Nivolumab/CCRT Followed by Nivolumab/Ipilimumab Misses PFS End Point in Select Stage III NSCLC

The addition of nivolumab (Opdivo) to concurrent chemoradiation (CCRT) followed by consolidation with nivolumab plus ipilimumab (Yervoy) did not significantly improve progression-free survival (PFS) over CCRT followed by durvalumab (Imfinzi) in patients with locally advanced, unresectable stage III non–small cell lung cancer (NSCLC), according to data from the phase 3 CheckMate 73L study (NCT04026412).

The data, which were presented during the 2024 ESMO Immuno-Oncology Annual Congress, showed that the median PFS in the nivolumab arm (n = 287; arm A) was 16.7 months (95% CI, 12.6-22.0) vs 15.6 months (95% CI, 13.7-19.8) in the control arm (n = 318; arm C; HR, 0.95; 95% CI, 0.77-1.19; P = .6460), missing the trial’s primary end point.

When broken down by PD-L1 expression, those in arm A (n = 90) or arm C (n = 93) who had a PD-L1 expression under 1% had a median PFS of 15.2 months (95% CI, 9.8-22.0) and 14.2 months (95% CI, 11.8-24.8), respectively (HR, 1.14; 95% CI, 0.78-1.65). Those in arm A (n = 175) or arm C (n = 195) who had a PD-L1 expression of 1% or higher had a median PFS of 16.9 months (95% CI, 11.9-25.1) and 14.3 months (95% CI, 11.1-20.0), respectively (HR, 0.85; 95% CI, 0.65-1.11). Lastly, those in arm A (n = 83) or arm C (n = 97) who had a PD-L1 expression of 50% or higher experienced a median PFS of 25.5 months (95% CI, 12.9-not reached [NR]) and 19.4 months (95% CI, 11.2-25.0), respectively (HR, 0.74; 95% CI, 0.50-1.11).

At a median follow-up of 30.5 months (range, 16.0-52.5), the median overall survival (OS) in arm A was 34.6 months (95% CI, 26.8-NR) vs 40.2 months (95% CI, 30.5-NR) in arm C (HR, 1.12; 95% CI, 0.87-1.43). The respective objective response rates (ORRs) were 68% (95% CI, 62%-73%) and 64% (95% CI, 59%-70%).

“These results emphasize the need to investigate novel efficacious treatment options for patients with unresectable stage III NSCLC and to inform future clinical research,” Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois (CHUV), in Lausanne, Switzerland, said in a presentation on the data.

The CheckMate 73L enrolled patients with stage III amenable to CCRT who did not previously receive systemic treatment and had an ECOG performance status 0 or 1. The study participants (n = 925) were randomly assigned 1:1:1 to arm A, B, or C. Those in arm A received nivolumab at 360 mg every 3 weeks plus chemotherapy every 3 weeks and radiation at 60 to 66 Gy, recovered for 3 to 6 weeks, and received consolidation treatment with nivolumab at 360 mg every 3 weeks and ipilimumab at 1 mg/kg every 6 weeks for up to 1 year. Those in arm B were given nivolumab at 360 mg every 3 weeks plus chemotherapy every 3 weeks and radiation at 60 to 66 Gy followed by a recovery period ranging from 3 to 6 weeks and consolidation treatment with nivolumab at 480 mg every 4 weeks up to 1 year. Those in arm C received chemotherapy every 3 weeks followed by radiation at 60 to 66 Gy, 3 to 6 weeks of recovery, and then durvalumab at 10 mg/kg every 2 weeks for up to 1 year.

In addition to the primary end point of the study being PFS by blinded independent central review for arm A vs arm C. Key secondary end points include OS for arm A vs arm C and for arm B vs arm C, as well as PFS for arm B vs arm C. Investigators also evaluated ORR for arm A vs arm C and for arm B vs arm C, as well as safety.

Baseline patient characteristics were generally balanced between the arms.

