Role of Genomic Instability in Immunotherapy with Checkpoint Inhibitors

Abstract

Aim: We evaluated whether tumor genome sequencing to detect the number and type of alterations could be used as a valuable biomarker for judging the potential utility of immune checkpoint inhibitors in patients with advanced cancers.

Materials and methods: We identified patients with solid tumors who were treated with checkpoint inibitors and had received commercially available next generation sequencing (NGS). Tumors profiled by Caris Life Sciences, Foundation Medicine and Guardant360 between 2013 and 2015. Patients were divided into 5 quintiles based on mutational load (pathogenic mutations plus variants of undetermined significance).

Results: Fifty patients with solid tumors on immunotherapy that had NGS reports available were identified. Top quintile patients had more genomic alterations (median=16.5) than the others (median=2) and had more pathogenic mutations in cell-cycle regulatory genes (100% versus 48%). The overall survival (OS) was significantly superior for patients in the top quintile (722 days) versus the others (432 days). We found no significant difference in progression-free survival (PFS) between the two groups. The objective response rate was numerically higher for the top quintile (50%) vs. others (20%). Programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PDL1) status by immunohistochemistry was not associated with outcomes.

Conclusion: The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved OS. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit.

Keywords: Immunotherapy; PD1; PDL1; genomic instability; next generation sequencing.