A novel MDM2 inhibitor, APG-115 (alrizomadlin), has demonstrated antitumor activity and good tolerability in patients with progressive salivary cancer, particularly adenoid cystic carcinoma, according to data presented by Swiecicki et al at the 2024 Multidisciplinary Head and Neck Cancers Symposium (Abstract 8).
Results of a phase I/II trial showed an overall response rate of 13% and a disease control rate of 94% with single-agent APG-115. Antitumor activity was more pronounced in patients with adenoid cystic carcinoma, with an overall response rate and disease control rate of 16% and 96%, respectively.
“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. “These data strongly support confirmatory clinical trials with APG-115 in adenoid cystic carcinoma.”
As Dr. Swiecicki explained, metastatic salivary gland cancers are a diverse group of rare cancers, with no approved therapeutics and even fewer off-label treatments supported by evidence. For patients with adenoid cystic carcinoma, he added, 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 an oral small-molecule MDM2 inhibitor.
Open-Label Multicenter Study
Based on these preclinical data, Dr. Swiecicki and colleagues hypothesized that APG-115 may show significant clinical activity in patients with P53 wild-type salivary gland cancer.
The phase I/II multicenter, open-label study enrolled 31 patients with measurable metastatic salivary gland cancer refractory to standard therapies. APG-115 was given orally at 160 mg daily in a 2-week-on, 1-week-off schedule.
The primary endpoint was determining the maximum tolerated dose; secondary efficacy endpoints included response rate, progression-free survival, and duration of response.
KEY POINTS
- APG-115 showed activity as a single agent in patients with progressive salivary gland cancers, especially adenoid cystic carcinoma, with an overall response rate of 13% and disease control rate of 94%.
- APG-115 also demonstrated an acceptable toxicity profile at the selected dose. Only two patients discontinued treatment due to adverse events, and no grade 4 toxicity was observed.
Study Results
As Dr. Swiecicki reported, 80% of enrolled patients had adenoid cystic carcinoma, with the remainder having various rare subtypes of salivary gland cancer; 60% of patients had received no prior systemic therapy.
The maximum tolerated dose was defined as the starting dose of 160 mg, with no de-escalations required. Confirmed partial responses were reported in four patients—all with adenoid cystic carcinoma—for an overall response rate of 13% and 16% in the adenoid cystic carcinoma subgroup.
In addition, 26 patients had stable disease, for a disease control rate of 94% overall and 96% in the adenoid cystic carcinoma subgroup. Estimated 6-month rate of progression-free survival was 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 those with adenoid cystic carcinoma.
“In the 26 patients with stable disease, more than half had a reduction in tumor size by greater than 10%,” said Dr. Swiecicki, who also noted the responses were durable, even after treatment discontinuation.
Two patients experienced serious treatment-related adverse events. The most common treatment-related adverse events included nausea, vomiting, and cytopenias.
According to Dr. Swiecicki, these findings support the further development of MDM2 inhibitors for patients with P53 wild-type salivary gland cancer, specifically those with 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 reported financial relationships with Ascentage Pharma, Astellas, Regeneron, and Remix Therapeutics. He also holds a patent for human papillomavirus circulating tumor DNA. For full disclosures of the study authors, visit astro.confex.com.
