Multicenter validation of an RNA-based assay to predict anti-PD-1 disease control in patients with recurrent or metastatic head and neck squamous cell carcinoma: the PREDAPT study

Abstract

Background: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors.

Methods: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high.

Results: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control.

Conclusions: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors.

Trial registration number: NCT04510129.

Keywords: biomarker; head and neck cancer; immune checkpoint inhibitor; next generation sequencing (NGS); tumor mutation burden (TMB).

Figure 1. Samples used to develop, train, and validate OncoPrism-HNSCC. Data from a total of 1205 samples were used to select features, refine the protocol, train the model, and validate the model. Data from 790 publicly available samples were used to select features. 415 patient samples were collected as part of the PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies trial. 116 samples were ineligible and were excluded from this study. 86 samples failed quality control (QC) and were excluded. Two patients were withdrawn from the study. Of the remaining patient samples, 161 were treated with monotherapy antiprogrammed cell death protein 1 (anti-PD-1) and 50 were treated with chemo-immunotherapy anti-PD-1. Of the monotherapy samples, 99 were used to train the model, and the remaining 62 monotherapy samples served as validation cohort 1. The 50 chemo-immunotherapy samples served as validation cohort 2. HNSCC, head and neck squamous cell carcinomas.

Figure 2. OncoPrism-HNSCC score and group are correlated with disease control in independent monotherapy and chemo-immunotherapy validation cohorts. Samples are ordered by their OncoPrism Score for the monotherapy-treated (A) and chemo-immunotherapy (D) validation cohorts. Lower scores are more likely to be progressors (gray) while higher scores are more likely to have disease control (orange). Based on their OncoPrism Score and predetermined thresholds (dotted lines), each patient sample is assigned to an OncoPrism group (low, medium, or high). OncoPrism groups are significantly correlated with disease control rate (DCR) in the monotherapy (p=0.004) (B) and chemo-immunotherapy (p=0.004) (E) validation cohorts. P values for the significance of the trend were calculated using Cochran-Armitage test. OncoPrism groups are significantly correlated with progression-free survival (PFS) in the monotherapy (p=0.015) (C) and chemo-immunotherapy (p=0.037) (F) validation cohorts. P values for PFS were calculated using log rank methods. HNSCC, head and neck squamous cell carcinomas.

Figure 3. OncoPrism-HNSCC outperforms existing assays programmed death-ligand 1 (PD-L1) combined positive score (CPS) and tumor mutational burden (TMB). Receiver operating characteristic (ROC) curves are shown for the monotherapy (A) and chemo-immunotherapy (B) cohorts. OncoPrism-HNSCC (orange) has a higher area under the curve (AUC) than PD-L1 CPS (gray) in both cohorts. In monotherapy (C) and chemo-immunotherapy (D) cohorts, OncoPrism-HNSCC (orange) has high sensitivity and specificity, while PD-L1 CPS (gray) has high sensitivity but low specificity. The distribution of CPS is similar in each validation cohort (E). (F) Sensitivity and specificity for OncoPrism-HNSCC (orange), PD-L1 CPS (gray), and TMB (blue) in 32 patients from the OncoPrism high and low groups. Error bars represent 95% CIs. HNSCC, head and neck squamous cell carcinomas.

Figure 4. (A) OncoPrism high patients have significantly longer progression-free survival (PFS) in combined positive score (CPS) ≥1 patients (p<0.001, log rank methods). (B) OncoPrism high patients have significantly longer PFS in CPS ≥20 patients (p<0.001, log rank methods). Cohort 1 and cohort 2 were combined for this analysis of programmed death-ligand 1 (PD-L1) CPS subgroups. (C) Immune checkpoint inhibitor (ICI) decision tree based on test results. Patients with recurrent or metastatic head and neck squamous cell carcinomas (HNSCC) tested with OncoPrism-HNSCC are categorized into the OncoPrism low, medium, or high group. Because OncoPrism-HNSCC has high specificity relative to PD-L1 CPS and OncoPrism high patients have longer PFS regardless of PD-L1 status, OncoPrism high patients should typically be treated with ICI regardless of PD-L1 status. OncoPrism low patients have low ICI disease control rate (DCR) and are not good candidates for ICI even if they are PD-L1 CPS ≥1. Patients in the OncoPrism medium group do not have a definitive treatment path; all test results and treatment options should be considered. Typically, ICI should be favored for OncoPrism medium patients who are PD-L1 CPS ≥1 while non-ICI or clinical trial options should be considered for PD-L1 CPS <1 patients. Tumor mutational burden (TMB) testing is not recommended for most patients with HNSCC. However, if TMB testing is performed, ICIs should be prioritized for TMB high patients given the high observed specificity of TMB. Only 9% of patients in our study were TMB high. Due to the low sensitivity of TMB, a TMB low result should not be strongly considered in treatment decisions. PD-1, programmed cell death protein 1.