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

Recurrent head and neck squamous cell carcinoma (rHNSCC) remains a significant clinical challenge, with recurrence rates of 40-60% after curative treatment. Salvage surgery is the standard of care, yet approximately 50% of patients experience re-recurrence within 2 years. For patients who have progressed on prior PD-1 inhibitor and platinum-based therapy, effective treatment options are extremely limited.

Becotatug vedotin is a novel anti-EGFR antibody-drug conjugate (ADC) that has demonstrated significant anti-tumor activity in HNSCC, with an ORR of 40% in Phase Ia/Ib and 43% in the post-immunotherapy Phase II study. Pucotenlimab (HX008) is a PD-1 inhibitor with an extended half-life (T1/2 = 21.76 days). Phase I/II data showed the combination achieved ORR of 60% in HNSCC with manageable toxicity.

This study investigates neoadjuvant becotatug vedotin plus pucotenlimab in resectable rHNSCC after immunotherapy progression.

TREATMENT REGIMEN:

• Neoadjuvant: Becotatug vedotin 2.3 mg/kg IV + Pucotenlimab 3 mg/kg IV, Q3W, 3 cycles
• Surgery: Salvage surgery 3-4 weeks after neoadjuvant completion
• Adjuvant: IMRT (60-66 Gy/30f) +/- platinum-based chemotherapy per NCCN/CSCO
• Maintenance: Pucotenlimab 3 mg/kg IV Q3W for 12 cycles or until progression/toxicity

Simon's two-stage design: Stage 1 (25 patients, >=3 MPR required) to Stage 2 (17 additional, total 42). H0 MPR=14%, H1 MPR=30% (alpha=0.05, power=0.8).

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Age 18-75 years at time of consent
• Histologically or cytologically confirmed recurrent head and neck squamous cell carcinoma
• Disease progression after prior treatment including both PD-1/PD-L1 inhibitor and platinum-based therapy (combined or sequential)
• EGFR protein expression positive by immunohistochemistry (IHC), with no EGFR-targeted therapy within 6 months prior to enrollment
• Willing to provide archived tumor tissue or undergo fresh tumor biopsy for EGFR testing
• 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
• Resectable disease with no distant metastasis, as assessed by a multidisciplinary team
• 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
• Signed informed consent prior to any study-specific procedures
• Life expectancy greater than 3 months
• Effective contraception during study and for 6 months after last dose

Exclusion criteria

• History of other malignancies (except cured basal cell carcinoma or cervical carcinoma in situ)
• Comorbidities requiring long-term immunosuppressive therapy or corticosteroids at immunosuppressive doses
• Immunodeficiency or history of organ transplantation (including interstitial pneumonia, hepatitis, nephritis, hyperthyroidism, hypothyroidism)
• 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
• High-dose systemic corticosteroids within 4 weeks prior to enrollment
• Pregnant or lactating women; fertile patients not using effective contraception
• Laboratory values not meeting inclusion criteria within 7 days
• Significantly impaired cardiac, hepatic, pulmonary, renal, or bone marrow function
• Severe uncontrolled comorbidities or active infections
• Concurrent participation in other clinical trials
• Refusal or inability to sign informed consent
• Other contraindications to study treatment as determined by the investigator
• Psychiatric disorders or mental illness resulting in lack of legal capacity