Introduction: The Therapeutic Vacuum in Adenoid Cystic Carcinoma
Adenoid cystic carcinoma (ACC) represents a distinct clinical challenge within the landscape of head and neck oncology. Characterized by an indolent but inexorable growth pattern, a high propensity for perineural invasion, and a frequent development of late-stage distant metastases (primarily to the lungs), ACC remains a disease with limited systemic therapeutic options. While primary localized disease is typically managed with surgical resection and adjuvant radiation therapy, the management of recurrent or metastatic (R/M) disease remains largely palliative.
Historically, cytotoxic chemotherapy has demonstrated minimal efficacy in R/M ACC, often yielding transient responses with significant toxicity. Targeted therapies, including multi-kinase inhibitors like lenvatinib and axitinib, have shown some promise in terms of disease stabilization but have failed to secure FDA approval for this specific indication due to toxicity profiles or modest objective response rates. Consequently, there is an urgent unmet medical need for novel, well-tolerated systemic agents that can provide durable disease control.
Mechanistic Rationale: Targeting the EGFR-MET Axis
The rationale for investigating amivantamab in ACC stems from the molecular landscape of these tumors. Epidermal growth factor receptor (EGFR) is frequently overexpressed in ACC, although mutations in the EGFR gene itself are rare. Despite this overexpression, first-generation EGFR tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (such as cetuximab) have largely underperformed in clinical trials for ACC.
However, the mesenchymal-epithelial transition (MET) pathway has emerged as a potential resistance mechanism and a co-driver in various malignancies. Amivantamab is a fully human IgG1-based bispecific antibody that targets both EGFR and MET. It functions through multiple mechanisms: blocking ligand binding, promoting receptor degradation, and inducing antibody-dependent cellular cytotoxicity (ADCC) via natural killer cells and macrophages. By simultaneously inhibiting two major signaling pathways, amivantamab was hypothesized to overcome the limitations of single-agent EGFR inhibition in ACC.
Study Design and Patient Population
The study, published in JAMA Otolaryngology–Head & Neck Surgery (Hanna et al., 2026), was a single-arm, open-label, phase 2 nonrandomized clinical trial conducted across three major US academic centers. The primary objective was to evaluate the best overall response rate (ORR) per RECIST 1.1 in patients with advanced ACC.
Between October 2022 and January 2025, the trial enrolled 21 patients with confirmed R/M ACC. Inclusion criteria required patients to be 18 years or older with disease not amenable to curative-intent therapy and documented radiographic progression within six months of enrollment. This progression requirement is critical in ACC trials to ensure that any observed disease stabilization is a result of the intervention rather than the naturally slow tempo of the disease.
Participants received intravenous amivantamab at weight-based doses (1050 mg for <80 kg; 1400 mg for ≥80 kg). The dosing schedule involved weekly administration for the first month (including a split dose on week 1 to mitigate infusion-related reactions), followed by biweekly dosing (days 1 and 15 of a 28-day cycle) until disease progression or unacceptable toxicity.
Key Findings: Efficacy and Clinical Benefit
Of the 21 patients enrolled, 18 were evaluable for efficacy. The cohort’s median age was 61 years, with a predominance of males (67%). Notably, 43% of patients were systemic therapy-naive, while 29% had received two or more prior lines of therapy, reflecting a heterogeneous but heavily pretreated population.
Objective Response and Disease Control
The study did not meet its primary endpoint of a high objective response rate. The best ORR was 5.6% (95% CI, 0%-27.6%), with only one patient achieving a confirmed partial response. Interestingly, this single responder possessed a type 1 ACC and a somatic EGFR variant, suggesting that specific molecular subsets might derive greater benefit from amivantamab.
Despite the low ORR, the clinical benefit rate (CBR)—defined as the sum of complete responses, partial responses, and stable disease lasting at least six months—was a significant 72.2% (95% CI, 48.8%-87.8%). Twelve patients (66.7%) achieved stable disease. For a disease like ACC, where the goal of therapy is often to delay symptomatic progression and maintain quality of life, this high rate of disease stabilization is clinically meaningful.
Safety and Tolerability Profile
Amivantamab was generally well tolerated, consistent with its known safety profile in other indications such as non-small cell lung cancer (NSCLC). The most common treatment-related adverse events (TRAEs) included:
- Acneiform dermatitis: 86%
- Infusion-related reactions (IRRs): 76%
- Fatigue: 71%
Most IRRs occurred during the first infusion and were managed with split-dose protocols and premedication. Grade 3 TRAEs were relatively rare, occurring in only 14% of patients (including cases of dermatitis, mucositis, and elevated alkaline phosphatase). No grade 4 or 5 treatment-related events were reported, suggesting that amivantamab has a more favorable toxicity profile compared to the multi-kinase inhibitors previously studied in this population.
Expert Commentary and Clinical Interpretation
The results of this trial highlight a recurring dilemma in ACC research: the disconnect between RECIST-defined objective responses and clinical utility. Because ACC is slow-growing, many investigators argue that ORR is an insufficient metric for evaluating drug efficacy. The fact that over 70% of patients achieved clinical benefit in a population that had demonstrated progression within the six months prior to enrollment suggests that amivantamab effectively altered the natural history of the disease for a majority of participants.
The identification of a partial response in a patient with a specific EGFR variant is particularly provocative. It underscores the importance of comprehensive genomic profiling in rare tumors. While ACC is often characterized by the MYB-NFIB translocation, secondary mutations in the EGFR or MET pathways may serve as biomarkers for patient selection in future studies.
Furthermore, the tolerability of amivantamab compared to agents like lenvatinib is a major consideration. In the R/M setting, where cure is not possible, the balance between efficacy and quality of life is paramount. Amivantamab’s lower incidence of grade 3 hypertension, proteinuria, and palmar-plantar erythrodysesthesia (hand-foot syndrome) makes it an attractive candidate for further investigation, perhaps in combination with other agents.
Conclusion: Moving the Needle in ACC
While the Phase 2 trial of amivantamab did not meet its primary ORR endpoint, it demonstrated robust disease control and a manageable safety profile in patients with recurrent or metastatic adenoid cystic carcinoma. These findings support the continued exploration of EGFR-MET inhibition in this disease space.
Future research should focus on identifying molecular biomarkers that predict response and investigating combination strategies that might convert stable disease into objective responses. For now, amivantamab represents a promising addition to the experimental armamentarium for a patient population with few other options.
Funding and Clinical Trial Information
This study was supported by Janssen Research & Development. ClinicalTrials.gov Identifier: NCT05074940.
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; doi:10.1001/jamaoto.2025.5404.
2. Ferrarotto R, et al. Lenvatinib in Recurrent or Metastatic Adenoid Cystic Carcinoma. J Clin Oncol. 2019;37(18):1561-1573.
3. Park MS, et al. Molecular landscape of salivary gland tumors: Therapeutic implications. Head Neck. 2021;43(1):345-358.
