A New Treatment for Salivary Gland Cancers: The MDM2 Inhibitor Alrizomadlin
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APG-115 (alrizomadlin), a new MDM2 inhibitor, is emerging as a well-tolerated treatment option with significant antitumor activity against salivary gland cancers, particularly in patients with advanced adenoid cystic carcinoma. Presented by Swiecicki and colleagues at the 2024 Multidisciplinary Head and Neck Cancers Symposium, these findings suggest that the new treatment offers a promising path in tackling salivary gland cancers, especially the challenging adenoid cystic carcinoma.
A Rare Group of Cancers with Limited Treatment Options
Salivary gland cancers are very rare cancers arising in the salivary glands. They can develop in the three pairs of major salivary glands in the head and neck (parotid, submandibular, and sublingual) and in various minor salivary glands. The most common type arises in the parotid gland. Symptoms may include swelling or a lump in the glands, pain, facial weakness or paralysis, and sometimes difficulty swallowing or speaking. Treatment options include surgery, radiotherapy, and, in some cases, chemotherapy. The course of salivary gland cancer varies according to cancer type, stage, and the patient's overall health. Early diagnosis is critical to managing these cancers.
The Importance of MDM2 in Cancer
The MDM2 (murine double minute 2) protein plays an important role in cancer biology, particularly as a negative regulator of the tumor-suppressing p53 protein. By regulating the cell cycle, p53 enables damaged DNA to be repaired and triggers programmed cell death in abnormal cells through apoptosis. This mechanism plays a critical role in preventing cancer. MDM2 suppresses p53 activity, leading to its proteasomal degradation through ubiquitination. This means that MDM2 overexpression or hyperactivation can suppress p53 function, allowing cells to divide uncontrollably and tumors to form.
MDM2's role in cancer, when considered in the context of the “14 Hallmarks of Cancer”, is particularly associated with the following features:
- Evading cell death: MDM2 suppresses p53's apoptotic function, allowing cancer cells to avoid programmed cell death.
- Sustained proliferative signaling: Suppression of p53 can override cell-cycle checkpoints and allow uncontrolled cell proliferation.
- Impaired genomic stability and DNA repair: Suppressing p53's ability to respond to DNA damage may cause genomic instability and mutation accumulation, contributing to cancer progression.
Although MDM2 inhibitors are considered potentially important agents in cancer treatment, no MDM2 inhibitor has yet been approved by the FDA (Food and Drug Administration in the United States).
Current Research
A phase I/II trial investigated the newly developed MDM2 inhibitor code-named APG-115, alrizomadlin. Results with single-agent APG-115 showed an overall response rate of 13% and a disease control rate of 94%. Antitumor activity was particularly evident in patients with adenoid cystic carcinoma, with overall response and disease control rates of 16% and 96%, respectively.
In metastatic salivary gland cancer, progression-free survival among untreated patients is very short, with a median of only 2.8 months.
APG-115 is an oral, small-molecule MDM2 inhibitor with this potential.
In light of these important findings, APG-115 was considered potentially capable of clinically meaningful activity in patients with nonmutant P53 salivary gland cancer. This hypothesis was tested in a phase I/II multicenter, open-label study involving 31 patients with measurable metastatic salivary gland cancer resistant to standard treatments. Patients received 160 mg of APG-115 daily for 2 weeks, followed by a 1-week break.
The study produced promising findings, particularly among patients with adenoid cystic carcinoma. The maximum tolerated dose was established as 160 mg without requiring dose reductions. Four patients, all with adenoid cystic carcinoma, had confirmed partial responses. Overall, disease was observed to be controlled and stable, indicating a high disease control rate. More than half of the patients had a reduction in tumor size of more than 10%, which was considered an indication of treatment effectiveness.
Some patients experienced treatment-related side effects, such as nausea, vomiting, and cytopenias, but the treatment was generally well tolerated. This study provides a strong basis for further development of APG-115 as a treatment option for patients with P53 wild-type salivary gland cancer, including adenoid cystic carcinoma.
In conclusion, the study's findings offer a promising alternative to current treatment options. Compared with historical treatment results, the progression-free survival and response rates demonstrate the potential of this new approach. Research on APG-115 may therefore be considered an important advance in treating salivary gland cancer.
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