Towards a mechanistic understanding of patient response to neoadjuvant SBRT with anti-PDL1 in human HPV-unrelated locally advanced HNSCC: Phase I/Ib trial results

Five-year survival for HPV-unrelated head and neck squamous cell carcinomas (HNSCC) remains below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy (SBRT) with anti-PDL-1 neoadjuvantly followed by adjuvant anti-PDL-1 with standard of care therapy (n=21) (NCT03635164). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic, and objective response, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Among evaluable patients at early median follow-up of 16 months (448 days, or 64 weeks), OS was 80.1% with 95% C.I. (62.0%, 100.0%), LRC and PFS were 75.8% with 95% C.I. (57.5%, 99.8%), and major pathological response (MPR) or complete response (CR) was 75% with 95% exact C.I. (51.6%, 100%). Circulating CD8/Treg ratio, CD4 effector memory T cells, and TCR repertoire at time of surgery emerged as biologic correlates of response to therapy. Using high-dimensional multi-omics and spatial data as well as biological correlatives pre- and post-treatment, three major changes were noted in responders within the tumor microenvironment (TME) (and within the blood) post-treatment: 1) an increase in effector T cells; 2) a decrease in immunosuppressive cells; and 3) an increase in antigen presentation. Non-responders appeared to fail due to a lack of one of these three identified steps needed for priming and maintaining activation of T cells. Multiple correlates for response, along with subsets of non-responders that may benefit from additional or alternative immunotherapies, were identified. This treatment is being tested in an ongoing phase II trial with a similar design, where we hope to confirm and expand on our understanding of the mechanisms underlying resistance to therapy. Tumor tissue collected from patients at time of initial biopsy and at time of surgery were used for RNA sequencing.