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.

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 > 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