Relationship of PD-L1 and a T-cell inflamed gene expression profile (GEP) to clinical response in a multicohort trial of solid tumors (KEYNOTE [KN]028)

Abstract

Background: Antibodies targeting the PD-1 pathway have shown durable clinical benefit in multiple cancers. In the KN028 trial, the antitumor activity and safety of pembrolizumab were investigated in 20 solid tumors. Associations between PD-L1 expression and a T-cell inflamed GEP with response to anti-PD-1 therapy were also evaluated. Method(s): KN028 is a nonrandomized, phase 1b multicenter trial in patients with PDL1 positive (>=1%, modified proportion score or interface pattern, QualTek IHC) advanced solid tumors treated with pembrolizumab 10 mg/kg Q2W for =1 dose of pembrolizumab and had measurable disease. Secondary endpoints included safety, PFS and OS. ORR by central radiology review (IRC). Exploratory endpoints included relationships between GEP score (FFPE extracted RNA analyzed on NanoString nCounter) and PD-L1 expression levels (combined positive score, Dako IHC) with ORR and PFS. Data cutoff date was Feb 20, 2017. Result(s): In the total study population (N=475), there were 66 responders among 471 evaluable patients. ORR (95% CI) by INV ranged from 4.2% (0.1, 21.1) to 33.3% (15.6, 55.3) in 19/20 tumor types; no responders were observed in pancreatic carcinoma. ORR>10% was observed in 13/20 types (58/66 responders). ORR (95% CI) by IRC ranged from 4.3% (0.1, 21.9) to 26.3% (9.1, 51.2) in 18/20 tumor types. Treatment related AEs occurred in 65.5% of patients (14.1% grade 3-5). PD-L1 expression (p=0.034) and GEP (p=0.012) were associated with ORR in meta-analysis across tumors. Data for PFS, OS and relationships between PD-L1, GEP and MSI status with ORR will also be presented. Conclusion(s): Pembrolizumab demonstrated favorable responses and manageable toxicity in the majority of the tumor types in KN028. Both PD-L1 and GEP score were predictive of clinical response, suggesting the utility of these biomarkers in selecting patients for immunotherapy and other novel therapies across a wide spectrum of tumor histologies.