Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p<0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders (p<0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs. 5%; p<0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs. 7%; p<0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+Tregs were lower in responders than non-responders at baseline (19% vs. 33%; p<0.01), and following nivolumab (12% vs. 20%; p<0.001). As in T effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders (p<0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs. 17%; p<0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors.