Johnson & Johnson's bispecific antibody Rybrevant (amivantamab) achieved a 45% objective response rate in patients with previously treated head and neck squamous cell cancer (HNSCC), according to Phase II data presented at ESMO 2025. The results represent a significant improvement over current standard of care options in this challenging indication.
Strong Efficacy Signal in Difficult-to-Treat Population
The Phase Ib/II OrigAMI-4 study (NCT06385080) evaluated subcutaneous Rybrevant monotherapy in 38 HPV-unrelated HNSCC patients who had previously received chemotherapy and a PD-(L)1 inhibitor. Among responders, one patient achieved a complete response while 12 achieved partial responses. An additional 15 patients experienced stable disease, resulting in an 82% clinical benefit rate.
The median duration of response reached 7.2 months, with median progression-free survival of 6.8 months. Overall survival data has not yet matured. Treatment-related discontinuations were low at 2%, with 7% of patients experiencing administration-related reactions, all grade 1 or 2.
"You're essentially doubling response rates versus standard of care," said Mark Wildgust, J&J oncology's vice-president of global medical affairs. Current second-line options include Keytruda monotherapy, which achieved a 16% response rate in the Keynote-012 study, and Erbitux, which produced a 24% response rate in the Interlink-1 trial.
Targeting EGFR Overexpression
Rybrevant's activity in HNSCC stems from its three-pronged mechanism targeting both EGFR and MET receptors while activating the immune system. According to Henar Hevia, Senior Director and EMEA therapeutic area lead of oncology at J&J, EGFR overexpression occurs in 80-90% of HNSCC cases, making it a logical target for investigation.
"Amongst the HNSCC patient population, EGFR overexpression can be seen in between 80% to 90% of cases, so it makes a lot of sense to investigate Rybrevant in this setting," Hevia stated. She noted that progression-free survival and objective response rates are higher than currently available drugs in this setting.
The bispecific was generally well tolerated, with the most common treatment-emergent adverse events being rash, fatigue, and hypoalbuminemia.
Advancing to First-Line Setting
Based on these encouraging results, J&J is preparing to launch the Phase III OrigAMI-5 study by the end of 2025. The trial will evaluate Rybrevant plus Keytruda plus carboplatin chemotherapy versus Keytruda plus 5-FU plus cisplatin or carboplatin in approximately 500 HPV-unrelated patients in the first-line setting.
The first-line benchmark is set by Keytruda plus chemotherapy, which has produced a 36% objective response rate. Additional insights into Rybrevant's first-line potential should emerge from cohort five of OrigAMI-4, which is testing the same combination in treatment-naive patients, with data expected in mid-to-late 2026.
Addressing Critical Unmet Need
The results address a significant unmet medical need in HNSCC, where five-year survival currently sits at 15% and one-third of patients fail to reach second-line treatment. Hevia expressed hopes that the company could "set a new standard of care with Rybrevant" in the HNSCC indication.
When asked about potential regulatory discussions, Wildgust remained cautious but open: "With all good data we talk to the regulatory agencies. We'll absolutely continue to do that."
Expanding Beyond Lung Cancer
Rybrevant first gained FDA approval in EGFR Exon 20-mutated non-small cell lung cancer in 2021, followed by full approval in certain NSCLC subsets in 2024. The drug has since become a cornerstone of second-line treatment for NSCLC and may advance to first-line based on superior results from the Phase III MARIPOSA study when combined with lazertinib.
J&J is also exploring Rybrevant's potential in colorectal cancer through the ongoing OrigAMI-2 trial, testing the drug in combination with mFOLFOX6 chemotherapy. The company's strategy focuses on leveraging Rybrevant's activity across solid tumors characterized by high EGFR expression rates.
