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Clinical Trial
. 2024 Jul 1;10(7):896-904.
doi: 10.1001/jamaoncol.2024.1143.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial

Nabil F Saba  1   2 , Stuart J Wong  3 , Tahseen Nasti  2   4 , Ashley Alesia McCook-Veal  2   5 , Mark W McDonald  2   6 , William A Stokes  2   6 , Allyson M Anderson  2 , Asari Ekpenyong  2 , Manali Rupji  2   5 , Marin Abousaud  7 , Soumon Rudra  2   6 , James E Bates  2   6 , Jill S Remick  2   6 , Nikhil P Joshi  8 , Neil M Woody  8 , Musaddiq Awan  3 , Jessica L Geiger  8 , Aditya Shreenivas  3 , Julia Samsa  8 , Matthew Christopher Ward  9 , Nicole C Schmitt  2   10 , Mihir R Patel  2   10 , Kristin A Higgins  2   6 , Yong Teng  1   2 , Conor E Steuer  1   2 , Dong M Shin  1   2 , Yuan Liu  2   5 , Rafi Ahmed  2   4 , Shlomo A Koyfman  8
Affiliations
Clinical Trial

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial

Nabil F Saba et al. JAMA Oncol. .

Abstract

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS).

Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation.

Design, setting, and participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023.

Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks.

Main outcomes and measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers.

Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed.

Conclusions and relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation.

Trial registration: ClinicalTrials.gov Identifier: NCT03521570.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Saba reported grants from BMS during the conduct of the study; personal fees from Merck, Exelixis, Eisai, GSK, Vaxxinex, Kura Oncology, BMS, Novartis, Merck EMD Serono, CUE, BionTech, Seagen, Inovio, Aveo, Coherus, Adagene, and Fulgent outside the submitted work. Dr McDonald reported support from Varian Medical Systems outside the submitted work. Dr Abousaud reported being a former employee of Emory Healthcare during the conduct of the study before employment at Astellas, which is not affiliated with this study. Dr Rudra reported grants from Varian Medical Systems outside the submitted work. Dr Bates reported support from Galera Therapeutics and Castle Biosciences outside the submitted work. Dr Awan reported grants from the National Institutes of Health (R21 grant) and nonfinancial support from Genentech Drug outside the submitted work. Dr Geiger reported personal fees from the Regeneron Advisory Board, the Merck Advisory Board, Astellas Education, and the EMD Serono outside the submitted work. Dr Shreenivas reported grants from Natera Research and support from Taiho outside the submitted work. Dr Ward reported personal fees from Bayer One, Xofigo, Varian Medical Systems, Exact Sciences, and Demos Medical outside the submitted work. Dr Schmitt reported grants from Astex Pharmaceuticals; and personal fees from Sensorion, Checkpoint Surgical, and Synergy Research, Inc, outside the submitted work. Dr Higgins reported support from AstraZeneca during the conduct of the study, Janssen Pharmaceuticals, and Picture Health; and grants from Jazz Pharmaceuticals outside the submitted work. Dr Steuer reported personal fees from Merck, Novocure, AstraZeneca, PharmaHealth, and Daiichi Sankyo outside the submitted work. Dr Koyfman reported personal fees from BMS during the conduct of the study; and personal fees from Merck, Regeneron, Galera Therapeutics, UpToDate, and Castle Biosciences outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram, Overall Survival, and Progression-Free Survival
Gray areas indicate 95% CI bands and gray plus signs indicate censored patients. PRO indicates patient-reported outcome; PT, prothrombin time; PTT, partial thromboplastin time; and TSH, thyroid stimulating hormone.
Figure 2.
Figure 2.. Biomarker Correlative Analyses
A, Representative dot plots of the proportion of PD1+, Ki67+, CD4 T cells, and FOXP3+ T regulatory cells before (BL) and 2 to 4 weeks after the first cycle of treatment (C1). B, Phenotype of proliferating cCD4 T cells in the peripheral blood after cycle 1 of nivolumab. Representative histograms of expression on PD1+, Ki67+, CD4, or FOXP3 T cells (shaded) in comparison with naive cCD4 cells (not shaded). C, Fold change of PD1+, Ki67+ T cells after 2 or 4 weeks concerning BL proliferation in the indicated T-cell subsets. The dotted line in the graph indicates the 1.5-fold cutoff for early proliferative response. Orange indicates the responders, and blue indicates the nonresponders. D, Progression-free survival in patients that showed cCD4 T-cell response (>1.5-fold response from BL) vs nonresponders (<1.5-fold response from BL). The gray plus signs indicate censored patients. HR indicates hazard ratio.
Figure 3.
Figure 3.. Quality of Life Scores
The figure shows spaghetti plots of median Functional Assessment of Cancer Therapy–General (FACT-G) scores at each cycle for subcategories (A) and overall score (B). Subcategory scores include physical well-being, social/family well-being, and functional well-being, on a scale from 0 to 28, and emotional well-being and a scale from 0 to 24. The overall score ranged from 0 to 108. Higher scores indicated better quality of life measurement. IMRT indicates intensity-modulated radiation therapy.
See this image and copyright information in PMC

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