FDA Orphan Drug Designation Granted to Melanoma Drug Alrizomadlin

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The FDA has granted an orphan drug designation to alrizomadlin, an MDM2-p53 inhibitor, for the treatment of stage 2b to 4 melanoma.

The FDA has granted an orphan drug designation (ODD) to alrizomadlin (APG-115), an MDM2-p53 inhibitor, for the treatment of stage 2b to 4 melanoma, according to a press release by Ascentage Pharma.1

Preclinical studies have found that alrizomadlin in combination with a PD-1 blockade enhances antitumor activity by activating adaptive antitumor activity. Alrizomadlin holds 5 other ODDs in gastric cancer, acute myeloid leukemia, soft tissue sarcoma, and retinoblastoma.1

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 American Society of Clinical Oncology’s 2021 Annual Meeting, as of December 25, 2020, 84 patients have been dosed in 6 cohorts, melanoma (n = 26), non-small cell lung cancer (NSCLC) (n = 23), ATM mutation (n = 9), liposcarcoma (n = 14), urothelial (n=9), and malignant peripheral nerve sheath tumor (MPNST) (n = 3).2

In the melanoma cohort, the ORR was 17.4% and the disease control rate (DCR) was 55.2%. Two PRs were pending confirmation at the time of data cutoff. There were 3 melanoma subgroups assessed in the study, including 8 patients with uveal melanoma, 5 with muscosal melanoma, 16 with cutaneous melanoma, and 3 with an unknown primary melanoma type.

An ORR of 40%, which was observed in the mucosal melanoma group, was the best ORR seen in all subgroups. Also, in the mucosal melanoma group 2 PRs, 1 of which was unconfirmed, and the DCR in the group was also 40%. 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.2

In order to participate, patients must be 12 years old or older. In part 1, patients must have histologically confirmed, unresectable, or metastatic melanoma, or an advanced solid tumor who have failed standard of care therapy and no further effective therapy is available, and an ECOG score of 0-2. In order to participate in part 2, patients must have a life expectancy of ≥3 months, adequate bone marrow and organ function, among others. Patients with any prior systemic MDM2-p53 inhibitor therapy, known central nervous system metastases, requirement for corticosteroid treatment, concurrent treatment with an investigational agent or device within 21 days prior to first dose, or a history of organ transplantation are not eligible to participate.

“At present, there is a large unmet medical need for the treatment of melanoma. Therefore, this ODD for alrizomadlin bears tremendous significance,” said Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, in a press release. “As the fifth ODD granted to alrizomadlin, and the twelfth obtained by Ascentage Pharma.


1.Ascentage Pharma’s MDM2-p53 inhibitor APG-115 (Alrizomadlin) granted an orphan drug designation by the FDA for the treatment of Stage IIB-IV melanoma, marking the twelfth obtained by the company. News release. July 21, 2021. Accessed July 21, 2021. https://prn.to/3rnPtRs.
2. 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