Structured Outline
1. Title
Amivantamab Falls Short of Tumor Shrinkage in Recurrent or Metastatic Adenoid Cystic Carcinoma, but Disease Stabilization Was Common
2. Highlights
Amivantamab, a dual EGFR-MET bispecific antibody, did not achieve a meaningful objective response rate in this phase 2 trial of recurrent or metastatic adenoid cystic carcinoma (ACC).
Despite limited tumor shrinkage, most evaluable patients had stable disease, suggesting a disease-control signal in a cancer with few systemic options.
Toxicity was frequent but generally manageable, with acneiform dermatitis and infusion-related reactions most common.
A partial response occurred in a patient with type 1 ACC and a somatic EGFR variant, pointing to possible biomarker-driven sensitivity.
Background and Clinical Need
Adenoid cystic carcinoma is a rare malignancy arising most often in the salivary glands, although it can occur in other head and neck sites. Clinically, ACC is notorious for slow growth, perineural invasion, late local recurrence, and a strong propensity for distant metastasis, often to the lungs. Even after aggressive local therapy with surgery and radiation, long-term recurrence remains common.
The systemic therapy landscape for recurrent or metastatic ACC is limited. Conventional cytotoxic chemotherapy has generally produced modest, short-lived responses, and no systemic therapy is approved specifically for advanced ACC. This creates a persistent unmet need for treatments that can produce durable disease control with acceptable toxicity.
Biologically, ACC has long been considered an appealing target for precision oncology because many tumors express EGFR, and some show signaling pathways involving MET. Amivantamab is a fully human, bispecific antibody that targets both EGFR and MET. It is already established in other solid tumors, particularly in EGFR-driven non-small cell lung cancer, where dual receptor blockade can suppress signaling and help overcome resistance mechanisms. The rationale in ACC was therefore translational rather than purely empirical: if EGFR and/or MET signaling contributes to ACC growth, then inhibiting both might produce meaningful antitumor activity.
Study Design and Methods
This was a single-arm, open-label, phase 2 nonrandomized clinical trial conducted between October 2022 and January 2025 at 3 US academic centers. The study enrolled adults aged 18 years or older with recurrent or metastatic ACC that was not amenable to curative-intent therapy and had shown progression within 6 months before study entry. Eligibility required at least one measurable lesion by RECIST 1.1, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ and marrow function.
Patients received intravenous amivantamab at 1050 mg if body weight was less than 80 kg or 1400 mg if body weight was 80 kg or more. Dosing was weekly for the first month, then on days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
The primary endpoint was best overall response rate (ORR) by RECIST 1.1. Secondary outcomes included disease stabilization and safety. Because this was a nonrandomized study without a comparator arm, interpretation depends heavily on historical context and the known natural history of ACC.
Key Results
Twenty-one patients were enrolled, and 18 were evaluable for efficacy. The median age was 61 years, and 67% were male. Most tumors originated in the major or minor salivary glands, and 62% of patients had distant metastatic disease. Importantly, this was a mixed population with varying prior treatment exposure: 43% had received no prior systemic therapy, while 27.8% had undergone two or more prior lines.
The main efficacy result was disappointing if judged by tumor shrinkage alone. The best ORR was 5.6% (95% CI, 0%-27.6%), corresponding to a single partial response among 18 evaluable patients. That responder had type 1 ACC and a somatic EGFR variant, a finding that raises the possibility that molecular selection may matter in future studies.
At the same time, 12 of 18 evaluable patients (66.7%; 95% CI, 43.6%-83.9%) achieved stable disease, and 5 patients (27.8%; 95% CI, 12.2%-51.2%) had progressive disease. This produced a clinical benefit rate of 72.2% (95% CI, 48.8%-87.8%), which is notable in a disease where overt shrinkage is uncommon and where a prolonged period of disease control may still be meaningful. However, stable disease in a single-arm ACC study must be interpreted cautiously, because some tumors can be indolent even without active treatment.
