Treatment with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to clinically meaningful overall survival (OS) results at 3 years as well as a manageable toxicity profile in special populations of patients with metastatic non–small cell lung cancer (NSCLC) in the phase 3b CheckMate 817 trial (NCT02869789).¹

Among patients with an ECOG performance status (PS) of 2, untreated metastases, renal or hepatic impairment, or controlled HIV infection, the OS rate at 3 years was 20.5%, compared with 33.7% in a more standard clinical trial population of patients with an ECOG PS of 0 or 1.

“These results support the use of combination nivolumab and ipilimumab as a first-line treatment for patients with metastatic NSCLC, including patients who [had an] ECOG PS 2 or ECOG PS 0 or 1 and had untreated brain metastases, renal or hepatic impairment, or positive HIV status,” wrote the study authors, led by Neal E. Ready, MD, PhD, a professor of medicine at Duke Cancer Institute. Their results were published in the Journal for Immuno Therapy of Cancer.¹

“CheckMate 817 is the first prospective study to evaluate patients with metastatic NSCLC and patient subgroups that are typically excluded from phase 3 randomized controlled trials,” Ready et al wrote.

The open-label, single-arm trial aimed to build upon the use of nivolumab and ipilimumab in patients with metastatic NSCLC explored in the CheckMate 012 (NCT01454102) and CheckMate 227 (NCT02477826) trials and further optimize the doses of the immunotherapy agents. The phase 1 CheckMate 012 trial focused on finding an optimal dose and schedule that was tolerable and held promising antitumor activity.² CheckMate 227 established a clinical benefit for the immunotherapy regimen compared with nivolumab monotherapy or platinum- doublet chemotherapy. It led to the FDA approval in patients with positive PD-L1 expression and no EGFR or ALK alterations.^3,4

The CheckMate 817 trial explored the use of a flat dose of nivolumab (240 mg every 2 weeks) and a weight-based dose of ipilimumab (1 mg/kg every 6 weeks). Eligible patients in CheckMate 817 had stage IV or recurrent NSCLC and no prior systemic therapy for advanced or metastatic disease. Patients with EGFR mutations or ALK translocations were excluded.

Patients were stratified by baseline characteristics, with those with an ECOG PS of 0 or 1, adequate renal and hepatic function, negative HIV status, and no active or untreated brain metastases in cohort A (n = 391), and those with an ECOG PS of 2 or ECOG PS of 0 or 1 with untreated asymptomatic brain metastases, renal impairment, hepatic impairment, or controlled HIV infection in cohort A1 (n = 198).

In cohort A, there was a median duration of treatment of 4.0 months (range, < 0.125.8), compared with 2.8 months (range, < 0.1-25.4) in cohort A1. Patients went on to receive subsequent systemic therapy in 35.5% of cohort A and 26.8% of cohort A1.

Cohort A Results

Median OS in the cohort was 16.8 months (95% CI, 14.6-22.4), and the median progression-free survival (PFS) was 5.8 months (95% CI, 4.5-7.6). The objective response rate (ORR) was 37.3% (95% CI, 32.5%-42.3%), and the median duration of response (DOR) was 27.6 months (95% CI, 32%-50%).

By PD-L1 expression, patients with positive expression had a median OS of 21.0 months (95% CI, 14.2-30.8) vs 15.3 months (95% CI, 12.5-19.2) for those with negative expression. The median PFS was 7.1 months (95% CI, 4.29.3) in those with positive PD-L1 expression and 5.3 months (95% CI, 4.1-6.3) with negative expression.

The ORRs were 43.8% (95% CI, 36.3%-51.4%) and 30.9% (95% CI, 24.3%-38.2%) with positive and negative PD-L1 expression, respectively, and median DORs were 29.9 months (95% CI, 15.2-39.8) and 25.8 months (95% CI, 16.8-34.3).

In patients with at least 50% PD-L1 expression, the median OS was 21.4 months (95% CI, 11.8-41.1) and the median PFS was 8.4 months (95% CI, 5.4-14.8).

Any-grade treatment-related adverse events (TRAEs) were reported in 77.0% of patients, including grade 3/4 events in 35.3%. Any-grade TRAEs led to a treatment discontinuation in 23.8% of patients. Four treatment-related deaths were reported.

The most common grade 3/4 immune-mediated AEs (imAEs) were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%). Common grade 3/4 TRAEs included hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events.

Cohort 1A Results

In the special patient populations, the median OS was 9.9 months (95% CI, 7.0-13.7) and the median PFS was 3.9 months (95% CI, 2.8-5.4). Those with an ECOG PS of 2 had a median OS and PFS of 9.0 months (95% CI, 5.5-12.9) and 3.6 months (95% CI, 2.8-5.4), respectively. Patients with untreated brain metastases had a median OS of 12.8 months (95% CI, 7.7-25.9) and a median PFS of 2.8 months (95% CI, 1.7-8.0) (TABLE¹).

In patients with renal impairment (n = 9), OS ranged from 1.4 to 45.3+ months, and the range was 0.4 to 35.5 or greater months for patients with hepatic impairment (n = 7). Patients with HIV infection (n = 4) had an OS ranging from 7.0 to 41.4 or greater months.

By tumor PD-L1 expression, patients with negative expression had a median OS of 10.5 months (95% CI, 7.0-15.6), 6.9 months (95% CI, 3.6-12.8) with positive expression of at least 1%, and 13.3 months (95% CI, 7.9-30.1) with expression of at least 50%. Median PFS was 3.9 months (95% CI, 2.6-6.2) in patients with negative PD-L1 expression, 3.3 months (95% CI, 2.8-6.0) with positive expression, and 9.6 months (95% CI,2.8-16.4) with at least 50% expression.

The ORR in the overall cohort was 25.8% (95% CI, 19.8%-32.4%) and the median DOR was 13.5 months (95% CI, 9.6-27.4). Those with positive PD-L1 expression had an ORR of 27.6% (95% CI, 18.0%-39.1%) and a median DOR of 24.8 months (95% CI, 10.0-not reached) compared with 24.2% (95% CI, 16.0%-34.1%) and 12.4 months (95% CI, 4.334.6) in those with negative expression.

“Although efficacy was lower in cohort A1 than in cohort A, encouraging clinical activity was observed regardless of tumor PD-L1 expression in cohort A1 overall as well as in subgroups,” Ready et al wrote.

Any-grade TRAEs were observed in 68.2% of all patients, with 29.3% of events being grade 3/4. TRAEs led to a treatment discontinuation in 16.2% of patients.

The most common grade 3/4 imAEs overall were diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%).

“Safety in the overall cohort A1, as well as in the ECOG PS 2 and untreated brain metastases subgroups, was comparable with that in cohort A,” the study authors noted. “Taken together, these findings for the first time prospectively demonstrate promising efficacy in these patient populations of high unmet need.”

References

1. Ready NE, Audigier-Valette C, Goldman JW, et al. First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817. J Immunother Cancer. 2023;11(2):e006127. doi:10.1136/jitc-2022-006127

2. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18(1):31-41. doi:10.1016/S1470-2045(16)30624-6

3. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

4. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) as first-line treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1≥1%. News release. Bristol Myers Squibb. May 15, 2020. Accessed February 23, 2023. https://bit.ly/3IACCoi