ERBIOTAX (TTCC-2022-02): A phase II, multicenter, randomized study of cetuximab with or without weekly paclitaxel after progression on first-line pembrolizumab plus platinum/5-FU in recurrent or metastatic head and neck squamous cell carcinoma.

TPS6131 Background: Pembrolizumab, with or without platinum–5FU (PF), is the current first-line (1L) standard of care for PD-L1–positive recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). However, no established standard of care exists after progression on immune checkpoint inhibitors (ICI). Emerging evidence suggests that cetuximab administered post-ICI achieves higher objective response rates (ORR) and longer progression-free (PFS) and overall survival (OS) compared with historical second-line (2L) cetuximab outcomes from the pre-ICI era. We hypothesize that 2L treatment with cetuximab +/- paclitaxel may be more effective after ICI failure than previously observed in the pre-ICI era. Methods: This is a multicenter, open-label, randomized, non-comparative, two-arm, investigator-initiated phase 2 trial. Patients will be randomized (2:1) to cetuximab plus paclitaxel (Arm A: ERBITAX) or cetuximab monotherapy (Arm B), administered on Days 1, 8 and 15 of 21-day cycles for 4 cycles, followed in both arms by biweekly cetuximab monotherapy until disease progression, death, unacceptable toxicity, or withdrawal of consent. A total of 65 evaluable patients will be enrolled: 41 in Arm A (H0: ORR 25%, H1: 45%, 80% power, two-sided alpha 0.05) and 24 in Arm B (H0: ORR 10%, H1: 30%, 80% power, two-sided alpha 0.05). The primary endpoint is ORR in each arm. Secondary endpoints include disease control rate (DCR), PFS, OS, health-related quality of life (EORTC QLQ-C30, EORTC QLQ-H&N35 and EuroQol EQ-5D) and safety. Baseline tumor tissue (all patients) and on-treatment samples (between cycles 2-5 in 50% of patients; optionally at progression), as well as serial plasma samples will be collected for translational exploratory studies. Patients must have histologically confirmed SCCHN of oral cavity, oropharynx (HPV-positive or HPV-negative), hypopharynx, or larynx, with confirmed progression per RECIST 1.1. on or after 1L pembro + PF. The study started enrollment in June 2025, with 7 patients enrolled by December 23, 2025. The total accrual period is 18 months. Clinical trial identifiers: NCT06856213; EUDRACT 2024-514953-31-00. Trial supported by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, providing study medication and financial support. Clinical trial information: NCT06856213 .