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Ado-trastuzumab emtansine a potential new treatment option for HER2-amplified advanced salivary gland cancer

Presented by
Dr Bob T. Li, Memorial Sloan Kettering Cancer Centre, USA
ASCO 2019
Medical writer: Kara Nyberg, PhD

Ado-trastuzumab emtansine, the antibody-drug conjugate more commonly known as T-DM1, demonstrated robust activity in HER2-amplified salivary gland cancer (SGC) within a phase II basket trial, warranting further investigation in this disease (Abstract 6001). Among the 10 patients with SGC treated with T-DM1, nine obtained an objective response, six of which were complete responses.

The median duration of response and median progression-free survival have yet to be reached despite a median follow-up of 12 months (range: 4 to 20 months).

To gain ground in this rare malignancy, researchers are capitalizing on the targetable mutations offered up by the diverse molecular landscape of SGC. HER2 gene amplification identified through next-generation sequencing (NGS) occurs in 8% of patients with SGC and approximately 30% of patients with the aggressive salivary duct carcinoma histologic subtype.1 Based on this information, lead investigator Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Centre, and colleagues hypothesized that patients with SGC found to be HER2 positive by molecular testing would benefit from T-DM1, which delivers a highly potent maytansine-derived antimitotic agent directly to HER2-bearing cells.

To test this hypothesis, patients with SGC participated in a single-arm basket trial that included several cohorts of patients with HER2-amplified advanced solid cancers. HER2 amplification was defined as a 2-fold or greater increase in HER2 gene copy number using the Memorial Sloan Kettering IMPACT platform or another validated NGS platform, or a HER2/CEP17 FISH ratio of at least 2.0. All patients received treatment with 3.6 mg/kg of intravenous T-DM1 every 3 weeks—the standard dosing regimen—until disease progression or unacceptable toxicity occurred. Responses were determined using the RECIST version 1.1 or the PET Response Criteria in Solid Tumours (PERCIST).

The 10 participants with SGC had a median age of 65 and 90% were male. Notably, these patients had already received a median of two prior systemic therapy regimens, which included HER2-targeted therapy for two patients and anti-androgen therapy for five patients.

Discussant Vanita Noronha, MD, of the Tata Memorial Centre, India, said that T-DM1 holds the potential to change clinical practice. “Ado-trastuzumab emtansine appears to be a good treatment option in patients with HER2-amplified salivary gland tumours,” and she believes the agent fulfills an unmet need.

SGC accounts for only 0.8% of all cancers. Diseases arising in the salivary ducts portend a particularly poor prognosis given its tendency to metastasize and the fact that no approved therapies exist for metastatic SGC.

Because NGS was used to screen patients for study entry, Dr. Li and colleagues felt it important to correlate HER2 gene amplification using this less conventional approach with the more standard FISH and immunohistochemistry (IHC) techniques. They found excellent concordance between the biomarker measures. Among the 10 patients with NGS-identified HER2 amplification (fold-change: 2.8 to s22.8), all eight patients tested had a FISH HER2/CEP17 ratio of at least 2.0, and all 10 patients had a HER2 IHC score of 3+.

The SGC cohort tolerated T-DM1 fairly well. Adverse events included thrombocytopenia (70%), transaminitis (60%), anaemia (20%), maculopapular rash (20%), and anorexia (10%), and all of these events were grade 1 or 2 in severity except for one case of grade 3 thrombocytopenia.

The plan now is to enroll 14 additional patients with SGC to expand the T-DM1 dataset, according to Dr. Li. “There are patients in need of this treatment. That is certainly the priority—to further accrue patients, complete the trial, publish the data, and hopefully have this treatment approved to benefit all patients,” he said.

Both Dr. Li and Dr. Noronha acknowledged that it would be nearly impossible to conduct a randomized controlled trial of T-DM1 given the rarity of SGC. Dr. Li said it took 2 years to enroll 10 patients with SGC in the basket trial, so a larger undertaking beyond the plan to enroll 24 total patients would prove challenging. He feels that T-DM1 will still be approved based on this small sample size, as has occurred with other agents in rare diseases.

  1. Zehir A, et al. Nat Med . 2017;23:703-13.

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