On February 14, 2026 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA and precision medicine, reported results from the SINERGY trial, a Phase 2 study in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Data was recently presented in an oral plenary at the 2026 MHNCS.
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Approximately 73K patients are diagnosed with head and neck cancer in the U.S. annually. The current standard of care for R/M HNSCC patients, based on the registrational KEYNOTE-048 trial, is immune checkpoint inhibition (ICI) either alone, or combined with chemotherapy; however, these regimens are suboptimal with efficacy and toxicity concerns. To help address these issues, SINERGY (NCT05420948) investigated whether personalized circulating tumor DNA (ctDNA) monitoring with Signatera can provide an early signal of treatment efficacy, enabling adaptive escalation or de-escalation of chemotherapy without reducing therapeutic benefit.
In the trial, 27 patients received initial treatment of either immunotherapy alone or in combination with chemotherapy. Based on Signatera ctDNA dynamics during treatment (ctDNA levels rising or falling), chemotherapy was either escalated or de-escalated.
The study met its primary endpoint (objective response rate), with the following key highlights:
74% of patients (20/27) were de-escalated from chemo-immunotherapy to immunotherapy alone, resulting in a median of 2 chemotherapy cycles across the full cohort, a substantial two-thirds reduction from the current standard of care (6 cycles).
Objective response rate (ORR) was strong at 63% (17/27; 95% CI: 42.4–80.6), comparing favorably to the 36% and 19% ORRs from KEYNOTE-048 patients receiving ICI with and without chemotherapy, respectively.
Severe toxicity of grade ≥3 was 48.1% (13/27), substantially lower than the 85% and 55% from KEYNOTE-048 patients receiving ICI with and without chemotherapy, respectively.
"The SINERGY trial is unique in that it adapted chemo-immunotherapy treatment guided by ctDNA dynamics. The trial demonstrated a promising response rate and survival, with roughly three-quarters of patients experiencing treatment de-escalation guided by ctDNA dynamics," said Ari J. Rosenberg, M.D., associate professor of medicine at the University of Chicago and presenting author of the study. "This led to a reduction in the number of chemotherapy cycles along with lower rates of high-grade toxicity compared with historical controls. With these results, there is great potential for ctDNA dynamics to optimize treatment in R/M HNSCC."
"This trial was designed to address an urgent need for treatment personalization that mitigates unnecessary toxicity while improving survival for patients with recurrent or metastatic head and neck cancer," said Alexey Aleshin, M.D., general manager of oncology and corporate chief medical officer at Natera. "We saw remarkable results that Signatera can inform therapeutic decision-making in real-time for this aggressive and difficult-to-treat cancer, laying the groundwork for changes in the standard of care."
(Press release, Natera, FEB 24, 2026, View Source [SID1234662955])