A total of 925 patients underwent randomization; 287 comprised arm A, 320 comprised arm B, and 318 comprised arm C. In arm A, 98.3% received CCRT, and 78% of those patients later received consolidation; 103 total patients completed treatment, and 3 patients were still receiving treatment at data cutoff. In arm B, 99.4% of patients received CCRT and 83% of those patients went on to receive consolidation; a total of 138 patients completed treatment and 4 patients were still receiving treatment at cutoff. Lastly, in arm C, 99.7% of patients received CCRT with 82% of those patients going on to receive consolidation; 144 total patients completed treatment and 2 were still receiving treatment at cutoff.

Additional efficacy data showed that the median PFS in arm B was 17.4 months (95% CI, 14.1-22.1) vs 15.6 months (95% CI, 13.7-19.8) in arm C (HR, 0.84; 95% CI, 0.69-1.04). The median OS in the respective arms was 39.5 months (95% CI, 31.6-NR) and 40.2 months (95% CI, 30.5-NR), respectively (HR, 0.97; 95% CI, 0.76-1.24). The ORR in arm B was 72% (95% CI, 67%-77%) vs 64% (95% CI, 59%-70%) in arm C.

In arms A, B, and C, disease progression occurred in 39%, 40%, and 46% of patients, respectively. Peters noted that the most common sites of distant metastases were the brain, liver, bone, and adrenal gland spanning the treatment arms.

“No new safety signals were observed with nivolumab or ipilimumab, although concurrent immunotherapy and CRT resulted in increased pneumonitis,” Peters said.

In arm A, adverse effects (AEs) occurred at any grade in 99% of patients and at grade 3 or 4 in 68% of patients. Any-grade and grade 3 or 4 AEs led to discontinuation for 25% and 16% of patients, respectively; any-grade and grade 3 or 4 serious AEs occurred in 55% and 36% of patients. Any-grade or grade 3/4 treatment-related AEs (TRAEs) were experienced by 95% and 57% of patients and they led to discontinuation for 22% and 14% of patients. Treatment-related SAEs occurred in 33% and 22% of patients, respectively.

In arm C, any-grade and grade 3 or 4 AEs occurred in 98% and 58% of patients, respectively; they led to discontinuation in 18% and 12% of patients. SAEs were reported in 43% and 28% of patients. TRAEs of any grade were experienced by 96% of patients; grade 3 or 4 TRAEs occurred in 49% of patients. Any-grade and grade 3/4 TRAEs led to discontinuation for 13% and 8% of patients, respectively. Any-grade treatment-related SAEs occurred in 23% and grade 3 or 4 SAEs were reported in 17% of patients.

The most common any-grade TRAEs reported in arm A, B, and C, respectively were nausea (29%; 26%; 31%), esophagitis (25%; 26%; 22%), anemia (35%; 32%; 36%), decreased white blood cell count (22%; 22%; 20%), decreased neutrophil count (18%; 21%; 17%), pneumonitis (22%; 25%; 14%), and fatigue (16%; 15%; 20%).

Treatment-related deaths occurred in 3% of those in arm A, 3% of those in arm B, and less than 1% of those in arm C. Fifteen treatment-related deaths were because of pneumonitis. Other causes included sepsis (n = 2), infection (n = 2), cardiac arrest (n = 1), tumor invasion of blood vessels (n = 1), and cytokine release syndrome (n = 1).

Disclosures: Dr Peters received consultancy feeds from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-star, Foundation Medicine, Genmab, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Qlucore, MSD, Merck Serono, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks. Honoraria was received from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, MSD, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda. She is a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, Arcus, AstraZeneca, BeiGene, Bristol Myers Squibb, Eli Lilly, GSK, iTeos, MSD, Mirati, PharmaMar, Promontory Therapeutics, Roche/Genentech, and Seattle Genetics. Travel or meeting support was provided by AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda.

Reference

Peters S, Tan DSW, Gerber DE, et al. CheckMate 73L: phase 3 study comparing nivolumab + concurrent chemoradiotherapy followed by nivolumab ± ipilimumab vs concurrent chemoradiotherapy followed by durvalumab for previously untreated, locally advanced stage III NSCLC. Presented at: 2024 ESMO Immuno-Oncology Annual Congress; December 11-13, 2024; Geneva, Switzerland. Abstract 650.