Association of RNA-sequencing signatures with clinical outcomes of pembrolizumab + chemotherapy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) enrolled in the phase 2 KEYNOTE-782 trial.
Authors: Enriqueta Felip, Santiago Ponce Aix, Jair Bar, Emilio Esteban, Delvys Rodriguez-Abreu, Tibor Csőszi, Maya Gottfried, Zsuzsanna Szalai, Mariano Provencio, Andrea Fülöp, Suman Rao, David Ross Camidge, Giovanna Speranza, Scott K. Pruitt, Steven Matthew Townson, Julie Kobie, E.J. Dettman, Andrey Loboda, Michael Nebozhyn, Andrew George Robinson
Journal: Journal of Clinical Oncology (2024)

8578 Background: KEYNOTE-782 (NCT03664024) was a single-arm phase 2 study designed to assess possible biomarkers of response (objective response rate [ORR]) to first-line pembrolizumab + chemotherapy (pemetrexed + carboplatin or cisplatin) in patients with previously untreated metastatic nonsquamous NSCLC. Herein, we examined relationships between the T-cell–inflamed gene expression profile (Tcell inf GEP) and other tumor microenvironment consensus signatures and efficacy of pembrolizumab + chemotherapy in an exploratory analysis of KEYNOTE-782. Methods: All patients were to receive pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m 2 Q3W, and 4 Q3W cycles of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m 2 . Using tumor samples, RNA sequencing was used to measure expression of the Tcell inf GEP and 10 non-Tcell inf GEP signatures (angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, and WNT). The association between each signature and clinical outcomes was analyzed using logistic regression (ORR) and Cox proportional hazards regression (progression-free survival [PFS] and overall survival [OS]); the prespecified significance level was α = 0.05 for Tcell inf GEP (hypothesized positive association) and α = 0.10 for non-Tcell inf GEP signatures (hypothesized negative associations). The clinical utility of Tcell inf GEP was descriptively assessed using a prespecified cutoff of the first tertile. The clinical database cutoff was November 5, 2021. Results: Of 117 patients enrolled, 69 (59.0%) had evaluable RNA-sequencing data. Tcell inf GEP was not associated with ORR ( P = 0.183), PFS ( P = 0.071), or OS ( P = 0.142); the area under the receiver operating characteristic curve for discriminating response was 0.56 (95% CI, 0.42-0.71). None of the 10 non-Tcell inf GEP consensus signatures showed a statistically significant association with clinical outcomes after adjusting for Tcell inf GEP (multiplicity adjusted P &gt; 0.10). ORR and median PFS were comparable in the Tcell inf GEP low and nonlow subgroups; there was a trend towards longer OS in the nonlow subgroup (Table). Conclusions: In this exploratory analysis of patients with metastatic nonsquamous NSCLC, none of the RNA-sequencing signatures evaluated were associated with clinical outcomes of pembrolizumab + chemotherapy. There was little evidence of clinical utility of Tcell inf GEP when evaluated as a dichotomous variable. Data support the use of pembrolizumab + chemotherapy as first-line therapy for patients with nonsquamous NSCLC regardless of consensus signature status. Clinical trial information: NCT03664024 . [Table: see text]