Response to Neoadjuvant Immunochemotherapy May Guide Surgical De-escalation in HPV-Negative Head and Neck Cancer

A single-arm phase 2 trial from Wuhan, China, published September 10, 2026, in Clinical Cancer Research, has found that patients with HPV-negative, locally advanced head and neck squamous cell carcinoma (HNSCC) who responded deeply to neoadjuvant immunochemotherapy could undergo less extensive surgery without sacrificing disease control. The trial, known as REMATCH, is described by its authors as the first prospective evidence that surgical extent can be adapted to tumor response in this setting, and its results now support moving the strategy into randomized phase 3 testing. [1]

Key Takeaways

• Among 50 patients who completed neoadjuvant immunochemotherapy, the objective response rate was 94%; at a median follow-up of 34.0 months, two-year disease-free survival was 90% in patients who qualified for reduced-volume surgery based on tumor regression, versus 20% in those who did not [1].
• All patients with laryngeal or hypopharyngeal cancer who underwent reduced-volume surgery retained laryngeal function, and quality-of-life scores at nine months after radiotherapy had largely improved or stabilized relative to baseline [1].
• Grade 3 adverse events occurred in 16% of patients related to the neoadjuvant regimen and 15% to surgery, with no grade 4 or 5 events, suggesting the response-adapted approach did not introduce new safety concerns [1].

A Longstanding Trade-off Between Cure and Function

Locally advanced HNSCC accounts for more than 60% of new diagnoses and carries a high risk of recurrence and metastasis, a burden that falls disproportionately on patients whose tumors are HPV-negative. For decades, clinicians treating this population have faced two imperfect options: definitive chemoradiotherapy without surgery, or radical surgery followed by radiotherapy. Kunyu Yang, MD, director of the Union Hospital Cancer Center at Tongji Medical College, Huazhong University of Science and Technology, and a corresponding author of the new study, has described radical surgery as frequently resulting in organ dysfunction and facial disfigurement, while chemoradiotherapy, though capable of preserving organs such as the larynx and pharynx, has been associated in long-term follow-up with dysphagia, feeding-tube dependence, and voice loss [2]. Behind those clinical descriptions lie ordinary, everyday consequences: a patient’s ability to eat a meal with family, speak on the phone, and be understood at work. Those functions are what response-adapted surgery is ultimately trying to protect, not as an afterthought to cure, but alongside it.

Yang’s group had previously reported that adding immunotherapy to neoadjuvant chemotherapy, administering the combination before surgery and radiotherapy rather than after, meaningfully improved outcomes in this same patient population. That earlier phase 2 trial, published in Clinical Cancer Research in 2022, treated 30 patients with locally advanced, resectable HNSCC with three cycles of chemotherapy plus the PD-1 inhibitor camrelizumab, reporting an objective response rate of 96.7% and a pathological complete response rate of 37.0% [3]. The tumor shrinkage observed in that cohort raised the question that the REMATCH trial (ClinicalTrials.gov identifier NCT05459415) was designed to answer: if a tumor has visibly regressed, does the surgeon still need to resect according to the cancer’s original, pretreatment extent?

Trial Design and Patient Flow

REMATCH enrolled patients with resectable, HPV-negative, stage III to IVA locally advanced HNSCC. All patients received three cycles of neoadjuvant immunochemotherapy combining the PD-1 inhibitor penpulimab (Anikora®; Akeso Biopharma) with nab-paclitaxel (Abraxane®; Bristol Myers Squibb) and cisplatin (Platinol®/Platinol-AQ®; Bristol Myers Squibb).

Response was assessed before the third cycle using both imaging and laryngoscopy, a combination that allowed the surgical team to evaluate both radiographic tumor shrinkage and the functional status of the larynx directly, the structure most closely tied to a patient’s voice and ability to swallow safely. Patients with at least 50% regression of the primary tumor underwent reduced-volume surgery to remove residual disease while sparing adjacent structures; those with less than 50% regression received standard-volume surgery with conventional pretreatment margins. All patients, regardless of surgical extent, received risk-adapted adjuvant radiotherapy. The trial’s primary endpoint was two-year disease-free survival [1].

