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Head and Neck Cancer

Berzosertib Fails to Improve Head and Neck Cancer Outcomes

Publication Title: A phase 1 study of berzosertib (M6620, VX‐970) in combination with cisplatin and radiation in patients with locally advanced head and neck squamous cell carcinoma (ETCTN 9950)

Summary

Question
This study examined whether combining berzosertib, an inhibitor of a protein called ATR (ataxia telangiectasia Rad3-related), with standard radiation therapy and cisplatin chemotherapy could improve outcomes in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The researchers aimed to evaluate the safety, tolerability, and preliminary efficacy of this combination treatment.
Why it Matters
Head and neck squamous cell carcinoma is a serious cancer that often presents at advanced stages, making treatment challenging. Standard therapy includes radiation and cisplatin, but many patients still experience cancer recurrence or spread. Berzosertib targets ATR, a protein involved in repairing damaged DNA, which tumor cells rely on to survive radiation and chemotherapy. By inhibiting ATR, berzosertib could potentially make tumor cells more sensitive to treatment, improving patient outcomes. If successful, this approach could provide a new option for patients with limited treatment choices.
Methods
The researchers conducted a phase 1 clinical trial involving 43 patients with LA-HNSCC. Participants received weekly doses of cisplatin and daily radiation therapy over six to seven weeks. Berzosertib was administered intravenously once weekly at escalating doses to determine the safest and most effective dose for future studies. Safety and preliminary efficacy were assessed, and treatment response was evaluated using imaging scans.
Key Findings
Berzosertib at a dose of 200 mg/m² weekly was determined to be safe and tolerable when combined with radiation and cisplatin. However, the treatment did not improve the complete response rate (the percentage of patients whose tumors were eliminated) compared to historical data for standard therapy alone. Among patients who completed treatment and had post-treatment imaging, the overall response rate (tumor shrinkage or elimination) was 78.8%. Side effects, such as fatigue, anemia, and mucositis, were common but manageable.
Implications
While the combination of berzosertib with radiation and cisplatin was safe, it did not significantly enhance treatment outcomes for patients with LA-HNSCC compared to existing therapies. This highlights the need for continued exploration of new treatment strategies to improve survival and reduce recurrence rates in this patient population.
Next Steps
The researchers recommend further studies to identify biomarkers that might predict which patients could benefit from ATR inhibition. Additionally, they suggest exploring alternative combinations or dosing strategies to enhance the efficacy of berzosertib in future trials.
Funding Information
This research was supported by the National Cancer Institute (NCI) as part of the Experimental Therapeutics Clinical Trials Network (ETCTN) under protocol ETCTN 9950. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Yale University also provided funding and support for this research.

Full Citation

Bhatia A, Chen Z, Zhang Y, Bruce J, Arnold S, Kaur V, Riess J, Fenton M, Burtness B, Saba N, Tara H, Steuer C, Shin D, Wasp G, Davis T, Patel M, Schmitz J, Bhateja P, Diavolitsis V, Zandberg D, Mitchell D, Kiesel B, Kunos C, Gore S, Carducci M, Beumer J, Owonikoko T. A phase 1 study of berzosertib (M6620, VX‐970) in combination with cisplatin and radiation in patients with locally advanced head and neck squamous cell carcinoma (ETCTN 9950). Cancer 2026, 132: e70346. PMID: 41823504, PMCID: PMC12984462, DOI: 10.1002/cncr.70346.

Authors

  • Aarti Bhatia, MD, MPH

    First Author
    Yale School of Medicine

    Associate Professor of Medicine (Medical Oncology)

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  • Taofeek K. Owonikoko

    Last Author
    School Building Streamline Icon: https://streamlinehq.comOther Institution

Additional Yale School of Medicine Authors

Other Authors

  • Zhengjia Chen;
  • Yuji Zhang;
  • Justine Yang Bruce;
  • Susanne Arnold;
  • Varinder Kaur;
  • Jonathan W. Riess;
  • Moon Fenton;
  • Nabil F. Saba;
  • Harold Tara;
  • Conor E. Steuer;
  • Dong M. Shin;
  • Garrett Wasp;
  • Thomas H. Davis;
  • Malini Patel;
  • John C. Schmitz;
  • Priyanka Bhateja;
  • Virginia Diavolitsis;
  • Dan P. Zandberg;
  • Darrion L. Mitchell;
  • Brian F. Kiesel;
  • Charles Kunos;
  • Steven D. Gore;
  • Michael Carducci;
  • Jan H. Beumer

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