Pembrolizumab and Chemoradiation Deliver Durable Responses in Stage III NSCLC

The immunotherapy combination of pembrolizumab (Keytruda) plus concurrent chemoradiation therapy (cCRT) continued to deliver durable responses and a manageable safety profile among patients with unresectable, locally advanced, stage III non–small cell lung cancer (NSCLC), according to data from the final analysis of the phase 2 KEYNOTE-799 trial (NCT03631784) presented during the 2025 European Lung Cancer Congress.¹

In cohort A (n=112), which comprised patients with squamous or nonsquamous NSCLC, pembrolizumab plus chemoradiation led to an overall response rate (ORR) of 71.4% (95% CI, 62.1%-79.6%). This included a complete response (CR) rate of 3.6% and a partial response (PR) rate of 67.9%.

The median time to response (TTR) was 2.1 months (range, 1.1-20.7), and the median duration of response (DOR) was 44.4 months (range, 1.9 + to 60.1+), with 46.2% of patients experiencing a response that lasted for at least 48 months. Moreover, the median progression-free survival (PFS) was 29.0 months (95% CI, 16.6-48.5), and the 48-month PFS rate was 38.9%; the median overall survival (OS) was 35.6 months (95% CI, 26.1-44.2), and the 48-month OS rate was 40.2%.

In cohort B (n = 61), which included only patients with nonsquamous NSCLC, pembrolizumab plus chemoradiation induced an ORR of 75.5% (95% CI, 66.0%-83.5%), which included a CR rate of 5.9% and a PR rate of 69.6%.

The median TTR was 2.1 months (range, 0.510.5), and the median DOR in this group was 48.5 months (range, 1.8 + to 60.0+), with 51.5% of patients experiencing a response that lasted for 48 months or longer. Additionally, the median PFS was 45.3 months (95% CI, 17.9-not reached [NR]), and the 48-month PFS rate was 46.3%. The median OS was 56.7 months (95% CI, 41.1-NR), and the 48-month OS rate was 54.7%.

“Pembrolizumab plus cCRT continued to show robust and durable antitumor activity after approximately 5 years of follow-up in patients with unresectable, locally advanced, stage III NSCLC,” Martin Reck, MD, PhD, of Airway Research Center North, German Center for Lung Research, in Grosshansdorf, Germany, said in a presentation of the data.

KEYNOTE-799 Study

The nonrandomized, open-label, interventional study enrolled patients (n = 216) with previously untreated, unresectable stage IIIA to IIIC NSCLC and had measurable disease by RECIST 1.1 criteria.

Those enrolled in cohort A received 200 mg of pembrolizumab every 3 weeks plus 200 mg/m² of paclitaxel every 3 weeks with area under the curve (AUC) 6 mg/mL/min of carboplatin every 3 weeks for cycle 1; 200 mg of pembrolizumab every 3 weeks plus 45 mg/m² once weekly with AUC 2 mg/mL/min of carboplatin once weekly and standard thoracic radiotherapy for cycles 2 to 3; and 200 mg of pembrolizumab every 3 weeks for cycles 4 to 17.

Those in cohort B were given 200 mg of pembrolizumab every 3 weeks plus 500 mg/m² every 3 weeks and 75 mg/m² of cisplatin every 3 weeks for cycle 1; 200 mg of pembrolizumab every 3 weeks plus 500 mg/m² every 3 weeks and 75 mg/m² of cisplatin every 3 weeks and standard thoracic radiotherapy for cycles 2 and 3; and 200 mg of pembrolizumab every 3 weeks for cycles 4 to 17.

The study’s primary end points were ORR by RECIST 1.1 and blinded independent central review (BICR), and incidence of grade 3 or higher pneumonitis. Secondary end points comprised PFS by RECIST 1.1 and BICR, OS, and safety.

Previous data from the study showed that at approximately 4 years of follow-up, the ORR, median PFS, and median OS in cohort A were 71.4% (95% CI, 62.1%-79.6%), 29.0 months (95% CI, 16.6-48.5), and 35.6 months (95% CI, 26.1-44.2).2 In cohort B, the ORR, median PFS, and median OS were 74.5% (95% CI, 64.9%-82.6%), 37.9 months (95% CI, 17.9-NR), and NR (95% CI, 41.1-NR).

