Tumor Genomic Profiles Associated with Clinical Benefit from Immune Checkpoint Inhibitor Therapy - An Exploratory...

The multicenter precision oncology registry INFINITY investigated biomarker-driven therapy and outcomes in patients with advanced malignancies not eligible for standard therapy in routine clinical care in Germany. Although programmed cell death (ligand) 1 (PD-(L)1) antibodies have changed the treatment landscape of several malignancies and PD-(L)1 expression level is predictive and therefore often used for treatment selection, existing predictive biomarkers are insufficient to identify patients who will benefit from PD-(L)1 inhibitor-based therapy. This project aimed to identify genomic tumor profiles predicting benefit from anti-PD-(L)1 therapy.

Patients from the INFINITY registry treated with anti-PD-(L)1 monotherapy were stratified into two cohorts using a case-control design: clinical benefit (treatment duration >182 days) and no clinical benefit (treatment duration 22-63 days). Tumor tissue samples from the virtual biobank were requested from local pathologies and sent to the central pathology for next‑generation sequencing (NGS) using the Oncomine^TM Comprehensive Assay Plus panel (Thermo Fisher, NGS pan-cancer assay).

Of the 26 patients with clinical benefit and 24 patients without clinical benefit, NGS-based genetic tumor profiles were available for 11 and 8 patients, respectively. Only patients with clinical benefit from anti-PD-(L)1 therapy showed genetic alterations in KEAP1, PIK3CA and MRE11.

Our analysis revealed a set of three genes (KEAP1, PIK3CA and MRE11) exclusively mutated in patients with clinical benefit from PD-(L)1-inhibitor therapy, possibly representing promising biomarker candidates. Given the small sample size and the heterogeneous tumor types included, these findings are exploratory, and validation in larger, preferably tumor-type-specific cohorts is required before any predictive value can be attributed to these genomic alterations.