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

Официальное название

Neoadjuvant Becotatug Vedotin (Anti-EGFR ADC) Combined With Pucotenlimab (Anti-PD-1) in Patients With Resectable Recurrent Head and Neck Squamous Cell Carcinoma Who Progressed on Prior PD-1/PD-L1 Inhibitor and Platinum-Based Therapy: A Prospective, Single-Arm, Multi-Center, Phase II Clinical Trial

Обзор

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.

Подробное описание

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:

1. Neoadjuvant: Becotatug vedotin 2.3 mg/kg IV + Pucotenlimab 3 mg/kg IV, Q3W, 3 cycles 2. Surgery: Salvage surgery 3-4 weeks after neoadjuvant completion 3. Adjuvant: IMRT (60-66 Gy/30f) +/- platinum-based chemotherapy per NCCN/CSCO 4. 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).

Вмешательства

• Препарат Becotatug Vedotin
  Becotatug vedotin as one of the drugs used in neoadjuvant therapy.
• Препарат Pucotenlimab
  Pucotenlimab as one of the drugs used in neoadjuvant therapy.

Первичные конечные точки

• Major Pathological Response Rate (MPR) [Срок оценки: At time of surgery, approximately 12 weeks after enrollment]

Вторичные конечные точки (12)

• Objective Response Rate (ORR) [Срок оценки: After 3 cycles of neoadjuvant therapy, approximately 9 weeks]
• Pathological Complete Response Rate (pCR) [Срок оценки: At time of surgery]
• Median Overall Survival (mOS) [Срок оценки: Up to 60 months from enrollment]
• Median Progression-Free Survival (mPFS) [Срок оценки: Up to 60 months from enrollment]
• Duration of Response (DoR) [Срок оценки: Up to 60 months]
• 6-Month Progression-Free Survival Rate [Срок оценки: 6 months after end of treatment]
• 12-Month Progression-Free Survival Rate [Срок оценки: 12 months after end of treatment]
• Incidence of Adverse Events (AEs) [Срок оценки: Through study completion, up to 90 days after last dose]
• Incidence of Serious Adverse Events (SAEs) [Срок оценки: Through study completion, up to 90 days after last dose]
• Quality of Life - DASS-21 [Срок оценки: Baseline, during treatment, and follow-up through 12 months]
• Quality of Life - PTGI [Срок оценки: Baseline and follow-up through 12 months]
• Quality of Life - EORTC QLQ-C30 [Срок оценки: Baseline, during treatment, and follow-up through 12 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 12 центров

• The First People's Hospital of Foshan — Foshan
• Cancer Hospital of Guangzhou Medical University — Гуанчжоу
• Guangdong Provincial People's Hospital — Гуанчжоу
• Guangzhou First People's Hospital — Гуанчжоу
• Sun Yat-sen University Cancer Center — Гуанчжоу
• The Third Affiliated Hospital of Sun Yat-sen University — Гуанчжоу
• Zhujiang Hospital of Southern Medical University — Гуанчжоу
• Qingyuan People's Hospital — Qingyuan
• … и ещё 4 центра

Публикации

• Burtness 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 metas PMID 31679945
• Ferris 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. E PMID 27718784
• Xu RH, et al. A first-in-human phase Ia/Ib trial of becotatug vedotin in patients with advanced solid tumors. ESMO Congress 2023.
• Xu RH, et al. Becotatug vedotin combined with pucotenlimab in patients with advanced solid tumors: A phase I/II study. 2024.
• Haddad R, et al. Neoadjuvant pembrolizumab in locally advanced head and neck squamous cell carcinoma (KEYNOTE-689). ESMO Congress 2025.

Идентификаторы

NCT: NCT07589049 · 2025-FXY-495

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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