Alrizomadlin Lands FDA Fast Track Designation for Melanoma

Alrizomadlin, a MDM2-p53 inhibitor has been granted a fast track designation by the FDA for the treatment of relapsed/refractory unresectable or metastatic melanoma who are relapsed or refractory to prior immune-oncologic agents.

Alrizomadlin (APG-115), a MDM2-p53 inhibitor has been granted a fast track designation by the FDA for the treatment of relapsed/refractory unresectable or metastatic melanoma who are relapsed or refractory to prior immune-oncologic agents, according to a press release by Ascentage Pharma.1

Alrizomadlin is meant to bind to MDM2 and activate tumor suppression by preventing MDM2’s interaction with p53. It has been granted 5 orphan drug designations by the FDA for the treatment of gastric cancer, acute myeloid leukemia, soft tissue sarcoma, retinoblastoma, and stage IIB-IV melanoma.

The designation is based on preclinical and preliminary data of a phase 1/2 study (NCT03611868) of the agent in combination with pembrolizumab (Keytruda) in a number of different cancer types. The interventional study has an estimated enrollment of 203 participants. The primary end points of the study are maximum tolerated dose, recommended phase II dose, and overall response rate.2

The study will be split into a single arm dose escalation and dose expansion portion. During part 1, patients were administered 50 mg, 100 mg, 150 mg, or 200 mg of the study drug along with the label dose of pembrolizumab. Alrizomadlin is administered orally every other day for 2 weeks on, 1 week off. During part 2, patients will receive 150mg of the study drug in combination with pembrolizumab until disease progression, unacceptable toxicity, or other discontinuation criteria.

According to data presented at the 2021 American Society of Clinical Oncology Annual Meeting, 26 patients had been dosed in the melanoma cohort of the study, and 84 patients dosed overall across 5 additional cohorts including non-small cell lung cancer (n = 23), ATM mutation (n = 9), urothelial (N=9), and malignant peripheral nerve sheath tumor (n = 3).3

The ORR in the melanoma cohort was 17.4% with a disease control rate (DCR) of 55.2%. For patients with mucosal melanoma, the ORR was 40% and the DCR was also 40%. At the time of data cutoff, there were 2 partial responses, 1 of which was unconfirmed. The cutaneous melanoma group had an ORR of 26.7% with 1 CR, 3 PRs, and 3 cases of SD. It was noted that 1 PR was unconfirmed in this group, and the DCR was 46.7%. Among patients with uveal melanoma, the ORR was 14.3% due to 1 PR, and there were 4 cases of SD for a DCR of 71.4%. Those with an unknown melanoma type did not achieve objective responses, but 2 patients had SD for a DCR of 100%.

Treatment-related adverse events (TRAEs) included were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade ≥3 TRAEs include thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). In total, 11 patients discontinued treatment due to AEs. Of those 11, 5 were treatment related, including 2 cases of grade 4 thrombocytopenia, 1 case of grade 2 vomiting, 1 case of grade 2 fatigue, and 1 case of grade 2 reversible encephalopathy syndrome.

In order to participate in the study, patients must have a life expectancy of ≥3 months, adequate bone marrow and organ function, and are willing to use appropriate contraception. Patients with prior systemic MDM2-p53 inhibitor treatment, received chemotherapy within 21 days prior to first dose, has known active central nervous system metastases, or had an allogenic tissue/solid organ transplant are not eligible to participate.

"Alrizomadlin is a key drug candidate in Ascentage Pharma's apoptosis-targeting pipeline. An ODD and a FTD have already been granted to alrizomadlin by the US FDA for the treatment of melanoma, signifying the enormous therapeutic potential of the asset," said Dajun Yang, PhD chairman & CEO of Ascentage Pharma in a press release. "This FTD will help strengthen our communications with the US FDA in the clinical development of alrizomadlin, speed up the clinical development of alrizomadlin in the US and globally, thus potentially accelerating the drug candidate towards NDA submissions. We will move forward in full speed with the clinical development of alrizomadlin in the hope of offering a new treatment option to patients with melanoma."

The study is currently recruiting in Arizona, Arkansas, California, the District of Columbia, Florida, Missouri, New York, Pennsylvania, Tennessee, Texas, and Virginia.

REFERENCES:
1.Ascentage Pharma's MDM2-p53 inhibitor alrizomadlin (APG-115) granted fast track designation by the US FDA for the treatment of relapsed/refractory unresectable or metastatic melanoma. News release. Ascentage Pharma. September 22, 2021. Accessed September 23, 2021. https://prn.to/39yzHep.
2.A study of APG-115 in combination with pembrolizumab in patients with metastatic melanomas or advanced solid tumors. ClinicalTrials.gov. Accessed September 23, 2021. https://bit.ly/3u5cyd2.
3.Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J Clin Oncol. 2021; 39(15)2506-2506. doi: 10.1200/JCO.2021.39.15_suppl.2506