Amivantamab in HPV-unrelated recurrent/metastatic head and neck squamous cell cancer after disease progression on immune checkpoint inhibitor and chemotherapy: Pivotal results from the phase 1b/2 OrigAMI-4 study.

6008 Background: Prognosis is poor for patients with HPV-unrelated recurrent/metastatic (R/M) head and neck squamous cell cancer (HNSCC) after disease progression on immune checkpoint inhibitor (ICI) and chemotherapy, with participants (pts) who received cetuximab showing an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 3.8 months (Fayette Clin Cancer Res 2025). In addition to EGFR, MET expression is also elevated in R/M HNSCC. Therefore, we evaluated amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, as monotherapy in HPV-unrelated R/M HNSCC after progression on platinum-based chemotherapy and a PD-(L)1 inhibitor. Methods: Cohort 1 of OrigAMI-4 (NCT06385080) evaluated subcutaneous (SC) amivantamab at a dose of 1600 mg (≥80 kg, 2240 mg) on Cycle 1 Day 1, then 2400 mg (≥80 kg, 3360 mg) on Cycle 1 Day 8 and Day 15, and then every 3 weeks. Pts with R/M HNSCC who had disease progression on a PD-(L)1 inhibitor and platinum-based chemotherapy were enrolled. Prior anti-EGFR therapy was exclusionary. The primary endpoint was ORR per RECIST v1.1. The sample size provided >99% power to reject the null hypothesis (ORR ≤10%) assuming an ORR of 30% with a 2-sided alpha of 5%. Secondary endpoints included duration of response (DoR), PFS, and safety. Results: As of 6 Jan 2026 (median follow-up: 9.0 months), the cohort was fully enrolled with 102 pts having received ≥1 dose of SC amivantamab. The median age was 63 years (range, 30–81), 77% were male, and 67% had an ECOG performance status of 1. All pts had received prior PD-(L)1 inhibitor and platinum-based chemotherapy. The confirmed ORR was 47% (48/102; 95% CI, 37–57), with 4 complete responses, 44 partial responses, and 39 pts with stable disease. A majority (79%) experienced shrinkage of target lesions. Among confirmed responders, the median DoR was 7.2 months (95% CI, 5.8–not estimable NE). Responses were rapid, with a median time to initial response of 6.6 weeks (range, 5.6–43.4). Median PFS was 6.8 months (95% CI, 5.2–8.2). Treatment-emergent adverse events (AEs) were mainly EGFR/MET-related, with the most common (>25%) being hypoalbuminemia, rash, dermatitis acneiform, paronychia, stomatitis, and fatigue. Administration-related reactions were seen in 13% of pts (all grade 1–2). In total, 6 (6%) pts discontinued due to treatment-related AEs. Longer follow-up, subgroup, and biomarker analyses will be presented at the meeting. Conclusions: SC amivantamab monotherapy demonstrated an ORR of 47%, with rapid and durable responses in pts with HPV-unrelated, R/M HNSCC after disease progression on an ICI and chemotherapy. The safety profile and tolerability are consistent with prior reports. Clinical trial information: NCT06385080 .