Pembrolizumab improves DFS in completely resected stage IB–IIIA NSCLC

Adjuvant pembrolizumab significantly improves disease-free survival (DFS) vs placebo in patients with completely resected, PD-L1–unselected, stage IB–IIIA non-small-cell lung cancer (NSCLC), a second interim analysis of the triple-blind phase III PEARLS/KEYNOTE-091 trial has shown.

According to the investigators, the results support pembrolizumab as a potential new treatment option for stage IB (tumours ≥4 cm in diameter), stage II or stage IIIA NSCLC after complete resection and, when recommended by national or local guidelines, adjuvant chemotherapy, regardless of PD-L1 expression. [Lancet Oncol 2022;doi:10.1016/S1470-2045(22)00518-6]

The trial included 1,177 patients (median age, 65 years; male, 68 percent; Eastern Cooperative Oncology Group performance status, 0 or 1) who were randomized 1:1 to receive pembrolizumab (n=590) or placebo (n=587) Q3W for up to 18 cycles. Of these patients, 333 had PD-L1 tumour proportion score (TPS) ≥50 percent (pembrolizumab group, n=168; placebo group, n=165). Most patients received 3–4 cycles of adjuvant chemotherapy (overall population, 80 percent in both groups; PD-L1 TPS ≥50 percent population, 80 percent vs 81 percent in the pembrolizumab vs placebo group), as per national or local guidelines, which suggested that adjuvant chemotherapy be considered for stage IB disease and strongly recommended adjuvant chemotherapy for stage II and stage IIIA disease.

The trial’s dual primary endpoints were DFS in the overall population and DFS in the PD-L1 TPS ≥50 percent population.

After a median follow-up of 35.6 months, median DFS was 53.6 months in the pembrolizumab group vs 42.0 months in the placebo group (hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.63–0.91; p=0.0014).

In the PD-L1 TPS ≥50 percent population, median DFS was not reached in either group, with no significant difference observed between the two groups (HR, 0.82; 95 percent CI, 0.57–1.18; p=0.14).

According to the investigators, the unexpected absence of DFS benefit for pembrolizumab in the PD-L1 TPS ≥50 percent population could be due to overperformance of the placebo group. In both the pembrolizumab and placebo groups, median DFS was numerically improved in patients with PD-L1 TPS ≥50 percent compared with those with PD-L1 TPS of 1–49 percent and <1 percent. “Longer follow-up will determine whether or not a significant difference in DFS emerges in the PD-L1 TPS ≥50 percent population,” they suggested.

Median overall survival was not reached in either group in the overall population (HR, 0.87; 95 percent CI, 0.67–1.15; p=0.17). At the time of data cut-off, 17 percent of pembrolizumab recipients and 19 percent of placebo recipients had died.

No new safety signals were identified in the current analysis.

In the overall population, grade ≥3 adverse events (AEs) occurred in 34 percent of pembrolizumab recipients vs 26 percent of placebo recipients. These AEs included hypertension (6 percent) and pneumonia (2 percent) in the pembrolizumab group, and hypertension (6 percent) and increased body weight (2 percent) in the placebo group, none of which were of greater risk in one treatment group than the other.

Serious AEs occurred in 24 percent vs 15 percent of pembrolizumab vs placebo recipients in the overall population. These events included pneumonia (2 percent), pneumonitis (2 percent) and diarrhoea (1 percent) in the pembrolizumab group, and pneumonia (2 percent) in the placebo group. “There was a greater risk of diarrhoea in the pembrolizumab vs placebo group,” the investigators noted.

Treatment-related AEs led to death in four patients (1 percent) treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death), and none of the patients treated with placebo.

According to the investigators, the results add to the evidence base supporting immune checkpoint inhibitors as adjuvant therapy in NSCLC. [Lancet 2021;398:1344-1357]