Alrizomadlin Granted FDA Fast Track Designation for Relapsed/Refractory Unresectable or Metastatic Melanoma


Patients with relapsed/refractory unresectable or metastatic melanoma may derive benefit from alrizomadlin, which has received a fast track designation from the FDA.

The FDA has granted a fast track designation to the novel MDM2-p53 inhibitor alrizomadlin (APG-115) for the treatment of patients with unresectable or metastatic melanoma that is either relapsed or refractory to previous immunotherapy agents, according to a press release from drug developer Ascentage Pharma.1

The indication is based on preliminary data from the ongoing phase 2 APG-115-US-002 trial (NCT03611868), which is examining the use of alrizomadlin in several types of immunotherapy-resistant advanced solid tumors with results were presented at the 2021 American Society of Clinical Oncology Annual Meeting.2 Patients in the study’s melanoma cohort (n = 32) achieved an overall response rate (ORR) of 24.1%, including 1 complete response and 6 partial responses. Moreover, a disease control rate (DCR) of 55.2% was reported in the overall patient population.

Alrizomadlin has previously been granted 5 orphan drug designations, with 1 being for the treatment of those with stage IIB to IV melanoma.

“Alrizomadlin is a key drug candidate in Ascentage Pharma’s apoptosis-targeting pipeline. An [orphan drug designation] and a [fast track designation] have already been granted to alrizomadlin by the US FDA for the treatment of melanoma, signifying the enormous therapeutic potential of the asset,” Dajun Yang, MD, PhD, chairman and chief executive officer at Ascentage Pharma, said in a press release. “This [fast track designation] 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 [new drug application] 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 oral novel, potent, small molecule MDM2-p53 agonist has demonstrated synergy with PD-1 inhibitors in both wild-type TP53 and TP53-mutant syngeneic murine models. By synergizing with immunotherapy, alrizomadlin is able to enhance T-cell mediated antitumor immunity.

The agent was administered every other day for 2 consecutive weeks followed by 1 week off for 21-day cycles. Several dose levels were included in the study, including 50 mg, 100 mg, 150 mg, and 200 mg followed of a 200-mg infusion of pembrolizumab (Keytruda) on day 1 of every 21-day cycle. The study also included several tumor types, including immunotherapy-resistant melanoma, immunotherapy-resistant non–small cell lung cancer (NSCLC) and STK-11–mutated lung adenocarcinoma, ATM-mutant and TP53 wild-type solid tumors, MDM2-amplified and TP53 wild-type liposarcoma, immunotherapy-resistant urothelial carcinoma, and malignant peripheral nerve sheathe tumor.

Efficacy of alrizomadlin across all cohorts in the phase 2 APG-115-US-002 trial (NCT03611868).

Efficacy of alrizomadlin across all cohorts in the phase 2 APG-115-US-002 trial (NCT03611868).

Patients needed to be 18 years or older with histologically confirmed unresectable or metastatic tumors to enroll on the study. Additionally, patients with melanoma, NSCLC, or urothelial carcinoma needed to be either refractory to or relapsed after treatment with a PD-1 or PD-L1 inhibitor. Moreover, patients needed to be refractory to standard-of-care therapies, have an ECOG performance status of 0 to 2, and have measurable disease by RECIST 1.1 criteria. Those who had previous received a MDM2-p53 inhibitor, had central nervous system metastases, or who have an active infection requiring systemic medications were not eligible to enroll on the study.

The median patient age was 64 years old, and the majority of the population was male (61.8%). The majority of patients received 3 or more prior therapies (36.3%), although others received 2 (26.5%), 1 (27.5%), and no (9.8%) prior therapies. Patients received a median number of 2.0 cycles of therapy (range, 1-22). The most common reasons for treatment discontinuation included progressive disease (61.8%), adverse effects (AEs; 18.4%), consent withdrawal (10.5%), and physician decision (4.0%).

Additional findings from the study highlighted ORRs for several other disease histologies, including uveal (n = 8; 14.3%), mucosal (n = 5; 40%), and cutaneous (n = 16; 26.7). Additionally, the DCR in patients with uveal melanoma was 71.4%, mucosal subtype was 40%, cutaneous was 46.7%, and unknown primary disease (n = 3) was 100%.

Common any-grade treatment-related AEs (TRAEs) included nausea (66.7%), decreased platelet count (43.2%), and vomiting (39.2%). Additionally, common grade 3 or higher TRAEs included decreased platelet count (22.6%), decreased neutrophil count (12.8%), and anemia (7.8%).


  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.
  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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