Pembrolizumab Plus cCRT Elicits Durable Antitumor Activity in Unresectable Stage III NSCLC

Martin Reck, MD, PhD

Pembrolizumab (Keytruda) paired with concurrent chemoradiation (cCRT) continued to showcase antitumor activity with manageable safety in 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%), which comprised 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 just included patients with nonsquamous NSCLC, pembrolizumab plus chemoradiation induced an ORR of 75.5% (95% CI, 66.0%-83.5%), which comprised a CR rate of 5.9% and a PR rate of 69.6%. The median TTR was 2.1 months (range, 0.5-10.5) 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.

Keeping Up With KEYNOTE-799 Study: Design, Treatment, Objectives

The nonrandomized, open-label, phase 2 study enrolled patients (n = 216) with previously untreated, unresectable stage IIIA to IIIC NSCLC who were at least 18 years of age and had measurable disease by RECIST v1.1. Patients were required to have an ECOG performance status of 0 or 1, an acceptable pulmonary function test, and a tumor sample for PD-L1 evaluation. Patients could not have previously received systemic immunosuppressive therapy up to 7 days.

Those enrolled in cohort A received 200 mg of pembrolizumab given every 3 weeks (Q3W) plus 200 mg/m2 of paclitaxel Q3W with area under the curve (AUC) 6 mg/mL/min of carboplatin Q3W for cycle 1; 200 mg of pembrolizumab Q3W plus 45 mg/m2 once weekly (QW) with AUC 2 mg/mL/min of carboplatin QW and standard thoracic radiotherapy for cycles 2 to 3; and 200 mg of pembrolizumab Q3W for cycles 4 to 17. Those in cohort B were given 200 mg of pembrolizumab Q3W plus 500 mg/m2 Q3W and 75 mg/m2 of cisplatin Q3W for cycle 1; 200 mg of pembrolizumab Q3W plus 500 mg/m2 Q3W and 75 mg/m2 of cisplatin Q3W and standard thoracic radiotherapy for cycles 2 and 3; and 200 mg of pembrolizumab Q3W for cycles 4 to 17.

The primary end points of the study were ORR by RECIST v1.1 and blinded independent central review and incidence of grade 3 or higher pneumonitis. Secondary end points comprised PFS by RECIST v1.1 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 was 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 was 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). 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 52.7% of patients, with 52.7% of patients experiencing grade 3 to 5 effects; 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 included nausea (cohort A, 20.5%; cohort B, 46.1%), anemia (33.0%; 26.5%), fatigue (28.6%; 26.5%), neutropenia (28.6%; 23.5%), asthenia (13.4%; 37.3%), esophagitis (17.0%; 23.5%), pneumonitis (19.6%; 20.6%), alopecia (31.3%; 4.9%), and reduced appetite (15.2%; 21.6%). The most frequent immune-mediated AEs experienced by at least 1% of patients included pneumonitis (cohort A, 22.3%; cohort B, 23.5%), hypothyroidism (16.1%; 14.7%), hyperthyroidism (8.9%; 7.8%), infusion reactions (8.9%; 2.0%), severe skin reactions (3.6%; 1.0%), colitis (0%; 2.9%), gastritis (2.7%; 2.0%), hepatitis (1.8%; 2.0%), thyroiditis (0%; 2.0%), encephalitis (0%; 1.0%), hypophysitis (0.9%; 1.0%), and myocarditis (0.9%; 1.0%).

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

Disclosures: Dr Reck disclosed personal fees from Accord, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Beigene, Biontech, Daiichi-Sankyo, GSK, Eli Lilly, Merck Serono, Mirati, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Novartis, PharmaMar, Regeneron, Roche, and Pfizer. Research funding was provided by MSD and medical writing assistance was provided by Aisling Towell, PhD, of ICON plc and assistance was funded by MSD.

References

1. Reck M, Frost N, Breder V, 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