头颈部鳞状细胞癌新辅助免疫治疗中反应适应性手术时机显示病理治疗反应增强

We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.

Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.

Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN- expression in the HPV- cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse.

Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.