Of the enrolled cohort, 50 patients completed the full neoadjuvant regimen, achieving an objective response rate of 94% (95% CI, 84%–99%). Forty-seven of those patients proceeded to surgery: 42 underwent reduced-volume surgery after achieving at least 50% tumor regression, and five underwent standard-volume surgery [1].

Outcomes Diverged Sharply by Response Depth

At a median follow-up of 34.0 months, two-year disease-free survival for the full per-protocol cohort was 83% (95% CI, 69%–91%). That headline figure masked a wide split between the two surgical groups. Patients who achieved deep tumor regression and underwent reduced-volume surgery had a two-year disease-free survival of 90% (95% CI, 77%–96%), with laryngeal function preserved in 100% of patients with laryngeal or hypopharyngeal cancer in that group, meaning every one of those patients kept the ability to speak and swallow that a more extensive resection might have taken from them.

Patients who had not regressed as substantially and underwent standard-volume surgery fared far worse, with a two-year disease-free survival of only 20% (95% CI, 0.8%–58%) [1]. The size of that gap, roughly 70 percentage points, is what the authors point to as evidence that early response to neoadjuvant therapy carries strong prognostic weight independent of what the subsequent surgery accomplishes; it also underscores how small the poor-responder subgroup was, five patients, a point that tempers how far that comparison can be generalized.

Safety and health-related Quality of Life

The trial reported grade 3 adverse events in 16% of patients related to the neoadjuvant immunochemotherapy regimen and in 15% of patients related to surgery, with no grade 4 or 5 events of either kind recorded [1]. At nine months after completing radiotherapy, most quality-of-life measures had either improved or stabilized relative to baseline. For patients navigating recovery from cancer treatment in the head and neck, where side effects can touch something as basic as eating with others or being heard clearly, that stabilization is a meaningful marker in its own right, not just a secondary statistic alongside survival.

Positioning Relative to KEYNOTE-689

REMATCH answers a different question than the phase 3 KEYNOTE-689 trial does, and the two should not be read as competing. KEYNOTE-689 (NCT03765918), led by Ravindra Uppaluri, MD, PhD, of the Dana-Farber Brigham Cancer Center, and Douglas Adkins, MD, of Washington University School of Medicine, randomized 714 patients with resectable, previously untreated stage III or IV HNSCC to standard-of-care surgery and adjuvant therapy with or without perioperative pembrolizumab (Keytruda®; Merck & Co/MSD), and found that adding the checkpoint inhibitor improved event-free survival without changing the surgical plan itself; the trial’s own report specifies that neoadjuvant pembrolizumab did not affect the likelihood of surgical completion [4].

REMATCH, by contrast, holds the immunochemotherapy backbone roughly constant and asks whether the subsequent surgery can be individually resized based on how well each tumor responded. The two lines of evidence are complementary rather than competing: one establishes that perioperative immunotherapy improves outcomes without disrupting standard surgery, and the other explores whether standard surgery itself can be safely scaled back when that immunotherapy works well.

Study Limitations

The authors clearly state the constraints of their data. REMATCH was a single-arm, single-center trial without a randomized control group directly comparing reduced-volume and standard-volume surgery within responders, so it cannot exclude the possibility that deep responders would have fared equally well with conventional, more extensive resection. The cohort was also heavily weighted toward laryngeal and hypopharyngeal cancers, which accounted for roughly 90% of patients, which may limit how confidently the approach generalizes to other head and neck subsites. The authors frame these results as feasibility and hypothesis-generating evidence, explicitly calling for phase 3 randomized trials to validate the de-escalation strategy before broader adoption [1].

