Background: Indoleamine 2,3-dioxygenase (IDO) catalyzes the degradation of tryptophan to kynurenine. In order to improve the clinical efficacy of PD-1 inhibition, we designed a novel neoadjuvant trial to test the immunological and therapeutic effects of nivolumab (nivo) and the IDO inhibitor BMS986205 in combination in previously untreated HNSCC utilizing an interim radiographic assessment to determine response treatment prior to surgery. Methods: We conducted an investigator-initiated, multi-institutional, two-arm, 3:1 randomized neoadjuvant trial in patients with previously untreated HNSCC of any stage who were candidates for complete surgical resection. Patients were stratified by HPV status. Patients in arm A received 480 mg of nivolumab alone. Subjects in arm B received BMS986205 100 mg po qday beginning 1 week prior to nivolumab 480 mg. Both groups were evaluated at week 5 with CT scans. Radiographic response was evaluated at both the primary site and any involved lymph nodes. Patients with at least a 10% reduction in volume at either the primary or lymph nodes with no evidence of progression continued on to a second cycle of the assigned treatment. Patients with stable disease or progression proceeded to surgery at week 5 without additional study treatment. Imaging, blood and tumor were obtained pretreatment and post treatment and used for immunological correlatives. 2 blinded independent pathologist provided pathologic treatment effect (pTE) scores for primary tumor and lymph nodes. The primary endpoint was radiographic response leading to additional study treatment. Results: 42 patients were randomized and completed treatment to the primary endpoint evaluation including 22 HPV+ oropharyngeal HNSCC. Four patients did not proceed with planned surgery: 2 progression, 1 patient preference, and 1 toxicity. 3 patients in Arm B developed hepatitis with 2 subjects having a delay in surgery. 36% of patients (n=4) in Arm A (nivo alone) and 42% of patients (n= 13) in Arm B (nivo+IDO) were considered radiographic responders and continued to a second cycle of therapy (p= 1.0). Pathologic treatment effect (pTE) was significantly higher in subjects who were treated with a second cycle: median of 85% pTE (responders) compared to median of 5% pTE (nonresponders) at the primary site (p=0.018) with 6/16 (38%) subjects in the radiographic responders and 1/20 (5%) in radiographic non-responders demonstrating a CR at the primary site. In the lymph node compartment, the median pTE was 73% compared to 23% in radiographic responders vs non-responders (p=0.04). Conclusions: In previously untreated HNSCC, nivolumab +/- IDO inhibitor demonstrated a significantly greater pTE after a second dose in radiographic responders. The addition of IDO-inhibitor to anti-PD1 did not result in a significant increase in radiographic or pathologic response over nivolumab alone. NCT03854032. Clinical trial information: NCT03854032.