A phase 1/2 study of the next-generation nectin-4–targeting antibody-drug conjugate CRB-701 (SYS6002) in patients with recurrent or metastatic head and neck squamous cell carcinoma.

6062 Background: CRB-701 is a next-generation Nectin-4–targeted monomethyl auristatin E (MMAE)-based antibody–drug conjugate with differentiated safety, efficacy and pharmacokinetics compared with other agents in the same class. As previously reported, CRB-701 demonstrated antitumor responses independent of Nectin-4 expression levels in solid tumors, notably in patients with heavily pretreated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, as well as urothelial carcinoma. Here, we provide data from this phase 1/2 trial in patients with recurrent or metastatic (R/M) HNSCC enrolled in dose escalation (part A) and dose optimization (part B) (NCT06265727). Methods: Patients with R/M HNSCC who had received ≥ 1 line of therapy were enrolled. Part A employed a Bayesian Optimal Interval design with four doses (1.8, 2.7, 3.6 and 4.5 mg/kg; each every 3 weeks [Q3W]) to determine the maximum tolerated dose. In part B, the pharmacologically active dose range identified in part A was evaluated using a time-to-event Bayesian optimal phase 2 design. Patients were randomized 1:1 to receive CRB-701 at 2.7 or 3.6 mg/kg Q3W. The primary endpoints for parts A and B were dose-limiting toxicities and objective response rate (ORR), respectively. A scan ≥ 4 weeks after the initial response was required to confirm partial and complete responses. Safety, tolerability and pharmacokinetics were also assessed. Nectin-4 expression and human papilloma virus (HPV)/p16 status were evaluated retrospectively. Results: As of September 2025, 60 patients with HNSCC were enrolled across parts A and B. The median (range) number of previous therapies was 3.0 (1–9) in the 2.7 mg/kg group and 3.0 (1–8) in the 3.6 mg/kg group; 85% of patients were refractory to immunotherapy and platinum-based regimens. The confirmed ORR was 33.3% (4/12 patients; unconfirmed ORR also 33.3%) at the 2.7 mg/kg dose, and 33.3% (7/21 patients; unconfirmed ORR, 47.6% [10/21 patients]) at the 3.6 mg/kg dose. Responses were observed regardless of HPV/p16 status. The safety profile of CRB-701 was broadly consistent with earlier findings: keratitis, fatigue, alopecia, dysgeusia and anemia were the most frequently reported treatment-emergent adverse events (≥ 15% of overall solid tumor population [N = 167]). An expanded efficacy analysis reporting an additional 6 months of follow-up, including ORR, duration of response and progression-free survival will be presented at the congress. Subgroup analyses by HPV status, treatment history and disease extent will also be presented. Conclusions: CRB-701 has shown promising efficacy in patients with heavily pretreated R/M HNSCC, along with a favorable safety profile compared with other MMAE-based therapies. Further investigation of CRB-701 is warranted in this difficult-to-treat patient population. Clinical trial information: NCT06265727 .