Nivolumab Plus Ipilimumab and Chemo Maintains OS Benefit in NSCLC

Treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy sustained an overall survival (OS) benefit compared with chemotherapy alone in patients with metastatic non–small cell lung cancer (NSCLC), irrespective of PD-L1 expression or histology, according to 5-year data from the phase 3 CheckMate 9LA trial (NCT03215706) presented at the 2024 ASCO Annual Meeting.¹

A greater magnitude of benefit was observed with nivolumab plus ipilimumab and chemotherapy vs chemotherapy alone in patients with [a] tumor expression of less than 1 or squamous histology,” investigators wrote in the poster presented at the meeting.

At a median follow-up of 64.5 months in the randomized CheckMate 9LA trial, the combination of nivolumab plus ipilimumab along with chemotherapy continued to show OS improvement at a rate of 18% in the experimental group vs 11% in those receiving chemotherapy alone (control group). At 5 years, 72% vs 35% of patients, respectively, were treatment-free. Investigators also reported a 5-year progression-free survival (PFS) rate of 10% in the experimental group vs 4% in the control group, and the overall response rate (ORR) was 38% vs 25%, respectively. The data cut-off was on December 15, 2023.

The median duration of response (DOR) in the experimental group was 12.4 months (95% CI, 8.7-20.2) compared with 5.6 months (95% CI, 4.4-7.1) in the control group. The 5-year DOR rates were 19% vs 8%, respectively.

Clinical outcomes demonstrated superiority for the combination compared with chemotherapy alone across subgroups stratified by tumor PD-L1 expression and histology. In the experimental group, those with a PD-L1 expression of less than 1 (n=135) showed a median OS of 17.7 months and a 5-year OS rate of 22% vs 9.8 months and a 5-year OS rate of 8% in the control group (HR 0.63, 95% CI 0.49-0.83). For those with a PD-L1 expression of 1 or greater, the median OS was 15.8 months, and the 5-year OS rate was 18% vs 10.9 months and a 5-year OS rate of 11%, respectively (HR 0.73, 95% CI 0.59-0.90).

The 5-year PFS for patients with a PD-L1 expression of 1% or less in the experimental group was 9% vs 3% in the control group and the ORR was 31% vs 20%, respectively. For those with a PD-L1 expression of 1 or greater in the experimental group the PFS was 10% vs 5% in the control group, and the ORR was 43% vs 28%, respectively.

Regarding histology, in patients with squamous NSCLC the median OS was 14.5 months in the experimental group vs 9.1 months in the control group, and with an HR of 0.63 (95% CI, 0.48-0.84). The OS rates were 18% vs 7%, respectively. For those with nonsquamous NSCLC the median OS was 17.8 months vs 12.0 months, respectively, and with an HR of 0.77 (95% CI, 0.64-0.94). The OS rates were 19% vs 12%, respectively.

There were 1150 patients included in the initial trial. Of these patients, 719 were randomly assigned 1:1, using an interactive web response system via permutated blocks, into 2 groups.2 In the experimental group (n=361), the regimen consisted of nivolumab at 360 mg administered through intravenous (IV) every 3 weeks plus ipilimumab at 1 mg/kg IV administered every 6 weeks.^1,2 This was then combined with histology-based, platinum doublet chemotherapy every 3 weeks for a duration of 2 cycles. In the control group (n=358), patients received chemotherapy alone every 3 weeks for 4 cycles.

The randomization process incorporated stratification based on tumor histology, sex, and PD-L1 expression levels.2 Maintenance pemetrexed was an option for patients with non-squamous NSCLC.¹

The trial met its primary end point of OS in the pre-planned interim analysis and in an exploratory longer-term follow-up analysis shown through these data.2 The assessments encompassed in the 5-year follow-up included OS, PFS, ORR, and efficacy by tumor PD-L1 expression.1 Exploratory analyses focused on evaluating the efficacy in patients who discontinued the combination due to treatment-related adverse events (TRAEs), as well as characterizing the clinical outcomes in 5-year survivors.

Eligible patients were treatment-naive, had no sensitizing EGFR or known ALK alterations, had histologically confirmed stage IV or recurrent NSCLC, and had an ECOG performance status of 0 or 1.

“Discontinuation of the combination due to TRAEs did not negatively affect long-term survival,” according to investigators. Of the patients who discontinued the combination (n=61) the median OS was 27.5 months, and the 5-year OS rate was 37%. This was compared with those who did not discontinue treatment of the combination (n=361), showing a median OS of 15.8 months and a 5-year OS rate of 18%.

In terms of the efficacy in 5-year survivors, the median PFS was not reached in the experimental group (95% CI, 44.8-NR) and was 16.8 months (95% CI, 7.1-NR) in the control group, and with an HR of 0.52 (95% CI,, 0.26-1.02). The 5-year PFS rate for these patients was 55% (95% CI, 39%-69%) vs 38% (95% CI, 19%-58%), and the ORR was 73% (95% CI, 58%-85%) vs 60% (95% CI, 41%-77%), respectively. The ongoing response at 5 years was 59% (95% CI, 35%-76%) in the experimental group and 46% (95% CI, 20%-69%) in the control group.

Regarding safety, investigators noted that “the incidence of grade 3 and 4 immune-mediated AEs in 5-year survivors in the nivolumab plus ipilimumab and chemotherapy group was generally low, regardless of the number of ipilimumab doses received.” Immune-mediated AE results were stratified by ipilimumab doses. For those receiving 1 to 5 doses of ipilimumab the most common grade 3 and 4 AEs were hepatitis (25%), rash (17%), pneumonitis (8%), and adrenal insufficiency (8%). For those receiving 6 to 15 doses of ipilimumab the most common grade 3 and 4 AEs, all occurring in 8% of patients each, were diarrhea/colitis, hepatitis, pneumonitis, nephritis and renal dysfunction, and adrenal insufficiency. For patients receiving 16 to18 doses of ipilimumab the only grade 3 and 4 AE reported was adrenal insufficiency in 4% of patients.

“These long-term results further support nivolumab plus ipilimumab and chemotherapy as an efficacious 1L treatment option for patients with metastatic NSCLC, particularly those with tumor PD-L1 expression less than 1% or squamous,” investigators wrote.

References:

1. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. J Clin Oncol. 2024;42(suppl 16):8560-8560. doi:10.1200/JCO.2024.42.16_suppl.8560

2. Paz-Ares L, Ciuleanu TE, 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