Neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab to de-escalate surgery and omit adjuvant radiation in locoregionally advanced head & neck squamous cell carcinoma (HNSCC)

BackgroundLocoregionally advanced HNSCC treated with surgery can carry functional morbidity, further intensified by adjuvant (adj) radiation (RT). The modest pathologic response rate of anti-PD1 therapy may be enhanced with a combination approach. This pilot study evaluates whether the combination of neoadjuvant (NA) cemiplimab + platinum-doublet chemotherapy + cetuximab is safe, feasible, and effective in pathologic down-staging to reduce the extent of surgery and justify omission of adj RT.Methods30 patients (pts) with resectable HNSCC warranting adj RT were enrolled. NA treatment consisted of cetuximab loading dose with cemiplimab followed by 3 cycles of cisplatin/carboplatin + docetaxel, cetuximab, and cemiplimab prior to surgery. Adj therapy was based on pathologic staging. Pts with ypT0-2N0 tumors without adverse features or ypT0-1N1 tumors with a major pathologic response (MPR) (<10% viable tumor) were offered adj cemiplimab in lieu of RT. Primary endpoint was safety (dose limiting toxicity (DLT) related to addition of cemiplimab). Secondary endpoints include feasibility (no surgical delay >20 weeks from start of NA therapy due to toxicity) and pathologic down-staging allowing for omission of adj RT.Results23 pts (21 oral cavity) completed treatment with no DLTs or surgical delays. Clinically staged T3 / T4 tumors were present in 12 / 8 pts (52% / 35%) (AJCC 8th Ed). 17/23 (74%) had a MPR and 7/23 (30%) had a pathologic complete response. 13/21 (62%) who would have required a free flap did not require it. Of the 13 (57%) pts eligible for omission of adj RT, 11 did not undergo RT and 9 received adj cemiplimab. All pts remain disease-free at a median follow-up of 7.3 months (range 0.2-34.9) (1 had a treated recurrence). 3 (13%) pts experienced a G3/4 AE attributed to cemiplimab including: G3 transaminitis (1), G3 infusion related reaction (1), G3 myasthenia gravis + G4 myocarditis (occurred outside DLT window) (1).ConclusionsNA cemiplimab with platinum-doublet chemotherapy and cetuximab has an acceptable toxicity profile, is feasible, and led to notable pathologic responses that allowed for reductions in the extent of surgery and omission of adj RT.Clinical trial identificationNCT04722523.Legal entity responsible for the studyMemorial Sloan Kettering Cancer Center.FundingRegeneron Pharmaceuticals the Serra Initiative on the Management of Head and Neck Cancer Side Effects, Memorial Sloan Kettering Cancer Center.DisclosureL. Dunn: Financial Interests, Personal, Advisory Board: Regeneron, Replimune, Merck; Non-Financial Interests, Institutional, Funding: Regeneron, IMVAQ, Replimune, Seagen. A.L. Ho: Financial Interests, Personal, Invited Speaker, discussed head and neck cancer therapies: Chinese American Hematologist and Oncologist Network; Financial Interests, Personal, Invited Speaker, Discussed salivary cancer therapies: Lurie Cancer Center (Northwestern); Financial Interests, Personal, Invited Speaker, discussed thyroid cancer therapies: Physician Education Resource; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapies: Endocrine Society; Financial Interests, Personal, Invited Speaker, Discussed head and neck cancer therapies: University of Pittsburgh Medical Center; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapeutics: New York University; Financial Interests, Personal, Advisory Board, Serve on DSMC: Affyimmune; Financial Interests, Personal, Other, Serve on the NCI Head and Neck Steering Committee: National Cancer Institute; Financial Interests, Personal, Advisory Board, Member of advisory board: Exelixis, Remix Therapeutics, Elevar Therapeutics, Prelude Therapeutics, Eisai, Ayala, Kura Oncology; Financial Interests, Personal, Other, Member of Safety Monitoring Committee: Kura Oncology; Financial Interests, Personal, Advisory Board, Member of advisory board: Merck; Financial Interests, Personal, Other, Consultant: ExpertConnect; Financial Interests, Personal, Advisory Board, Member of advisory board and consulting: Rgenta; Financial Interests, Personal, Advisory Board, Advisory Board: Coherus; Financial Interests, Personal, Advisory Board: Nested Therapeutics; Financial Interests, Personal, Full or part-time Employment: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Other, Listed as inventor for: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Serve as PI. also served on paid advisory board: Ayala; Financial Interests, Institutional, Coordinating PI, Serve as trial PI, also serve on paid SMC/advisory board: Kura Oncology; Financial Interests, Institutional, Local PI, Trial PI and served on an advisory board: Elevar Therapuetics; Financial Interests, Institutional, Coordinating PI, PI of IIT: Novartis, Merck, Bristol Meyer Squibb; Financial Interests, Institutional, Coordinating PI, PI of several IIT trials: Bayer; Financial Interests, Institutional, Coordinating PI, PI of trial: Bioatla, TILT Biotherapeutics, Genentech Roche, Astellas, Celldex; Financial Interests, Institutional, Local PI, PI of trial: OncC4; Financial Interests, Institutional, Coordinating PI, PI of several IITs: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of trial and was part of paid advisory board: Eisai; Financial Interests, Institutional, Local PI, co-PI of trial: Poseida Therapuetics; Financial Interests, Institutional, Local PI: Hookipa; Financial Interests, Institutional, Coordinating PI, PI of IST clinical trial: Verastem; Financial Interests, Institutional, Coordinating PI, PI of Remix sponsored trial: Remix Therapeutics; Non-Financial Interests, Advisory Role: Cellestia, Inxmed; Non-Financial Interests, Member of Board of Directors: International Thyroid Oncology Group; Non-Financial Interests, Leadership Role: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, for the head and neck working group: Alliance for Clinical Trials in Oncology. E.J. Sherman: Financial Interests, Personal, Financially compensated role: Fore Biotherapeutics, Affyimmune, Eli Lilly, Eisai, Novartis. W. Wong: Financial Interests, Institutional, Coordinating PI: Hookipa Pharma; Financial Interests, Institutional, Local PI: Bioatla. L. Michel: Financial Interests, Personal, Other, Consulting agreement: Kisoji biotechnology. T.K.W. Hung: Financial Interests, Personal, Advisory Board: Regeneron. B. Singh: Financial Interests, Personal, Other, Co-owner: Auricula Hearing; Financial Interests, Personal, Advisory Board: CinRx; Financial Interests, Personal, Other, PI - patent: DCN1 inhibitors. L. Morris: Financial Interests, Personal, Other, an inventor on IP owned by MSKCC and licensed to PGDX, unrelated to this work: PGDX. S. McBride: Financial Interests, Personal, Other, Consulting: Pfizer, Bayer, Janssen. N. Riaz: Financial Interests, Personal, Research Funding: Repare Therapuetics, BMS, Pfizer. N. Lee: Financial Interests, Personal, Advisory Board: Merck, Merck EMD, Nanobiotix; Financial Interests, Personal, Other, Consulting Fee: Regeneron, Galera, Yinming Consulting LTD, Shanghai consulting group; Financial Interests, Personal, Stocks or ownership: Nanobiotix; Financial Interests, Personal, Other, Travel support: Varian. D. Pfister: Financial Interests, Institutional, Research Funding: Akeso Biopharma, Hookipa Biotech. All other authors have declared no conflicts of interest.