CRB-701 Shows Antitumor Activity in HNSCC

The next-generation Nectin-4–targeting antibody-drug conjugate (ADC) CRB-701 (SYS6002) demonstrated antitumor activity and a manageable safety profile in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), according to updated data from a phase 1/2 study (NCT06265727).¹

Results shared during the 2026 ASCO Annual Meeting showed that among 41 patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with CRB-701 monotherapy at 2.7 mg/kg or 3.6 mg/kg every 3 weeks, the confirmed objective response rate (cORR) was 4 (20.0%) at 2.7 mg/kg (95% CI, 7.1-40.1) and 5 (14.7%) at 3.6 mg/kg (95% CI, 0-17.1) in the non-OPSCC subgroup (n = 34 and n = 37, respectively).

In the overall HNSCC population, cORR was 5 (14.7%) at 2.7 mg/kg (95% CI, 6.0-26.3) and 9 (24.3%) at 3.6 mg/kg (95% CI, 13.3-38.6). The majority of patients with OPSCC were HPV-positive and had previously received both platinum-based chemotherapy and anti–PD-L1 therapy.

Median duration of response (DOR) in the overall HNSCC population was 4.8 months at 2.7 mg/kg and 6.3 months at 3.6 mg/kg. Median progression-free survival (PFS) was 4.2 months (95% CI, 2.6-5.3) at 2.7 mg/kg and 5.6 months (95% CI, 4.1-7.7) at 3.6 mg/kg in the overall HNSCC cohort. In the OPSCC subgroup at 3.6 mg/kg, median PFS was 7.4 months (95% CI, not evaluable) compared with 4.2 months (95% CI, 1.3-4.2) in the non-OPSCC group. Responses were observed across all subgroups when stratified by prior lines of therapy (3 or more vs fewer than 3) and disease extent (locally recurrent vs metastatic).

Antitumor responses were observed across all Nectin-4 expression levels, including patients with both high and low Nectin-4 expression. Anatomical subtype and HPV status appeared to be among the major factors contributing to response.

CRB-701 Safety and Ocular Toxicity in HNSCC

The safety profile of CRB-701 in patients with HNSCC was consistent with the overall safety population across all tumor types. The most common treatment-related adverse events (TRAEs) occurring in 20% or more of the overall safety population (n = 317) included dysgeusia (approximately 30%), fatigue (approximately 23%), alopecia (approximately 22%), and keratitis (approximately 49%).

Keratitis was the most notable ocular toxicity and was observed in 33 of 75 patients with HNSCC (44.0%) at any grade, with grade 3 events occurring in 7 (9.3%). At the 2.7 mg/kg dose level (n = 36), any-grade keratitis was observed in 13 patients (36.1%), with grade 3 in 2 (5.6%). At the 3.6 mg/kg dose level (n = 39), any-grade keratitis occurred in 20 patients (51.3%), with grade 3 in 5 (12.8%). No grade 4 or 5 keratitis events were reported. Ocular toxicities were reversible and manageable through dose delays and reductions, as well as prophylactic eye drops. Dose interruptions and reductions were used frequently to manage ocular toxicity; discontinuations due to ocular events were uncommon.

The median duration of keratitis exposure was 86.0 days (range, 1-367) at 2.7 mg/kg and 93.0 days (range, 1-477) at 3.6 mg/kg. Relative dose intensity was 97.7% and 85.7% at the 2.7 mg/kg and 3.6 mg/kg dose levels, respectively. Grade 3 events were also more common at the 3.6 mg/kg dose (51.3% vs 36.1%).

CRB-701 Phase 1/2 Study Design and HNSCC Patient Characteristics

In the phase 1/2 study, patients were randomized 1:1 to 2.7 mg/kg or 3.6 mg/kg every 3 weeks. The study enrolled patients with R/M HNSCC who had received at least 1 prior line of systemic therapy. HPV status was retrospectively confirmed using p16 immunohistochemistry and/or HPV genomic assays.

As of April 1, 2026, a total of 317 patients had received at least 1 dose of CRB-701 monotherapy across all tumor types, of whom 75 patients with HNSCC were treated at 2.7 mg/kg or 3.6 mg/kg every 3 weeks; 41 had OPSCC and 34 had non-OPSCC. The safety population included 71 evaluable HNSCC patients, with 4 not evaluable. A total of 34 patients with non-OPSCC and 30 with OPSCC were included in the efficacy population.

Key baseline characteristics in the HNSCC cohort (n = 75) included a median age of 62 years (range, 24-78), with 67 patients (89.3%) male. ECOG performance status was 0 in 35 patients (46.7%) and 1 in 37 patients (49.3%). The median number of prior therapies was 3 (range, 1-9). Among patients with OPSCC, 35 (85.4%) were HPV-positive; in the non-OPSCC subgroup, 8 (23.5%) were HPV-positive. Disease extent was locally recurrent and metastatic in 39 patients (52.0%) and locally recurrent in 24 (32.0%).

An ongoing dose expansion phase is evaluating CRB-701 in combination with pembrolizumab (Keytruda) in the first-line setting for OPSCC.

Reference

1. Mantia C, Hanna GJ, Loriot Y, et al. 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. J Clin Oncol. 2026;44(suppl 16):6062. doi:10.1200/JCO.2026.44.16_suppl.6062