Background: Despite the success of anti-PD-1 in recurrent/metastatic head and neck cancer, incorporation in the curative setting with induction therapy has yet to be investigated. Favorable prognosis of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) has led to interest in treatment de-escalation. OPTIMA 2 evaluated nivolumab (nivo) with nab-paclitaxel and carboplatin followed by risk/response adaptive de-intensified treatment for locoregionally advanced HPV+ OPC. We report the primary analysis and outcomes. Methods: OPTIMA 2 enrolled locoregionally advanced HPV+ OPC. Nivo, nab-paclitaxel, and carboplatin were administered for 3 cycles. High-risk (HR) included any of the following: T4, N2c-N3 (AJCC 7^th edition), > 20 pack year smoking history, non-HPV16 subtype; All others were low-risk (LR). Arm A included LR with ≥50% post-induction shrinkage by RECIST received single-modality de-escalation with low-dose radiation (RT) alone (50 Gy) or transoral robotic surgery (TORS). Arm B included HR with ≥50% shrinkage or LR with <50% received intermediate-dose chemoradiation (CRT) to 45-50Gy. Arm C included all others and received regular dose CRT to 70-75Gy. Adjuvant nivo was administered for 6 months. The primary endpoint was deep response rate (DRR) ≥50% shrinkage to induction therapy. Results: From September 2017 until March 2020, 73 patients (pts) were eligible and started treatment. One pt died during induction. The DRR following induction was 70.8% (95% CI 60.3%, 81.3%). Median follow-up 23.1 months. Median age 61 (range 39-85), T4 12.3%, N2c/N3 19.2%, LR 47.9%, and HR 52.1%. De-escalated treatment was administered in 84.9%. Arm A N = 28, Arm B N = 34, and Arm C N = 10. 2-year progression free survival (PFS) for full cohort was 90.4% (95% CI = 79.3%, 95.7%). 2-year PFS for Arms A, B, and C were 96.3%, 85.8%, and 100.0% respectively. 2-year overall survival (OS) for full cohort was 93.3% (95% CI = 82.4%, 97.5%). 2-year OS for Arm A, B, and C were 96.0%, 91.9%, and 100.0% respectively. Among TORS (N = 9), pathologic complete response (pCR) rate was 66.7%. G-tube rates in Arms A, B, and C were 7.1%, 44.1%, and 75.0% respectively (p = 0.0001). Grade 4 toxicity in arms A, B, and C, were observed in 7.1%, 8.8%, and 10.0% of pts respectively. There were 3 local failures and no distant failures. Conclusions: Nivo/nab-paclitaxel/carboplatin followed by risk/response adaptive de-escalated treatment in locoregionally advanced HPV+ OPC demonstrates excellent survival outcomes with reduced toxicity and enteral feeding rates, including high risk disease. Induction chemoimmunotherapy demonstrates a high rate of deep clinical response and represents a promising de-escalation approach that incorporates anti-PD1 in the definitive setting. High pCR rate was observed following nivo/nab-paclitaxel/carboplatin. Clinical trial information: NCT03107182