Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide in head and neck cancer: the CONFRONT phase I-II trial

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2025-03-14 DOI:10.1016/j.esmoop.2025.104498

M.C. Merlano , N. Denaro , M. Paccagnella , A. Abbona , D. Galizia , S. Alfieri , C. Bergamini , E. Orlandi , A.M. Merlotti , S. Bondi , L. Licitra , O. Garrone

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引用次数: 0

Abstract

Background

Inhibition of the programmed cell death protein 1–programmed death-ligand 1 (PD-1–PD-L1) axis results in a modest objective response rate (ORR) in recurrent/metastatic head and neck squamous cell carcinoma. This study aimed to evaluate whether the addition of metronomic chemotherapy and a single fraction of radiotherapy could synergistically operate with anti-PD-L1 treatment.

Patients and methods

We conducted a phase I-II study evaluating avelumab (10 mg/kg intravenously every 2 weeks), low-dose cyclophosphamide (50 mg/day, fixed dose, without treatment breaks), and a single fraction of radiotherapy (8 Gy) to one lesion. The phase II portion of the study followed Simon’s two-stage optimal design. A total of 6 patients were enrolled in phase I, and 20 patients were accrued and analyzed in phase II before determining progression to the second stage (51 patients). The primary endpoint was ORR. Further, a panel of circulating cytokines was analyzed to explore potential toxicity and/or efficacy markers.

Results

Between January 2019 and June 2020, 20 patients were enrolled. In phase I, only one dose-limiting toxicity was observed among the six patients, allowing progression to phase II. At the end of stage I, five objective responses (2 complete responses and 3 partial responses) were recorded, failing to meet the threshold of six responses required to reject the null hypothesis. The median progression-free survival and overall survival were 3.0 and 9.2 months, respectively. Treatment was well tolerated. Low baseline levels of transforming growth factor-beta (TGF-β) and/or interleukin (IL)-4 were associated with a higher risk of immune-related adverse events (irAEs), whereas high baseline levels of IL-6 and vascular endothelial growth factor (VEGF) correlated with poor outcomes.

Conclusions

Our results did not achieve the ORR threshold required to reject the null hypothesis in this cohort of unselected patients with relapsed/metastatic head and neck cancer. IL-6 and VEGF were associated with overall survival, whereas TGF-β and IL-4 correlated with irAEs.

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来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.