As reported in the Journal of Clinical Oncology by Yang et al, the phase III KEYNOTE-789 trial has shown no significant improvement in progression-free or overall survival with the addition of pembrolizumab to pemetrexed/platinum in EGFR tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant metastatic nonsquamous non–small cell lung cancer (NSCLC).
Study Details
In the global double-blind trial, 492 patients were randomly assigned between July 2018 and August 2020 to receive pembrolizumab plus pemetrexed/platinum (n = 245) or placebo plus pemetrexed/platinum (n =247). Treatment consisted of 35 cycles of pembrolizumab at 200 mg or placebo every 3 weeks plus pemetrexed at 500 mg/m2 and investigator’s choice of cisplatin at 75 mg/m2 or carboplatin at AUC 5 every 3 weeks for four cycles followed by pemetrexed at 500 mg/m2 maintenance therapy.
Overall, 61% of patients were from East Asia. The primary endpoints were progression-free survival and overall survival. Final progression-free survival testing was performed at the second interim analysis (data cutoff in December 2021), and overall survival was tested at final analysis (data cutoff in January 2023). Efficacy boundaries were P = .0117 for both progression-free and overall survival.
Progression-Free and Overall Survival
At median time from random assignment to data cutoff of 28.6 months (95% confidence interval [CI] = 16.0–40.4 months), the median progression-free survival was 5.6 months (95% CI = 5.5–5.8 months) in the pembrolizumab group vs 5.5 months (95% CI = 5.4–5.6 months) in the control group (hazard ratio [HR] = 0.80, 95% CI = 0.65–0.97, P = .0122, failing to meet the efficacy boundary). Rates at 6, 12, and 24 months were 42.8% vs 32.6%, 14.0% vs 10.2%, and 4.7% vs 3.5%, respectively.
At median time from random assignment to data cutoff of 42.0 months (range = 29.5–53.9 months), the median overall survival was 15.9 months (95% CI = 13.7–18.8 months) in the pembrolizumab group vs 14.7 months (95% CI = 12.7–17.1 months) in the control group (HR = 0.84, 95% CI = 0.69–1.02, P = .0362, failing to meet the efficacy boundary). Rates at 12, 24, and 36 months were 61.6% vs 59.4%, 30.6% vs 26.4%, and 14.6% vs 11.4%, respectively.
Adverse Events
Grade ≥ 3 treatment-related adverse events occurred in 43.7% of the pembrolizumab group vs 38.6% of the control group; the most common adverse events in both groups were decreased neutrophils (22.9% vs 21.1%), anemia (12.7% vs 9.3%), and decreased white blood cell counts (10.6% vs 8.9%). Grade ≥ 3 immune-related adverse events occurred in 4.5% of the pembrolizumab group.
Treatment-related adverse events led to discontinuation of any component of treatment in 16.3% vs 11.8%. Treatment-related death occurred in one patient in the pembrolizumab group (due to myocarditis) and two patients in the control group (due to bone marrow failure and general physical health deterioration).
The investigators concluded: “[The] addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong [progression-free survival or overall survival] vs placebo plus chemotherapy in KEYNOTE-789.”
James Chih-Hsin Yang, MD, PhD, National Taiwan University Hospital and Cancer Center, Taipei, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit JCO.com.
