Nivolumab plus ipilimumab confers sustained survival benefit in advanced NSCLC
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Nivolumab plus ipilimumab continued to provide long-term OS benefits compared with chemotherapy as initial treatment for advanced non-small cell lung cancer, according to study results presented during the ASCO20 Virtual Scientific Program.
“With distinct but complementary mechanisms of action, nivolumab [Opdivo, Bristol-Myers Squibb] plus ipilimumab [Yervoy, Bristol-Myers Squibb] improved long-term survival for patients with melanoma, renal cell carcinoma and NSCLC,” Suresh S. Ramalingam, MD, FASCO, deputy director of Winship Cancer Institute of Emory University, said during a presentation. “Nivolumab plus ipilimumab is indicated in the U.S. as first-line treatment for adult patients with metastatic NSCLC expressing 1% or greater PD-L1 with no EGFR or ALK genomic tumor aberrations.”
The randomized, phase 3 CheckMate 227 trial included 1,739 patients with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC. All patients had ECOG performance status of 0 or 1, and they had no known sensitizing EGFR or ALK mutations.
In part 1, researchers randomly assigned 1,189 patients with PD-L1 expression of 1% or greater to one of three regimens: 3 mg/kg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks (n = 396); 240 mg nivolumab every 2 weeks (n = 396); or histology-based chemotherapy (n = 397).
They also randomly assigned 550 patients with tumor PD-L1 expression of less than 1% to the nivolumab-plus-low-dose ipilimumab regimen (n = 187), 360 mg nivolumab every 3 weeks plus histology-based chemotherapy (n = 177) or chemotherapy alone (n = 186).
As Healio previously reported, the study met its co-primary endpoint of prolonged PFS with nivolumab plus ipilimumab compared with chemotherapy among patients with high tumor mutational burden (10 mutations per megabase or greater). Results with minimum follow-up of 29.3 months showed significantly longer OS with the combination vs. chemotherapy among patients with tumor PD-L1 expression of 1% or greater or less than 1%.
In the current study, Ramalingam and colleagues reported data with at least 3 years of follow-up (median, 43.1 months).
Results showed a sustained OS benefit for patients with PD-L1 expression of 1% or greater with the immunotherapy combination vs. chemotherapy (median, 17.1 months vs. 14.9 months; HR = 0.79; 95% CI, 0.67-0.93). Three-year OS rates among these patients were 33% with the immunotherapy combination, 29% with nivolumab alone and 22% with chemotherapy alone.
“Notably, with this extended follow-up, the HR remained the same and is unchanged from prior reports,” Ramalingam said. “Of note, 76% of patients in the chemotherapy group went on to receive subsequent immunotherapies, with approximately 35% of patients in the immunotherapy combination group receiving subsequent systemic therapy.”
Patients with 1% or greater PD-L1 expression who received nivolumab alone had median OS of 15.7 months (HR vs. chemotherapy = 0.9; 95% CI, 0.77-1.06).
Among patients with low PD-L1 expression, median OS was 17.2 months with the immunotherapy combination vs. 12.2 months with chemotherapy (HR = 0.64; 95% CI, 95% CI, 0.51-0.81). Three-year OS rates among these patients were 34% with the immunotherapy combination, 20% with nivolumab alone and 15% with chemotherapy alone.
Researchers also observed higher 3-year PFS rates with nivolumab plus ipilimumab vs. chemotherapy alone among patients in the higher PD-L1 expression group (18% vs. 4%) and the lower PD-L1 expression group (13% vs. 2%).
Moreover, 38% of patients with PD-L1 expression of 1% or greater who responded to nivolumab plus ipilimumab remained in response at 3 years, compared with 4% of those who responded to chemotherapy (median duration of response, 23.2 months vs. 6.7 months).
Researchers observed a similar pattern among those with PD-L1 expression of less than 1%. In that group, 34% of those assigned the immunotherapy combination and 0% of those assigned chemotherapy maintained responses for 3 years (median duration of response, 18 months vs. 4.8 months).
“These results speak to the durability of responses that are substantially more favorable with nivolumab plus ipilimumab,” Ramalingam said.
Results of a landmark analysis showed patients with 1% or greater PD-L1 expression who achieved complete or partial response at 6 months had a higher 3-year OS rate with nivolumab plus ipilimumab vs. chemotherapy alone (70% vs. 39%). The same was true for patients with PD-L1 expression of less than 1% (82% vs. 25%).
Safety results appeared consistent with previous findings, according to the researchers.
“Patients receiving treatment with nivolumab plus ipilimumab and who are benefiting from this treatment can continue to receive their maximum 24 months of therapy without increases in new adverse events,” Ramalingam said. “This dual immunotherapy regimen is a novel chemotherapy-sparing first-line treatment option for patients with advanced NSCLC.”
Perspective
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This updated analysis of CheckMate 227 part 1 data continues to show benefit with this immunotherapy combination and, with recent FDA approval of front-line nivolumab plus ipilimumab for patients with NSCLC and PD-L1 expression greater than 1%, it becomes another option for our patients. However, I am not sure the updated results will affect the regimen I use. I still think chemoimmunotherapy combinations are the standard of care for the majority of these patients, particularly given the lack of benefit among the original group of patients in this study with PD-L1 expression of 1% to 49%.
Yet, there is clearly a benefit with the addition of ipilimumab for some patients, and many of those who initially responded are demonstrating very durable responses. We need to identify reliable biomarkers that help us select this subpopulation. This is particularly important given a toxicity profile that is comparably significant but less predictable than chemotherapy. The most intriguing data continue to be those showing benefit among patients with PD-L1 expression less than 1%, but I would like to see more dedicated data in this space.
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