0.66; 95% CI, 0.55-0.90).

Regarding safety, the most commonly reported grade 3 to 4 treatment-related adverse events (TRAEs) were neutropenia (7% in the experimental arm vs 9% in the control arm), anemia (6% vs 14%, respectively), diarrhea (4% vs 1%), increased lipase (6% vs 1%), and asthenia (1% vs 2%). Serious TRAEs of any grade occurred in 106 patients (30%) in the experimental group and in 61 (18%) in the control group.

A total of 7 patients (2%) died in the experimental group due to TRAEs including acute kidney failure, diarrhea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia (1 patient each). Moreover, 6 patients (2%) died in the control group due to TRAEs including anemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis (1 patient each).

“Similar to previous reports of nivolumab plus ipilimumab in studies of first-line treatment in patients with NSCLC, most treatment-related select adverse events (those with a potential immunological cause) observed in the experimental group in CheckMate 9LA were of low grade and mostly resolved,” the authors noted. “Additionally, toxicity that is typically associated with chemotherapy (most notably nausea, anemia, and neutropenia) occurred less frequently in the experimental group than in the control group.”

Importantly, this study is not without limitations, including the short follow-up duration, which did not allow for assessment of the durability of the dual immunotherapy with chemotherapy regimen. In addition, chemotherapy is no longer standard of care in this setting due to treatment advances made over the course of the trial; therefore, using chemotherapy as the control therapy was another limitation of the trial.

Reference:

Paz-Ares L, Ciuleanu T, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. doi: 10.1016/S1470-2045(20)30641-0