Abstract 4217: Tumor mutational burden (TMB), T cell-inflamed gene expression profile (GEP) and PD-L1 are independently associated with response to pembrolizumab (Pembro) in patients with advanced melanoma in the KEYNOTE (KN)-006 study
Authors: Ribas Antoni , Robert Caroline , Schachter Jacob , Long Georgina V. , Arance Ana , Carlino Matteo S. , Larkin James , Webber Andrea L. , Lunceford Jared , Zhao Qing , Cristescu Razvan , Nebozhyn Michael , Zhang Chunsheng , Blumenschein Wendy , Krepler Clemens , Ibrahim Nageatte , Daud Adil , Grob Jean-Jacques 
Published: August 2019

Abstract
Background: Biomarkers may aid in identifying pts who can benefit from checkpoint blockade therapies. Biomarkers of response to anti-PD-1 therapy include TMB and inflammatory biomarkers such as PD-L1 expression and T cell-inflamed GEP. Effects of TMB and GEP on clinical outcomes were evaluated for Pembro (anti-PD-1) and Ipi (anti-CTLA-4) monotherapies in the KN-006 study.
Methods: In this phase 3, controlled, open label study, 834 pts were randomized to receive Pembro 10 mg/kg every 2 or 3 wks or 4 doses of Ipi 3 mg/kg every 3 wks. Data were available for analysis of TMB (whole exome sequencing) in 216 pts (Pembro n=151 and Ipi n=65), for GEP (RNA, NanoString nCounter) in 641 pts (Pembro n=461 and Ipi n=180) and 134 pts had both TMB and GEP data available. All pts with TMB data and 458 pts with GEP data had PD-L1 expression data (PD-L1 IHC 22C3 pharmDx, MEL score). Statistical testing was prespecified prior to merging biomarker and clinical outcome data. Relationships between biomarkers and best overall response (BOR) were assessed by logistic regression and by area under the ROC (AUROC) curve; progression free survival (PFS) and overall survival (OS) by Cox proportional hazards regression. Prespecified cutoffs were -0.318 for GEP and 175 (mutations/exome) for TMB. Clinical data cutoff was Dec 04, 2017.
Results: TMB, GEP and PD-L1 MEL were significantly associated with BOR, PFS and OS in the Pembro arm (p&lt;0.050). Response rates to Pembro therapy were greater in pts who had high levels of both TMB ≥175 and GEP ≥-0.318 or TMB ≥175 and PD-L1 MEL ≥2 compared with those with low levels of these biomarkers (54% vs 14% and 51% vs 33%, respectively). TMB, GEP and PD-L1 MEL remained significantly associated with response to Pembro for BOR and PFS, and in general for OS, when assessed in joint models. TMB showed low correlations with GEP (0.14; p=0.057) and PD-L1 (0.22; p=0.001); GEP and PD-L1 were moderately correlated (0.60; p&lt;0.001). In Ipi-treated pts, TMB was not significantly associated with BOR (p=0.428) and trended toward significance for PFS (0.098) and OS (p=0.099); GEP was also not significantly associated with BOR (p=0.188) but was significantly associated with PFS (p=0.012) and OS (p&lt;0.001). AUROCs (95% CI) were 0.64 (0.55, 0.73) and 0.53 (0.35, 0.70) for TMB, and 0.64 (0.59, 0.7) and 0.56 (0.45, 0.67) for GEP with Pembro and Ipi. Note the observed TMB relationship with Ipi is based on an assessment of limited data in that arm and definitive conclusions cannot be made.
Conclusion: TMB and inflammatory biomarkers (GEP and PD-L1) showed statistically significant and independent associations with BOR, PFS and OS in Pembro-treated pts with advanced melanoma. Only GEP showed significant associations with PFS and OS for Ipi, potentially indicating a prognostic value.
Citation Format: Antoni Ribas, Caroline Robert, Jacob Schachter, Georgina V. Long, Ana Arance, Matteo S. Carlino, James Larkin, Andrea L. Webber, Jared Lunceford, Qing Zhao, Razvan Cristescu, Michael Nebozhyn, Chunsheng Zhang, Wendy Blumenschein, Clemens Krepler, Nageatte Ibrahim, Adil Daud, Jean-Jacques Grob. Tumor mutational burden (TMB), T cell-inflamed gene expression profile (GEP) and PD-L1 are independently associated with response to pembrolizumab (Pembro) in patients with advanced melanoma in the KEYNOTE (KN)-006 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4217.