Becotatug Vedotin Combined With Pucotenlimab as Neoadjuvant Therapy for Resectable Recurrent Head and Neck Squamous Cell Carcinoma After Progression on Immunotherapy: A Prospective Phase II Study

This is a prospective, single-arm, multi-center, Phase II clinical trial evaluating the efficacy and safety of neoadjuvant becotatug vedotin (an anti-EGFR antibody-drug conjugate) combined with pucotenlimab (HX008, an anti-PD-1 monoclonal antibody) in patients with resectable recurrent head and neck squamous cell carcinoma (rHNSCC) who have progressed on prior PD-1/PD-L1 inhibitor and platinum-based therapy. A total of 42 EGFR-positive patients will be enrolled using Simon's two-stage design across 11 centers in China (Stage 1: 25 patients; Stage 2: 17 additional patients with 5% dropout). Enrolled patients will receive 3 cycles of neoadjuvant becotatug vedotin (2.3 mg/kg, IV, Q3W) plus pucotenlimab (3 mg/kg, IV, Q3W), followed by salvage surgery (3-4 weeks later), adjuvant radiotherapy +/- chemotherapy per NCCN/CSCO guidelines, and pucotenlimab maintenance therapy (3 mg/kg, Q3W) for up to 12 cycles or until disease progression or unacceptable toxicity. The primary endpoint is major pathological response (MPR) rate. The null hypothesis MPR rate is 14% (historical data) and the target MPR rate is 30% (alpha=0.05, power=0.8, one-sided). Secondary endpoints include objective response rate (ORR), pathological complete response (pCR), survival outcomes, quality of life, and safety.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

INCLUSION CRITERIA:

1. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
2. Age 18-75 years at time of consent
3. Histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma
4. Disease progression after prior treatment including both PD-1/PD-L1 inhibitor and platinum-based therapy (combined or sequential)
5. EGFR protein expression positive by immunohistochemistry (IHC), with no EGFR-targeted therapy within 6 months prior to enrollment
6. Willing to provide archived tumor tissue or undergo fresh tumor biopsy for EGFR testing
7. At least one measurable extracranial lesion per RECIST v1.1; previously treated lesions must demonstrate clear progression 3 or more months after last local treatment
8. Resectable disease with no distant metastasis, as assessed by a multidisciplinary team
9. Adequate organ function within 7 days prior to enrollment: ANC at least 2.0 x 10\^9/L, platelet count at least 100 x 10\^9/L; total bilirubin less than 1.5 x ULN, ALT/AST less than 2.5 x ULN; serum creatinine less than 1.5 x ULN
10. Signed informed consent prior to any study-specific procedures
11. Life expectancy greater than 3 months
12. Effective contraception during study and for 6 months after last dose

EXCLUSION CRITERIA:

1. History of other malignancies (except cured basal cell carcinoma or cervical carcinoma in situ)
2. Comorbidities requiring long-term immunosuppressive therapy or corticosteroids at immunosuppressive doses
3. Immunodeficiency or history of organ transplantation (including interstitial pneumonia, hepatitis, nephritis, hyperthyroidism, hypothyroidism)
4. HIV/AIDS; untreated active hepatitis B (HBV-DNA at least 500 IU/mL); hepatitis C (HCV-RNA above detection limit); or HBV/HCV co-infection
5. High-dose systemic corticosteroids within 4 weeks prior to enrollment
6. Pregnant or lactating women; fertile patients not using effective contraception
7. Laboratory values not meeting inclusion criteria within 7 days
8. Significantly impaired cardiac, hepatic, pulmonary, renal, or bone marrow function
9. Severe uncontrolled comorbidities or active infections
10. Concurrent participation in other clinical trials
11. Refusal or inability to sign informed consent
12. Other contraindications to study treatment as determined by the investigator
13. Psychiatric disorders or mental illness resulting in lack of legal capacity

• BACKGROUNDBurtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1. PMID 31679945
• BACKGROUNDFerris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8. PMID 27718784
• BACKGROUNDXu RH, et al. A first-in-human phase Ia/Ib trial of becotatug vedotin in patients with advanced solid tumors. ESMO Congress 2023.
• BACKGROUNDXu RH, et al. Becotatug vedotin combined with pucotenlimab in patients with advanced solid tumors: A phase I/II study. 2024.
• BACKGROUNDHaddad R, et al. Neoadjuvant pembrolizumab in locally advanced head and neck squamous cell carcinoma (KEYNOTE-689). ESMO Congress 2025.