As reported in The Lancet Oncology by O’Brien et al, the second interim analysis of the phase III PEARLS/KEYNOTE-091 trial has shown significantly improved disease-free survival with adjuvant pembrolizumab vs placebo in patients with completely resected stage IB to IIIA non-small cell lung cancer (NSCLC) irrespective of PD-L1 expression status, with a numeric improvement among patients with a PD-L1 tumor proportion score (TPS) of ≥ 50%.

Study Details

In the triple-blind study, 1,177 patients with any PD-L1 expression status from sites in 29 countries were randomly assigned between January 2016 and May 2020 to receive pembrolizumab at 200 mg (n = 590) or placebo (n = 587) every 3 weeks for up to 18 cycles. Adjuvant chemotherapy was not mandatory; however, it was to be considered for patients with stage IB disease and was strongly recommended for those with stage II and IIIA disease, according to national and local guidelines; a maximum of four cycles was permitted. The dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 TPS ≥ 50%, with analysis performed in the intention-to-treat population. The TPS ≥ 50% population consisted of 168 patients in the pembrolizumab group and 165 patients in the placebo group.

Disease-Free Survival

Median follow-up at data cutoff (in September 2021) for the second interim analysis was 35.6 months (interquartile range = 27.1–45.5 months). Overall, adjuvant chemotherapy was received by 86% of patients in both groups in the total population and by 85% of both groups in the TPS ≥ 50% population.

In the overall population, median disease-free survival was 53.6 months (95% confidence interval [CI] = 39.2 months–not reached) in the pembrolizumab group vs 42.0 months (95% CI = 31.3 months–not reached) in the placebo group (HR = 0.76, 95% CI = 0.63–0.91, P = .0014).

In the TPS ≥ 50% population, disease-free survival events were observed in 32% of the pembrolizumab group and 38% of the placebo group. Median disease-free survival was not reached (95% CI = 44.3 months–not reached) in the pembrolizumab group vs not reached (95% CI = 35.8 months–not reached) in the placebo group (HR = 0.82, 95% CI = 0.57–1.18, P = .14).

As of data cutoff, death had occurred in 98 patients (17%) in the total pembrolizumab group and 111 patients (19%) in the total placebo group (HR = 0.87, 95% CI = 0.67–1.15, P = .17).

Adverse Events

Grade ≥ 3 adverse events occurred in 34% of patients in the pembrolizumab group vs 26% of the placebo group. The most common were hypertension (6%) and pneumonia (2%) in the pembrolizumab group and hypertension (6%) in the placebo group. Serious adverse events occurred in 24% vs 15% of patients, most commonly pneumonia (2%) and pneumonitis (2%) in the pembrolizumab group and pneumonia (2%) in the placebo group. Adverse events led to treatment discontinuation in 20% vs 6% of patients. Adverse events led to death in 11 patients (2%) in the pembrolizumab group and 6 patients (1%) in the placebo group. Death was considered related to treatment in four patients in the pembrolizumab group (due to cardiogenic shock and myocarditis in one, septic shock and myocarditis in one, pneumonia in one, and sudden death in one) and in no patients in the placebo group.

The investigators concluded, “Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in [patients with] completely resected, PD-L1–unselected, stage IB to IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB to IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression.”

Mary O’Brien, MD, of the Lung Unit, Royal Marsden Hospital, London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.