KEYNOTE-867: A Phase III, Randomized, Double-Blind Study of Stereotactic Body Radiotherapy With Pembrolizumab for Unresected Stage I or II Non–Small Cell Lung Cancer

Purpose Stereotactic body radiotherapy (SBRT) is standard of care for inoperable stage I or II non–small cell lung cancer (NSCLC). KEYNOTE-867 (ClinicalTrials.gov identifier: NCT03924869 ) evaluated the addition of pembrolizumab to SBRT in participants diagnosed with stage I or II NSCLC that was inoperable or in participants who refused surgery. Methods Adults with untreated, stage I or II (T1 to limited T3, N0, M0) NSCLC (AJCC 8 th edition) that was inoperable, or adults who refused surgery, were randomly assigned 1:1 to thoracic SBRT to primary tumors for ≤2 weeks concomitantly with pembrolizumab 200 mg or placebo once every 3 weeks for ≤17 cycles. The primary end point was event-free survival (EFS) by blinded independent central review. Results A total of 448 participants were randomly assigned to SBRT plus pembrolizumab (n = 227) or SBRT plus placebo (n = 221). The median time from random assignment to the data cutoff date (June 11, 2024) for the prespecified first interim analysis was 20.6 (range, 1.3-56.8) months. The median EFS (95% CI) was 31.2 (22.5 to 39.1) months and 28.3 (19.8 to 33.1) months for the pembrolizumab and placebo arms, respectively (hazard ratio, 0.92 [95% CI, 0.69 to 1.24]; P = .2932). Among participants who received ≥1 dose of study treatment, grade 3-5 treatment-related adverse events (AEs) occurred in 46/226 (20.4%) participants in the pembrolizumab arm and 8/218 (3.7%) participants in the placebo arm. There were five treatment-related deaths all of which occurred in the pembrolizumab arm (2.2%). Conclusion The addition of pembrolizumab to SBRT did not improve EFS and was associated with a higher incidence of treatment-related AEs compared with SBRT alone in participants with inoperable stage I or II NSCLC. Based on the benefit-risk profile, the KEYNOTE-867 trial was prematurely stopped, and all study treatment was discontinued.