Five-Year Data Support Pembro + CRT for NSCLC

Pembrolizumab plus concurrent chemoradiotherapy shows ongoing antitumor activity after about 5 years of follow-up in patients with unresectable, locally advanced, stage III non–small cell lung cancer (NSCLC), according to final results from the phase 2 KEYNOTE-799 trial.

The findings support continued investigation of this regimen, and phase 3 of the trial is in progress, first author Martin Reck, MD, PhD, reported at the European Lung Cancer Conference 2025.

Study participants were adults aged 18 years or older with unresectable stages IIIA-C NSCLC and adequate pulmonary function assigned to either Cohort A, which included patients with either squamous or nonsquamous disease histology, or Cohort B, which included only those with nonsquamous histology.

Those in Cohort A received 200 mg pembrolizumab plus carboplatin plus paclitaxel every 3 weeks for cycle one, followed by 200 mg pembrolizumab every 3 weeks plus carboplatin and paclitaxel and standard thoracic radiotherapy for cycles two and three. Cohort B received three cycles of 200 mg pembrolizumab every 3 weeks plus cisplatin and pemetrexed, with standard thoracic radiotherapy in cycles two and three. Both cohorts received 14 additional cycles of pembrolizumab.

At a median follow-up of 59.2 months and 54.4 months, the overall response rate (ORR) — a primary endpoint of the study — was 71.4% among 112 patients in Cohort A and 75.5% among 102 patients in Cohort B, respectively, said Reck, head of the department of thoracic oncology and of the clinical trial department in the Department of Thoracic Oncology at the LungenClinic Grosshansdorf, Grosshansdorf, Germany.

The ORR in Cohort A was slightly higher among patients with programmed death ligand 1 (PD-L1) expression (greater than 75% vs greater than 65% ORRs for PD-L1–positive and PD-L1–negative patients, respectively), but no significant difference was seen based on PD-L1 expression in Cohort B.

Median progression-free survival (PFS) was 29.0 and 45.3 months, and overall survival was 35.6 and 56.7 months in Cohorts A and B, respectively, Reck said.

The 5-year outcomes are similar to those seen at 4 years and reported at the 2024 American Society of Clinical Oncology conference. At 4 years, the ORRs were 71.4% vs 74.5%, median PFS was 29.0 vs 37.9 months, and median OS was 35.6 months vs not reached in Cohorts A and B, respectively.

For the primary safety endpoint of grade 3 or higher treatment-related adverse events, the rates at 5 years were 65.2% and 51.0% in Cohorts A and B, respectively.

Grade 3 pneumonitis occurred in 8.0% and 6.9% of patients in the cohorts, respectively, which was the “quite encouraging” and unchanged from the primary analysis, he noted.

“The safety was manageable, and we couldn’t see any new safety events appearing with the simultaneous chemo-immuno-radiotherapy,” he added. 

Invited discussant Sara Ramella, MD, professor of radiation oncology at Campus Bio-Medico University, Rome, Italy, pointed out that the pneumonitis incidence in KEYNOTE-799 did not differ much from that seen in nonimmunotherapy trials, which is encouraging, but she urged attention to “the technique used and the application of innovative constraints” to reduce the risk for lung damage.

She also noted a need for further research on the influence of radiotherapy modality on outcomes in patients treated with concurrent immunotherapy and chemoradiotherapy, as factors such as volumes, doses, and technique may influence patients’ immune response and therefore their response to immunotherapy. 

KEYNOTE-799 was funded by Merck Sharp & Dohme LLC. Reck reported receiving personal fess from Accord, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Beigene, Biontech, Daiichi-Sankyo, GSK, Eli Lilly, Serck Serono, Mirati, Merck Sharp & Dhome LLC, Novartis, PharmaMar, Regeneron, Rocke, and Pfizer. Ramella disclosed financial relationships with AstraZeneca, Roche, Merck, Amgen, Tema Sinergie, and Elekta.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at [email protected] or on X: @SW_MedReporter.