Abstract 5859: Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous cell carcinoma

Abstract

Abstract Background: Objective response rates for patients with advanced head and neck squamous cell carcinoma (HNSCC) receiving PD-1/L1 immune checkpoint inhibitors (ICI) without chemotherapy remain under 25%. Some studies suggest that HNSCC patients with human papillomavirus (HPV)-associated disease and high tumor mutational burden (TMB) derive greater benefit, although these findings do not yet guide patient selection. We hypothesized that uniform genomic analysis of a larger cohort may help place the predictive value of TMB in a broader biological context and identify more robust predictors of response. Methods: 274 patients with biopsy-proven HNSCC treated with ICI at our institution from June 2014 to September 2018 were identified. Following targeted massively parallel sequencing, single nucleotide variant calling, and quality control measures, 127 samples were available for analysis. Clinical records were reviewed to determine radiographic response and overall survival. Responders included complete or partial responders by RECIST v1.1. Nonresponders included those with progressive or stable disease. We evaluated associations between genomic features and response using standard statistical methods. Results: TMB for the entire cohort was significantly higher among responders (p = 0.01, Fisher's); however, it had poor predictive power (AUROC = 0.68). Among the entire cohort, somatic mutations in NOTCH1 were enriched in responders (12/26 R, 17/101 NR, p = 0.003). After correcting for TMB, NOTCH1 remained associated with complete or partial response (p < 0.05, logistic regression). After adjusting for mutations in NOTCH1, no significant difference in TMB was observed between responders and nonresponders (p > 0.05, logistic regression). Among HPV-negative responders, somatic mutations in CDK12, a transcription-associated kinase whose loss is associated with genomic instability, neoantigen burden, and T cell infiltration, were enriched (3/26 R, 0/101 NR, p = 0.008, Fisher's). Conclusion: Through uniform genomic analysis of the largest ICI-treated HNSCC cohort to-date, we validated prior findings regarding the significance of TMB and NOTCH1 as correlates of response for ICI in HNSCC. We also show that TMB alone is insufficient as a predictor of response. We identify CDK12 as a variant with a mechanistic relationship to tumor immunology as a possible correlate of response in HPV-negative patients, which warrants further investigation. Citation Format: Nisarg A. Patel, Natalie I. Vokes, Haitham Elmarakeby, Glenn J. Hanna, Eliezer M. Van Allen. Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5859.