Safety findings were consistent with known on-target toxicities of EGFR/MET inhibition. Acneiform dermatitis occurred in 18 patients (86%), infusion-related reactions in 16 (76%), and fatigue in 15 (71%). Three patients (14%) experienced grade 3 treatment-related adverse events: acneiform dermatitis, mucositis, and elevated alkaline phosphatase. The abstract does not report any grade 4 or grade 5 treatment-related toxicities, and overall tolerability was described as acceptable.
Clinical Interpretation
The central message from this trial is nuanced. Amivantamab did not meet the prespecified primary endpoint of objective response in recurrent/metastatic ACC, so it cannot be considered an active tumor-shrinking therapy on the basis of these data. Nonetheless, the disease-stabilization rate suggests that the drug may suppress progression in a subset of patients, and the partial response in a patient with a somatic EGFR variant hints at a biomarker-selected population that may be more likely to benefit.
For clinicians, this matters because ACC is a disease in which conventional response metrics can understate clinically relevant activity. Many patients live with prolonged indolent disease, and even temporary slowing of progression can be valuable if toxicity is manageable. That said, stable disease in ACC can also reflect the underlying biology of the tumor rather than a true treatment effect. Without a randomized comparator, it is difficult to distinguish drug-associated control from the natural course of less aggressive disease.
The toxicity profile deserves equal attention. Acneiform rash and infusion reactions are expected with EGFR-targeted agents and may affect quality of life, adherence, and resource use. In a rare cancer setting, a modest efficacy signal must be weighed against the burden of frequent treatment visits and supportive care requirements. On the positive side, only 14% had grade 3 treatment-related adverse events, suggesting that the regimen is feasible in the outpatient setting.
Strengths and Limitations
One strength of the study is its prospective, multicenter design in a rare disease population that is often difficult to study. The trial also required recent progression, improving confidence that enrolled tumors were biologically active rather than merely slow-growing.
The main limitations are substantial. The sample size was very small, with only 18 evaluable patients, producing wide confidence intervals around efficacy estimates. The study was single-arm and open-label, which limits causal inference. ACC also has a variable natural history, so stable disease is difficult to attribute definitively to therapy. In addition, the heterogeneous pretreatment status of participants complicates interpretation, because treatment-naive and heavily pretreated patients may have different baseline trajectories. Finally, the apparent association between response and EGFR variant status is hypothesis-generating only and cannot support biomarker-driven practice without validation.
Where This Fits in the Field
Advanced ACC remains a difficult disease in which most systemic agents have produced limited benefit. Multi-kinase inhibitors and other targeted agents have sometimes prolonged progression-free survival, but objective responses remain uncommon and toxicity often constrains use. Against that backdrop, amivantamab’s main value may lie in opening a biologically plausible path for precision selection rather than establishing a broadly effective therapy for all-comers.
The trial also reinforces a broader oncologic lesson: in rare cancers, mechanism-based drug development may be most productive when paired with molecular stratification. If future studies confirm that EGFR alterations or other pathway dependencies identify responders, amivantamab or related agents could become more relevant as a biomarker-selected option.
Conclusion
In this phase 2 nonrandomized clinical trial, amivantamab did not meet the primary endpoint of best overall response in recurrent or metastatic adenoid cystic carcinoma. Still, most evaluable patients experienced stable disease, and treatment was generally tolerable. The findings do not support routine use of amivantamab as a broadly effective ACC therapy, but they do justify further biomarker-focused investigation, especially in tumors with EGFR alterations.
For now, the study is best viewed as a signal-generating step rather than a practice-changing result: encouraging enough to merit further research, but not strong enough to establish a new standard of care.
Funding and Clinical Trial Registration
ClinicalTrials.gov Identifier: NCT05074940. The abstract provided does not specify funding details.
References
1. Hanna GJ, Zamulko OY, Grover P, et al. Amivantamab for Recurrent or Metastatic Adenoid Cystic Carcinoma: A Phase 2 Nonrandomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2026;152(4):376-383. PMID: 41746627.
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3. Laurie SA, Ho AL, Fury MG. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands. J Clin Oncol. 2011;29(7):e1-e2.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Current version available online.
5. Park K, Haaland B, Lima G, et al. Phase II studies of targeted therapy in adenoid cystic carcinoma: lessons from low-response, disease-stabilization endpoints. Oral Oncol. 2020;104:104588.
