Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness

Abstract

Advanced and metastatic squamous cell carcinomas (SCC) are common and difficult-to-treat malignancies. We assessed 75 immunotherapy-treated patients with SCC from a clinically annotated database of 2,651 patients, as well as 9,407 patients from a deidentified database for molecular features that might influence checkpoint blockade response. SCCs had higher tumor mutational burdens (TMB) than non-SCCs (P < 0.0001). Cutaneous SCCs had the highest TMB (P < 0.0001), with 41.3% demonstrating a very high TMB (≥50 mutations/Mb). In immunotherapy-treated patients with SCC, higher TMB (≥12 mutations/Mb) correlated with a trend to higher clinical benefit rate [stable disease ≥ 6 months or partial/complete remission; 60% vs. 29%; (high vs. low TMB); P = 0.06] and significantly longer median time-to-treatment failure (TTF; 9.9 vs. 4.4 months; P = 0.0058). Cutaneous SCCs had the highest clinical benefit [11/15 patients (73%) vs. 20/60 (33%) non-cutaneous (P = 0.008)], TTF (P = 0.0015), and overall survival (P = 0.06) with immunotherapy treatment. In conclusion, among a diverse set of SCCs, higher TMB and cutaneous disease associated with better immunotherapy outcome.

Figure 1:. TTF and OS for patients with advanced SCC treated with PD-1/PD-L1 blockade.

(A) Kaplan Meier analysis of time-to-treatment failure (TTF) for cutaneous squamous cell carcinoma (SCC) vs. other SCCs. (B) Kaplan Meier analysis for overall survival (OS) for cutaneous SCC vs. other SCCs. (C) Kaplan Meier analysis for TTF for tumor mutational burden (TMB) <12 vs ≥12 mutations/Mb. (D) Kaplan Meier analysis for OS for TMB <12 vs. ≥12. (E) Kaplan Meier analysis for TTF for all SCCs categorized by TMB low vs. intermediate vs. high. (F) Kaplan Meier analysis for OS for all SCCs categorized by TMB low vs. intermediate vs. high. Number of patients/group indicated.