First-Line Subcutaneous Amivantamab Plus Pembrolizumab Shows Efficacy in PD-L1+ HNSCC

The first-line combination of amivantamab and hyaluronidase-lpuj (Rybrevant Faspro; subcutaneous amivantamab) with pembrolizumab (Keytruda) generated responses with an expected safety profile in patients with recurrent or metastatic, PD-L1–positive, human papillomavirus (HPV)–unrelated head and neck squamous cell carcinoma (HNSCC), according to findings from cohort 2 of the phase 1/2 OrigAMI-4 trial (NCT06385080), which were presented at the 2026 Multidisciplinary Head and Neck Cancers Symposium.¹

In this cohort, patients who received subcutaneous amivantamab plus pembrolizumab every 3 weeks (n = 39) achieved a confirmed overall response rate (ORR) of 56% (95% CI, 40%-72%). In total, there were 6 complete responses, 4 of which were confirmed at the time of the analysis. There were also 18 partial responses, all of which were confirmed. At a median follow-up of 10.4 months (range, 1.6-12.5), 46% of patients were still receiving the study treatment, and at the data cutoff date, 64% of confirmed responders (n = 14/22) were still receiving treatment. The rate of tumor shrinkage of target lesions was 82%, and the clinical benefit rate (CBR) was 74% (95% CI, 58%-87%). Furthermore, the median time to first response was 9.7 weeks, the median progression-free survival (PFS) was 7.7 months (95% CI, 5.0-not evaluable [NE]), and the median overall survival (OS) was NE.

“This was in the first-line treatment setting, but [the combination] showed a response rate of 56%,” Ranee Mehra, MD, said in an interview with OncLive®. “We're seeing activity of [amivantamab] as monotherapy and in combination, now in different lines of therapy, for head and neck cancer.”

Mehra is director of head and neck medical oncology and a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center at the University of Maryland Medical System in Baltimore.

What was the design of the OrigAMI-4 trial?

The open-label OrigAMI-4 trial includes 5 cohorts. Cohort 1 investigated subcutaneous amivantamab monotherapy in patients with HPV-unrelated recurrent or metastatic HNSCC who had been previously treated with platinum-based chemotherapy and PD-L1/PD-1–directed immunotherapy. This cohort excluded patients who had received prior EGFR-directed therapy. Notably, findings from cohort 1 supported the February 20, 2026, FDA granting of breakthrough therapy designation for subcutaneous amivantamab monotherapy in this population.²

In cohort 2, patients with HPV-unrelated, PD-L1–expressing recurrent or metastatic HNSCC who were treatment naive for advanced disease received subcutaneous amivantamab once weekly during the initial treatment period followed by every-3-weeks dosing with weight-based adjustments.^1,3 In this cohort, subcutaneous amivantamab was administered at 1600 mg (2240 mg for those with a body weight ≥80 kg) on cycle 1 day 1, and at 2400 mg (3360 mg if body weight ≥80 kg) every week for the remainder of cycle 1 and every 3 weeks from cycle 1 onward.³ Intravenous (IV) pembrolizumab was administered at 200 mg every 3 weeks.

ORR serves as the primary end point across cohorts. Secondary end points for cohort 2 include duration of response (DOR), CBR, PFS, OS, and safety.

What was the safety profile of subcutaneous amivantamab plus pembrolizumab?

The safety profile of the combination in cohort 2 of OrigAMI-4 was deemed consistent with the safety profiles of the individual agents, and the investigators reported no new safety signals.¹ The most common treatment-emergent adverse effects (AEs) included rash (49%), paronychia (46%), hypoalbuminemia (41%), dermatitis acneiform (38%), increased aspartate aminotransferase levels (38%), increased alanine aminotransferase levels (36%), and stomatitis (36%). In total, 15% of patients experienced administration-related reactions, all grades 1 and 2. Additionally, 4 patients discontinued treatment due to treatment-related AEs.

“The administration of amivantamab as a subcutaneous [formulation] resulted in fewer infusion- or administration-related reactions than what had historically been seen with the IV administration,” Mehra noted.

What does the future look like for investigating subcutaneous amivantamab in HNSCC?

The data from cohort 2 of OrigAMI-4 supported the initiation of the ongoing phase 3 OrigAMI-5 trial (NCT07276399), which is evaluating subcutaneous amivantamab plus carboplatin and pembrolizumab vs 5-fluorouracil plus pembrolizumab and platinum-based chemotherapy (either carboplatin or cisplatin) in the first-line setting in patients with HPV-unrelated recurrent or metastatic HNSCC, irrespective of PD-L1 expression.^1,4 Patients will be included if they are at least 18 years of age, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST 1.1 criteria.¹ OS and ORR serve as the coprimary end points. Secondary end points are PFS, DOR, safety, and quality-of-life (QOL) objectives.

“Patients with recurrent or metastatic head and neck cancer can be symptomatic from their disease, so having treatment options that will result in significant and deep responses is vital to improve their QOL,” Mehra stated. “The data I presented in cohort 2 [of OrigAMI-4] were with pembrolizumab and amivantamab, but [enrollment to this cohort] required PD-L1 expression of at least 1. In OrigAMI-5, with the addition of carboplatin, [enrollment is] allowed for patients irrespective of PD-L1 expression. This gives the opportunity for more patients to be on the study and receive the combination therapy.”

References

1. Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) plus immunotherapy shows strong clinical benefit with 56 percent overall response rate in first-line recurrent or metastatic head and neck cancer. News release. Johnson & Johnson. February 19, 2026. Accessed March 4, 2026. https://www.jnj.com/media-center/press-releases/rybrevant-faspro-amivantamab-and-hyaluronidase-lpuj-plus-immunotherapy-shows-strong-clinical-benefit-with-56-percent-overall-response-rate-in-first-line-recurrent-or-metastatic-head-and-neck-cancer
2. Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) plus immunotherapy shows strong clinical benefit with 56 percent overall response rate in first-line recurrent or metastatic head and neck cancer. News release. Johnson & Johnson. February 19, 2026. Accessed March 4, 2026. https://www.jnj.com/media-center/press-releases/rybrevant-faspro-amivantamab-and-hyaluronidase-lpuj-plus-immunotherapy-shows-strong-clinical-benefit-with-56-percent-overall-response-rate-in-first-line-recurrent-or-metastatic-head-and-neck-cancer
3. A study of amivantamab alone or in addition to other treatment agents in participants with head and neck cancer (OrigAMI-4). ClinicalTrials.gov. Updated February 13, 2026. Accessed March 4, 2026. https://clinicaltrials.gov/study/NCT06385080
4. A study of amivantamab in addition to standard of care agents (SOC) compared with SOC alone in participants with recurrent/​metastatic head and neck cancer (OrigAMI-5). ClinicalTrials.gov. Updated February 13, 2026. Accessed March 4, 2026. https://clinicaltrials.gov/study/NCT07276399