Revisiting the Final Analysis

The median follow-up in cohorts A and B was 59.2 months (range, 54.3-64.5) and 54.4 months (range, 43.5-64.2).¹ Of the 112 patients in cohort A who started treatment, 44 completed treatment and 68 discontinued treatment; the most common reason for discontinuation was adverse effect (AE; n = 41).

Further, of the 102 patients in cohort B who started treatment, 54 completed treatment and 48 discontinued; the most common reason for discontinuation in this group was also AE (n = 24).

The median age at baseline in cohorts A and B was 66 years (range, 46-90) and 64 years (range, 35-81). More than half of patients were male (67.9%; 60.8%), White (79.5%; 72.5%), not from the east Asia geographic region (88.4%; 90.2%), and current or former smokers (94.6%; 95.1%).

In cohort A, 54.5% of patients had an ECOG performance status of 1; 44.1% of those in cohort B had this status.

In cohort A, 36.6% of patients had stage IIIA disease, 56.3% had stage IIIB disease, and 7.1% had stage IIIC disease; in cohort B, these respective rates were 38.2%, 41.2%, and 20.6%. In cohort A, the PD-L1 tumor proportion score (TPS) was less than 1% for 18.8% of patients and 1% or higher for 58.9% of patients; in cohort B, 27.5% and 39.2% of patients had a PD-L1 TPS of under 1% and 1% or higher, respectively.

Additional Efficacy Data

In cohort A, those with a PD-L1 TPS under 1% (n = 21) experienced an ORR of 66.7%; those with a TPS of 1% or higher (n = 66) experienced an ORR of 77.3%. Within this cohort, those with squamous disease (n = 75) experienced an ORR of 72.0%, and those with nonsquamous disease (n = 37) had an ORR of 70.3%. In cohort B, those with a PD-L1 TPS under 1% (n = 28) and 1% or higher (n = 40) experienced ORRs of 78.6% and 72.5%, respectively. Those with nonsquamous disease (n = 102) had an ORR of 75.5%.

Safety Spotlight

The median treatment duration was 9.1 months (range, 0.03-14.06) in cohort A and 11.0 months (range, 0.03-13.54) in cohort B. In cohort A, 8.0% of patients experienced grade 3 to 5 pneumonitis. Treatment-related AEs (TRAEs) were experienced by 93.8% of patients, with 65.2% of cases grade 3 to 5 in severity. TRAEs led to discontinuation of any therapeutic component for 33.9% of patients and proved fatal for 3.6% of patients.

Immune-mediated AEs and infusion reactions occurred in 59 (52.7%) patients in cohort A and 46 (45.1%) patients in cohort B; these AEs led to discontinuation of any component for 19.6% of patients and proved fatal for 3.6% of patients.

In cohort B, 8.0% of patients experienced grade 3 to 5 pneumonitis. TRAEs were reported in 97.1% of patients, with 51.0% of these effects grade 3 to 5 in severity. TRAEs led to discontinuation of any agent or proved fatal for 20.6% and 1.0%, respectively. Immune-mediated and infusion reactions were reported in 45.1% of patients, with 8.8% of these effects grade 3 to 5 in severity. Immune-mediated AEs led to discontinuation of any component or proved fatal for 12.7% and 1.0% of patients, respectively.

The most common TRAEs to occur in at least 20% of patients and the most frequent immune-mediated AEs experienced by at least 1% of patients are listed in TABLES 1 and 2.¹

“These results support continued investigation of pembrolizumab plus cCRT in patients with unresectable, locally advanced, stage III NSCLC,” Reck concluded.

REFERENCES:

1. Reck M, Lee KH, Frost N, et al. Pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in unresectable locally advanced non-small cell lung cancer (NSCLC): final analysis of KEYNOTE-799. J Thorac Oncol. 2025;20(3):S124-S125. doi:10.1016/S1556-0864(25)00380-6

2. Reck M, Lee KH, Forst N, et al. Four-year outcomes and circulating tumor DNA (ctDNA) analysis of pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in unresectable, locally advanced, stage III non–small-cell lung cancer (NSCLC): from KEYNOTE-799. J Clin Oncol. 2024;42(suppl 16):8057. doi:10.1200/JCO.2024.42.16_suppl.8057