FDA Grants Orphan Drug Designation to Alrizomadlin for Stage IIB-IV Melanoma


The FDA has granted an orphan drug designation to alrizomadlin as a potential therapeutic option for patients with stage IIB-IV melanoma.

The FDA has granted an orphan drug designation to alrizomadlin (APG-115) as a potential therapeutic option for patients with stage IIB-IV melanoma, according to an announcement from Ascentage Pharma, the drug developer.1

Alrizomadlin is an oral selective, small molecule, MDM2-p53 inhibitor. The agent was designed to block MDM2-p53 protein–protein interaction and to restore p53-mediated apoptosis in tumor cells with wild-type TP53 or MDM2 amplification.2

“At present, there is a large unmet need for the treatment of melanoma. Therefore, this orphan drug designation for alrizomadlin bears tremendous significance,” Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, stated in a press release. “As the fifth orphan drug designation granted to alrizomadlin, and the twelfth obtained by Ascentage Pharma, this designation reaffirms Ascentage Pharma’s leadership in the number of orphan drug designations granted to any Chinese biopharmaceutical company, demonstrating our capabilities in global innovation.”

Preclinical data have indicated that when combined with PD-1 blockade in wild-type p53 and mutated p53 syngeneic murine tumor models, the regimen increased CD8+ T cells and promoted a shift from M2 to M1 macrophages in the tumor microenvironment. Moreover, the combination also was found to regulate host immunologic responses and tumor immune escape mechanisms.

In a phase 1/2 trial (NCT03611868), alrizomadlin is being explored in combination with pembrolizumab (Keytruda) in patients with metastatic melanoma or advanced solid tumors. The trial is comprised of 2 phases: the dose-escalation phase and the dose-expansion phase.

The first phase examined alrizomadlin given once daily at doses ranging from 50 mg to 100 mg to 150 mg to 200 mg, for 2 consecutive weeks and 1 week off in 21-day treatment cycles. The agent was paired with pembrolizumab, delivered intravenously for 30 minutes at a dose of 200 mg on day 1 of a 21-day treatment cycle. In this portion of the research, investigators set out to determine dose-limiting toxicities with the regimen and a recommended phase 2 dose (RP2D).

The RP2D for alrizomadlin was determined to be 150 mg once daily plus pembrolizumab at 200 mg on day 1 of a 21-day cycle. The second portion of the research evaluated the regimen in 6 cohorts. Cohort A would include 34 patients with immunotherapy-resistant melanoma; cohort B would enroll 15 patients with immunotherapy-resistant non–small cell lung cancer (NSCLC) and 10 patients with STK-11–mutated lung adenocarcinoma; and 20 patients with solid tumors harboring ATM mutations and wild-type p53 will comprise cohort C.

Additionally, 15 patients with liposarcoma and MDM2 amplification and wild-type p53 will comprise cohort D; 15 patients with immunotherapy-resistant urothelial carcinoma will be enrolled to cohort E; and 10 patients with malignant peripheral nerve sheathe tumor (MPNST) will comprise cohort E.

To be eligible for inclusion, patients needed to be at least 18 years of age, have histologically confirmed unresectable or metastatic solid tumors, be refractory to standard-of-care approaches, an ECOG performance status of 0 to 2, and measurable disease per RECIST v1.1 criteria. For patients with melanoma, NSCLC, or urothelial carcinoma, they needed to have relapsed/refractory disease following treatment with a PD-1/PD-L1 inhibitor.

The primary end point of the second portion of the research is to evaluate the safety and efficacy of the combination, specifically objective response rates (ORRs) per RECIST v1.1 or iRECIST criteria.

Among the 102 patients enrolled to the trial, the median age was 64 years (range, 23-89), 61.8% were male, 50.0% had an ECOG performance status of 1, 36.3% received 3 or more prior lines of therapy, and the median number of cycles received was 2 (range, 1-22).

Moreover, 31.4% of patients had melanoma, 18.6% had NSCLC, 16.7% had liposarcoma, 11.8% had urothelial carcinoma, 10.8% had an ATM-mutated solid tumor, 5.9% had MPNST, and 4.9% had STK11-mutated lung adenocarcinoma.

Results indicated that the ORRs achieved with the doublet in the melanoma (n = 32), NSCLC (n = 19), STK-11 (n = 5), ATM (n = 11), liposarcoma (n = 17), urothelial carcinoma (n = 12), and MPNST (n = 6) cohorts were 24.1%, 6.7%, 0%, 0%, 6.2%, 12.5%, and 16.7%, respectively. The disease control rates (DCRs) in these cohorts were 55.2%, 46.7%, 25.0%, 44.4%, 81.2%, 12.5%, and 66.7%, respectively.

When taking a closer look at ORRs in the patients with immunotherapy-resistant melanoma, it was found that the ORRs achieved with the doublet in patients with uveal (n = 8), mucosal (n = 5), cutaneous (n = 16), or unknown primary (n = 3) disease were 14.3%, 40%, 26.7%, and 0%, respectively. The DCRs in these cohorts were 71.4%, 40%, 46.7%, and 100%, respectively.

Regarding safety, the combination was determined to be well tolerated, with no overlapping adverse effects with the 2 agents reported.


  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. Ascentage Pharma. July 21, 2021. Accessed July 21, 2021. https://prn.to/3wRdhhH
  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(suppl 15):2506. doi:10.1200/JCO.2021.39.15_suppl.2506
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