A novel MDM2 inhibitor has demonstrated antitumor activity in progressive salivary cancer, particularly adenoid cystic carcinoma, according to data presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium.

Results of the phase I/II trial showed an overall response rate of 13% and a disease control rate of 94% with single-agent APG-115 (alrizomadlin). Antitumor activity was more pronounced in patients with adenoid cystic carcinoma, with an overall response rate of 16% and a disease control rate of 96%.

“APG-115 monotherapy demonstrates promising antitumor activity in patients with p53 wild-type salivary gland cancer, with good tolerability,” said lead study author Paul L. Swiecicki, MD, Clinical Associate Professor of Medical Oncology and Internal Medicine at the University of Michigan Rogel Cancer Center, Ann Arbor. “These data strongly support confirmatory clinical trials with APG-115 in adenoid cystic carcinoma.”

“These data strongly support confirmatory clinical trials with APG-115 in adenoid cystic carcinoma.”

— Paul L. Swiecicki, MD

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As Dr. Swiecicki explained, metastatic salivary gland cancers are a diverse group of rare cancers, with no approved therapeutics and few off-label treatments supported by evidence. For patients with adenoid cystic carcinoma, he said, VEGF inhibitors tend to be the standard of care, with response rates ranging from 0% to 15% and progression-free survival in the range of 5 to 10 months. The median progression-free survival in patients with untreated disease is 2.8 months.

According to Dr. Swiecicki, MDM2 gene amplifications are common in these tumors, and preclinical evidence supports the activity of MDM2 inhibitors both as monotherapy and in combination with chemotherapy. APG-115 is a potent oral small-molecule MDM2 inhibitor.

Open-Label, Multicenter Study

Based on preclinical data, Dr. Swiecicki and colleagues hypothesized that APG-115 would have significant clinical activity in p53 wild-type salivary gland cancer. Their phase I/II -multicenter, open-label study enrolled 31 patients with measurable metastatic salivary gland cancer refractory to standard therapies demonstrating at least 20% growth over the past year. APG-115 was given orally every other day at 150 mg in a 2-weeks-on, 1-week-off schedule.

The primary endpoint was the determination of the maximally tolerated dose. Secondary efficacy endpoints included response rate, progression-free survival, and duration of response.

Activity in p53 Wild-Type Salivary Gland Cancer

As Dr. Swiecicki reported, 80% of enrolled patients had adenoid cystic carcinoma, with the remainder consisting of various rare subtypes. About 60% of patients had received no prior systemic therapy.

The maximally tolerated dose was defined as the starting dose of 150 mg. Confirmed partial responses occurred in four patients, all with adenoid cystic carcinoma, for a response rate of 13% in the overall population and 16% in the subgroup with adenoid cystic carcinoma.

In addition, 26 patients had stable disease, for a disease control rate of 94% overall and 96% in patients with adenoid cystic carcinoma. Estimated rates of 6-month progression-free survival were 72% in all patients and 84% in those with adenoid cystic carcinoma, with a median progression-free survival of 10.3 months overall and 10.5 months in the adenoid cystic carcinoma subgroup.

“In the 26 patients with stable disease, more than half had a reduction in tumor size by greater than 10%,” said Dr. Swiecicki. He also noted that responses were durable, even after treatment discontinuation.

Two patients experienced dose-limiting toxicities. The most common serious treatment-related adverse events included nausea, vomiting, and cytopenias.

According to Dr. Swiecicki, these findings support further development of MNM2 inhibitors in patients with p53 wild-type salivary gland cancer, specifically adenoid cystic carcinoma.

“Given the historical rates of response and progression-free survival, we are quite encouraged by these results,” Dr. Swiecicki concluded. 

DISCLOSURE: Dr. Swiecicki has received honoraria from Astellas, Regeneron, Elevar Therapeutics, Prelude Therapeutics, CDR-Life, and Remix Therapeutics; has received research funding from Ascentage Pharma; and is a co-inventor of an institutional novel human papillomavirus circulating tumor DNA assay, patent pending.

REFERENCE

1. Pearson A, Muzaffar J, Kirtane K, et al: Phase I/II study of a novel MDM-2 inhibitor (APG-115-alrizomadlin) in p53 wild type salivary gland cancers. 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 8. Presented February 29, 2024.

EXPERT POINT OF VIEW

Glenn J. Hanna, MD, Director of the Center for Cancer Therapeutic Innovation (Early Drug Development Program); a medical oncologist at the Center for Head and Neck Oncology, Dana-Farber Cancer Institute; and Associate Professor of Medicine, Harvard Medical School, Boston, told The ASCO Post that he sees potential for MDM2 inhibitors in this difficult-to-treat patient population, but the safety profile may be a limiting factor.

Glenn J. Hanna, MD

“In our previous experience with MDM2 inhibitors, issues with cytopenias limited the ability to dose every day, so on/off dosing is required,” he said. “Combinations with chemotherapy have also been shown to cause too much toxicity with respect to cell counts.”

Given the high unmet need for patients with adenoid cystic carcinoma, however, Dr. Hanna suggested that even the overall response rate of 13% might be enough to warrant additional investigation.

“It’s interesting to see an early and encouraging signal in salivary gland cancers,” said Dr. Hanna. “Very few drugs have any response rate in adenoid cystic carcinoma, so it’s nice to see some responses.” 

DISCLOSURE: Dr. Hanna has received research support from ACCRF, Actuate, Elevar, Gateway for Cancer Research, Genentech, Remix, and Kura Oncology; and has served as a consultant or advisor to Elevar, Kura Oncology, Prelude, and Remix.