Disclosures

The published manuscript reports funding and author disclosures; the trial’s earlier-stage development was supported by the National Natural Science Foundation of China and the Key Research and Development Program of Hubei Province.

Clinical Trials
Reducing Excision Margins After Neoadjuvant Chemoimmunotherapy for HPV Negative Resectable Locally Advanced HNSCC – ClinicalTrials.gov ID NCT05459415
Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689) – ClinicalTrials.gov ID NCT03765918

Highlights of Prescribing Information

Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Penpulimab (Anikora® and 安尼可 (Annike); Akeso Biopharma)* [Prescribing Information]
Nab-paclitaxel (Abraxane®; Bristol Myers Squibb) [Prescribing Information]
Cisplatin (Platinol®/Platinol-AQ®; Bristol Myers Squibb) [Prescribing Information]

* 安尼可 (Annike) is the brand name for penpulimab used for its commercialization in China. Anikora® is the international brand name; in the United States, penpulimab-kcqx, the generic name, is used. Akeso independently developed the drug. However. Akeso manages its broader clinical development and commercialization through a joint venture with Chia Tai-Tianqing Pharmaceutical Group (a subsidiary of Sino Biopharmaceutical). In the United States, penpulimab-kcqx received US Food and Drug Administration (FDA) approval for treating advanced non-keratinizing nasopharyngeal carcinoma (NPC)

References

[1] Zhang X, Zhou Y, Huang J, Peng G, Zhang Z, Wen L, Zhao X, Wan C, Zhong Y, Fan G, Zhang L, Li M, Hong X, Shi L, Wu B, Guo F, Chen S, Jia Y, Xu Z, Xiao G, Yu J, Huang Q, Li Y, Qin Y, Wang W, Wang M, Yao M, Ma H, Hu Y, Yang K. Response-Adapted Surgery after Neoadjuvant Immunochemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma (REMATCH): A Single-Arm Phase II Trial. Clin Cancer Res. 2026 Sep 10:OF1-OF9. doi: 10.1158/1078-0432.CCR-26-1337. Epub ahead of print. PMID: 42717678.
[2] American Association for Cancer Research (AACR). Response to Neoadjuvant Immunochemotherapy May Allow for Surgical De-escalation in Head and Neck Cancers. Press release, September 10, 2026.
[3] Zhang Z, Wu B, Peng G, Xiao G, Huang J, Ding Q, Yang C, Xiong X, Ma H, Shi L, Yang J, Hong X, Wei J, Qin Y, Wan C, Zhong Y, Zhou Y, Zhao X, Leng Y, Zhang T, Wu G, Yao M, Zhang X, Yang K. Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial. Clin Cancer Res. 2022 Aug 2;28(15):3268-3276. doi: 10.1158/1078-0432.CCR-22-0666. PMID: 35766967.
[4] Uppaluri R, Haddad RI, Tao Y, Le Tourneau C, Lee NY, Westra W, Chernock R, Tahara M, Harrington KJ, Klochikhin AL, Braña I, Vasconcelos Alves G, Hughes BGM, Oliva M, Pinto Figueiredo Lima I, Ueda T, Rutkowski T, Schroeder U, Mauz PS, Fuereder T, Laban S, Oridate N, Popovtzer A, Mach N, Korobko Y, Alpuim Costa D, Hooda-Nehra A, Rodriguez CP, Bell RB, Manschot C, Benjamin K, Gumuscu B, Adkins D; KEYNOTE-689 Investigators. Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer. N Engl J Med. 2025 Jul 3;393(1):1-14. PMID: 40532178.

This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. The REMATCH trial is a single-arm, single-center phase 2 study without a randomized comparator; its authors describe the findings as feasibility evidence supporting further phase 3 investigation rather than a basis for changing the current standard of care.

Featured image: Doctor discussing treatment options. Photo courtesy: © 2019 – 2026 Fotolia/Adobe/ Used with permission.

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