Role of genomic instability in immunotherapy with checkpoint inhibitors.

Abstract

3052 Background: Checkpoint inhibitors have shown significant activity against a variety of cancers. However, biomarkers that predict responses to these agents have remained elusive. We hypothesized that tumors with greater genomic instability generate a more robust immune response that results in better survival. Methods: We retrospectively identified patients (pts) with solid tumors that were treated with checkpoint inhibitors and that had received commercially available next generation sequencing (NGS) between 2013-2015. Based on the skewed distribution of genomic alterations pts in the top quintile were compared to the other 4 quintiles combined. This procedure was done before examining mortality to avoid selecting cutoff points that could accentuate the mutation-outcome relationship. The functional significance of VUS’s in DNA damage repair pathways were predicted using PolyPhen. All p-values were two-sided and p-values less than 0.05 were considered statistically significant. Results: 50 pts were identified; most had either melanoma or NSCLC (top quintile 90% v others 86%, respectively). Median age (66 v 65) and median number of prior therapies (2 v 1) were similar. All pts had stage 4 disease. Top quintile pts had more genomic alterations (median 16.5) than the others (median 2) (p < 0.001); differences were both in median number of pathogenic mutations (3.5 vs. 1, p < 0.001) and VUS’s (12.5 vs. 1, p < 0.001). Pathogenic alterations in cell cycle regulatory genes (100% versus 48%, p = 0.017) were more common in the top quintile. Overall survival was superior for pts in the top quintile (722 days) versus the others (432 days) [HR 5.78; CI 1.40 – 15.12; p = 0.029]. Similar trends were seen regardless of histology. Progression free survival numerically favored the top quintile [not reached vs. 89 days, HR 2.11; CI 0.80-4.45; p = 0.154] as did objective response rate (50%) vs. others (20%), p = 0.101. PD1 and PDL1 status by immunohistochemistry were not associated with outcomes. Conclusions: The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved overall survival. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit.