Frameshift events predict anti–PD-1/L1 response in head and neck cancer

Abstract

Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.

Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer

“…The association between high TMB and improved outcomes in the current study may reflect immunogenic potential -whereby high TMB facilitates neoantigen recognition and a resulting immunologic response to attack the tumor. But independent of TMB, HPV + patients appear to have higher response rates to immune checkpoint blockade (24)(25)(26).…”

“…In evaluating the molecular landscape of metastatic HPV tumors, we first assessed TMB, a measure of total mutation events in the coded genome, as it holds significant promise as a biomarker for response to immunotherapy (24). Our own work has recently shown that TMB is lower among virally mediated recurrent head .…”

“…34); or targeting 447 genes and selected intronic regions of 60 genes (OncoPanel version 3; ref. 24). Hybrid-capture libraries were sequenced on an Illumina HiSeq 2500 using 2 × 100 paired-end reads.…”

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…HPV status was predictive of improved response to durvalumab . Furthermore, a higher number of some subtypes of tumor‐infiltrating lymphocytes (TILs), such as PD‐1 + TIM‐3 + CD8 + TILs and PD‐1 + LAG‐3 + CD8 + TILs, and higher tumor mutation burden (TMB) and CD8 + TILs, all predicted improved response to anti‐PD‐1 or anti‐PD‐L1 therapies …”

“…122 Furthermore, a higher number of some subtypes of tumor-infiltrating lymphocytes (TILs), such as PD-1 + TIM-3 + CD8 + TILs and PD-1 + LAG-3 + CD8 + TILs, and higher tumor mutation burden (TMB) and CD8 + TILs, all predicted improved response to anti-PD-1 or anti-PD-L1 therapies. 133 Several recent conference presentations have also highlighted novel data regarding predictive biomarkers in the era of immunotherapy ( Table 2). For example, PD-1 + CD8 + effector T cells and PD-1 + Treg cells in tumor tissue predicted response to nivolumab, 136 whereas mutational load and IFN-γ gene expression profile (GEP) predicted response to pembrolizumab.…”