At the ESMO Congress 2026, Paul L. L. Swiecicki (Ann Arbor, United States) presented results from the phase Ib/II OrigAMI-4 trial (NCT06385080), evaluating amivantamab, an EGFR-MET bispecific antibody, in combination with pembrolizumab and carboplatin as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
The investigational combination demonstrated encouraging preliminary antitumor activity, achieving a confirmed objective response rate (ORR) of 77% in patients with HPV-unrelated disease, including three complete responses. However, the small study population and limited follow-up warrant further investigation.
Methods
OrigAMI-4 is a phase Ib/II study investigating amivantamab plus pembrolizumab and carboplatin in previously untreated recurrent or metastatic HNSCC.
Cohort 5 enrolled patients with PD-L1 combined positive score (CPS) ≥1 who received subcutaneous amivantamab hyaluronidase-lpuj every three weeks, alongside pembrolizumab and carboplatin for a maximum of six cycles.
The primary endpoint was investigator-assessed ORR according to RECIST v1.1.
Efficacy was evaluated separately in patients with HPV-unrelated HNSCC, defined as tumors of the oral cavity, hypopharynx, larynx, or p16-negative oropharynx, and those with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC).
Key Takeaways
At the March 18, 2026, data cutoff, 30 patients had received treatment, with 29 included in the efficacy analysis. The median age was 66 years, 73% were male, and the median follow-up was 7.7 months.
- HPV-unrelated disease: Confirmed ORR was 77% (17/22; 95% CI, 55–92%), including three complete responses and 14 partial responses.
- Disease control: Among patients with HPV-unrelated HNSCC, four achieved stable disease and one experienced progressive disease.
- Response durability: At the data cutoff, 65% (11/17) of confirmed responses in HPV-unrelated disease were ongoing.
- HPV-positive oropharyngeal cancer: ORR was 29% (2/7), with two partial responses. One response remained ongoing.
- Additional HPV-positive outcomes: Two patients achieved stable disease, two had progressive disease, and one was not evaluable.
- Safety: The most common adverse events included anemia, hypoalbuminemia, thrombocytopenia, stomatitis, and hypomagnesemia.
- Administration-related reactions: Reactions attributed to amivantamab occurred in 13% of patients, with no grade ≥3 events reported.
The safety profile was generally consistent with the known profiles of the individual agents. Updated results with longer follow-up were identified for presentation at the congress.
Conclusion
The phase Ib/II OrigAMI-4 study demonstrated promising preliminary antitumor activity with amivantamab, pembrolizumab, and carboplatin as first-line treatment for recurrent or metastatic HNSCC.
The 77% confirmed response rate in HPV-unrelated disease, including complete responses and ongoing responses at the data cutoff, supports further investigation of EGFR-MET bispecific antibody therapy in this setting.
However, the small, nonrandomized cohort and short follow-up limit conclusions about comparative efficacy, response durability, and long-term safety.
The findings have supported the development of the global randomized phase III OrigAMI-5 trial (NCT07276399), which is evaluating amivantamab plus pembrolizumab and carboplatin against pembrolizumab, fluorouracil, and platinum chemotherapy in patients with HPV-unrelated recurrent or metastatic HNSCC.
Further evaluation will determine whether this combination can improve outcomes compared with established first-line treatment strategies.
Source: ESMO Congress 2026, OrigAMI-4 Abstract; OrigAMI-4 (NCT06385080).
