Pembrolizumab Produces Prolonged Survival in NSCLC With PD-L1 TPS ≥ 90%

Biagio Ricciuti, MD

Treatment with frontline pembrolizumab (Keytruda) demonstrated meaningful improvements in long-term survival in patients with EGFR- or ALK- wild-type non–small cell lung cancer (NSCLC) and a tumor proportion score (TPS) of at least 90% vs those with a TPS between 50% and 89%, according to 3-year findings from a correlative analysis presented at the 2022 ASCO Annual Meeting.

The median progression-free survival was 6.3 months (95% CI, 4.9-10.8) in the TPS of 90% or higher group vs 4.7 months (95% CI, 3.8-6.1) in the TPS of 50% to 89% group (HR, 0.69; 95% CI, 0.55-0.86; P <.001). The median overall survival was 29.0 months (95% CI, 21.0-45.3) in the TPS of 90% or more group vs 17.8 months (95% CI, 15.3-20.9) in the TPS of 50% to 89% group (HR, 0.40; 95% CI, 0.33-0.50; P <.0001).

The objective response rate in patients with a PD-L1 TPS of 50% to 89% was 32.0% vs 47.9% in those with a PD-L1 TPS of 90% or more (P <.001).

Of note, a gene mutation enrichment analysis showed that certain genomic alterations were significantly enriched in tumors with a PD-L1 TPS of 50% to 89% compared with 90% or more. Mutations in FBXW7, STK11, KEAP1, and CTNNB1 were more common in the TPS 50% to 89% group. Additionally, those with TPS or 90% or more had high rates of tumor infiltrating T-cells, including CD8-positive (P = .04) and CD8-positive/PD-1–positive (P = .02) cells.

“From this comparison, we learned that tumors with the PD-L1 expression of 90% to 100% were significantly less likely to harbor mutations in genes that have been shown previously to correlate with resistance to immunotherapy such as STK11, KEAP1, FBXW7, and others,” Biagio Ricciuti, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, and lead author of this study, said. “Overall, this suggests that these tumors with very high PD-L1 expression may have unique immunophenotypic features, in addition to the biomarker itself, and may continue to explain why these patients derive benefit from immunotherapies.”

Patients with PD-L1 TPS of 50% or greater who received frontline pembrolizumab monotherapy for advanced NSCLC were enrolled and were stratified to either the PD-L1 TPS of 50% to 89% group (n = 284) or PD-L1 TPS of 90% or more group (n = 169). The median age was 69 years (range, 35-93) in the 50% to 89% group and 70 years (30-88) in the 90% or higher group, with 51.1% vs 58.0% of patients being women, and 90.9% vs 94.7% being current or former smokers. Most patients in both groups at 80.9% vs 79.9%, respectively, had an ECOG performance score of 0 or 1. Oncogenic driver mutations observed in the TPS 50% to 89% vs TPS 90% groups were KRAS in 30.3% vs 36.1%, BRAF in 4.2% vs 3.5%, and MET in 1.7% vs 4.7%, respectively. Close to 1 in 4 patients from both group (37.7% vs 38.5%) did not have any mutations identified.

Reference

Ricciuti B, Elkrief A, Victor J, et al. Three-year outcomes and correlative analyses in patients with non–small cell lung cancer (NSCLC) and a very high PD-L1 tumor proportion score (TPS) ≥ 90% treated with first-line pembrolizumab. J Clin Oncol. 2022;40(suppl 16):9043. doi:10.1200/JCO.2022.40.16_suppl.9043