Neoadjuvant Nivolumab Plus Chemotherapy and Response-Adaptive Therapy for HPV+ Oropharyngeal Cancer (2024)

• ¹Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois

• ²University of Chicago Comprehensive Cancer Center, Chicago, Illinois

• ³Section of Otolaryngology−Head and Neck Surgery, University of Chicago, Chicago, Illinois

• ⁴Department of Public Health Sciences, University of Chicago, Chicago, Illinois

• ⁵Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

• ⁶Department of Radiology, University of Chicago, Chicago, Illinois

• ⁷Sysmex-Inostics Inc, Baltimore, Maryland

• ⁸Department of Pathology, University of Chicago, Chicago, Illinois

• ⁹Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland

Key Points

Question Is neoadjuvant nivolumab with chemotherapy followed by response-adapted locoregional therapy effective and well tolerated in patients with human papillomavirus−positive oropharyngeal carcinoma (HPV⁺ OPC)?

Findings This phase 2 nonrandomized clinical trial of 73 patients with locoregionally advanced HPV⁺ OPC who were treated with neoadjuvant nivolumab-based therapy demonstrated a deep response (≥50% tumor shrinkage) in 70.8% of the evaluable participants. This response led to reduced local treatment for 86.0% of participants, excellent 2-year survival, and improved functional outcomes; moreover, the expression of programmed death-ligand 1 and clearance of circulating tumor HPV-DNA were associated with improved progression-free survival.

Meaning These findings demonstrate that neoadjuvant nivolumab with chemotherapy followed by response-adaptive treatment can provide excellent overall survival and functional outcomes, including in patients with high-risk HPV⁺ OPC.

Importance Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus−positive oropharyngeal cancer (HPV⁺ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV⁺ OPC may increase efficacy while reducing toxicity.

Objective To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV⁺ OPC.

Design, Setting, and Participants This phase 2 nonrandomized clinical trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV⁺ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023.

Interventions Addition of nivolumab to neoadjuvant nab-pacl*taxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV⁺ OPC stages III to IV.

Main Outcomes and Measures Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated.

Results The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS.

Conclusions and Relevance This phase 2 nonrandomized clinical trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV⁺ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection.

Trial Registration ClinicalTrials.gov Identifier: NCT03107182

Targeted and Immune Therapy Surgery Surgical Oncology Cancer Survivorship Head and Neck Cancer Otolaryngology Clinical Pharmacy and Pharmacology Oncology

Citation

Rosenberg AJ, Agrawal N, Juloori A, et al. Neoadjuvant Nivolumab Plus Chemotherapy Followed By Response-Adaptive Therapy for HPV⁺ Oropharyngeal Cancer: OPTIMA II Phase 2 Open-Label Nonrandomized Clinical Trial. JAMA Oncol. Published online June 06, 2024. doi:10.1001/jamaoncol.2024.1530

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