Subcutaneous Amivantamab Displays Activity in Recurrent/Metastatic HNSCC

Subcutaneous amivantamab with hyaluronidase-lpuj (Rybrevant Faspro) exhibited rapid and durable antitumor activity and manageable safety among patients with head and neck squamous cell carcinoma (HNSCC) treated in the second- or third-line setting, according to findings from the phase 1b/2 OrigAMI-4 trial (NCT06385080) published in Oral Oncology.¹

An efficacy analysis revealed that among 38 patients, the investigator-assessed confirmed objective response rate (ORR) was 45% (95% CI, 29%-62%), with a confirmed clinical benefit rate (CBR) of 76% (95% CI, 60%-89%). Moreover, a complete response (CR) was observed in 1 patient (3%), with an additional 16 (42%) experiencing partial responses (PRs). Additionally, 82% of patients experienced a shrinkage of their target lesions.

Among responders, a median time to response of 6.4 weeks (range, 5.7-18.3) was observed, and the median duration of response (DOR) was 7.2 months (95% CI, 5.3-not estimable [NE]). Moreover, 47% experienced a DOR of at least 6 months. A total of 65% of responders remained on treatment as of data cutoff.

Regarding survival, the median progression-free survival (PFS) was 6.8 months (95% CI, 4.2-9.0), and the overall survival (OS) data were immature at the data cutoff date.

“Most patients who develop recurrent or metastatic disease that is not amenable to further surgery or radiation will be treated initially with immunotherapy, either alone or in combination with standard chemotherapy. However, most of these patients will ultimately have disease progression and will need a second line of therapy,” study author Jessica Geiger, MD, medical oncologist of Cleveland Clinic’s Head & Neck Oncology team, stated in a news release on the study findings.² “There’s been no consensus or standard treatment beyond frontline therapy in these patients. The [ORR] of current second-line treatments is [15% to 20%] and there are limited treatment options, so there’s a huge unmet need within this population.”

Investigators in the phase 1b/2 trial recruited patients 18 years and older with histologically or cytologically confirmed recurrent or metastatic HNSCC deemed incurable by local therapies. Those eligible for enrollment also had primary tumors in the oropharynx, oral cavity, hypopharynx, or the larynx; an ECOG performance score of 0 or 1; and disease progression on or after treatment with anti–PD-(L)1 checkpoint inhibition and platinum-based chemotherapy.

Patients received subcutaneous amivantamab co-formulated with 2000 U/mL of recombinant human hyaluronidase PH20 delivered to the abdomen. Amivantamab was given at a dose of 1600 mg or 2240 mg for patients 80 kg or greater in body weight on cycle 1, day 1, with subsequent weekly doses in cycle 1 given at 2400 mg or 3360 mg, respectively. Beginning cycle 2 day 1, amivantamab was given every 3 weeks at 2400 mg or 3360 mg. Additionally, at the discretion of the investigator, optional prophylactic management of dermatologic adverse effects (AEs) was administered.

Among patients evaluated in the overall population, the median age was 63.5 years (range, 30-81), with 53% of patients younger than 65 years. Most patients were male (76%), Asian (45%) or White (43%), and were from Eastern Asia (42%) or North America (31%). The median baseline body weight was 61 kg (range, 40-96), and 91% of patients weighed less than 80 kg. Most patients had an ECOG performance status of 1 (67%).

The median time from initial HNSCC diagnosis was 22 months (range, 3-270), and the median time from metastatic disease diagnosis to first dose was 10 months (range, 0-43). Most tumors were located in the oral cavity (49%). Most patients had stage IVC disease at screening (63%) and had received prior radiotherapy (88%) or related surgery (83%).

The primary end point of the trial was investigator-assessed ORR per RECIST v1.1 assessment. Secondary end points included CBR, time to response, DOR, PFS per RECIST v1.1 assessment, OS, and safety.

In the safety population (n = 86), 92% of patients experienced at least 1 treatment-emergent AE (TEAE). Grade 3 or higher TEAEs occurred in 47% of patients, with serious TEAEs occurring in 34%. The most frequent TEAEs included stomatitis (23%), dermatitis acneiform (20%), rash (19%), and paronychia (17%). Moreover, common TEAEs related to MET inhibition included hypoalbuminemia (31%) and peripheral edema (14%).

The most common grade 3 or higher TEAEs included dermatitis acneiform (7%) and anemia (6%). Additionally, administration-related reactions to amivantamab were observed in 7% of patients and were grade 1 (5%) or 2 (2%) in severity. TEAEs leading to dose interruption, reduction, or discontinuation occurred in 43%, 17%, and 7% of patients, respectively. The most common TEAEs leading to amivantamab discontinuation considered unrelated to study treatment included pneumonia aspiration and myocardial ischemia (n = 1), pneumonia aspiration (n = 1), cerebrovascular accident (n = 1), sudden death (n = 1), and cardiac arrest and post-procedural hemorrhage (n = 1).

References

1. Harrington KJ, Rosenberg AJ, Yang MH, et al. Subcutaneous amivantamab in recurrent/metastatic head and neck squamous cell cancer after disease progression on checkpoint inhibitor and chemotherapy: preliminary results from the phase 1b/2 OrigAMI-4 study. Oral Oncol. 2025;171:107791. doi:10.1016/j.oraloncology.2025.107791
2. EGFR-MET bispecific antibody shows promise for metastatic head & neck cancer. News release. Cleveland Clinic. February 12, 2026. Accessed February 12, 2026. https://tinyurl.com/5zzz5rhs