On June 6, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released the updated results from a Phase II study of the MDM2-p53 inhibitor alrizomadlin (APG-115) plus pembrolizumab in adults and children with various solid tumors in a Poster Discussion session at the 58th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ascentage Pharma, JUN 6, 2022, View Source;ascentage-pharma-releases-updated-results-demonstrating-the-therapeutic-potential-of-alrizomadlin-apg-115-plus-pembrolizumab-in-patients-with-solid-tumors-who-progressed-on-immunotherapies-301562392.html [SID1234615664]).

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Entering the fifth consecutive year in which its abstracts were selected for presentations by the ASCO (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma showcased results from multiple clinical trials of its five drug candidates, including the much-anticipated data of alrizomadlin plus pembrolizumab, updated from the data at last year’s oral presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting. The updated results further validate the combination therapy’s efficacy in patients with immuno-oncologic- (I-O) drug-resistant or recurrent melanoma, including two complete responses (CRs), an objective response rate (ORR) of 11% and a disease control rate (DCR) of 57%. The abstract also reports favorable clinical benefit in patients with malignant peripheral nerve sheath tumour (MPNST), demonstrated by a DCR of 50%. MPNST is a rare pediatric type of sarcoma lacking effective treatment options.

"Ascentage’s novel oral MDM2 inhibitor (alrizomadlin APG-115) continues to be well tolerated in combination with pembrolizumab and provides clinical benefit in several I-O relapse refractory tumor types, specifically various melanoma subtypes as well as MPNST, a rare pediatric sarcoma tumor with no available approved therapies", said Dr Bartosz Chmielowski, MD, Associate Professor from the Melanoma and Sarcoma program at UCLA, who presented the updated results at ASCO (Free ASCO Whitepaper) 2022.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented, "Alrizomadlin, a China-developed novel drug with first-in-class potential, is the first MDM2-p53 inhibitor entering clinical studies in China. These data we presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting validates alrizomadlin’s therapeutic potential in patients with solid tumors that progressed on I-O drugs, thus signaling a potential new treatment option for patients with solid tumors. Furthermore, we are proud to be able to present clinical development progress for a number of Ascentage Pharma’s drug candidates, which highlight our capabilities in global innovation. Honoring our mission of addressing unmet clinical needs in China and around the world, we are now accelerating our clinical programs to bring more safe and effective therapeutics to patients in need."

The highlights of this abstract on alrizomadlin are as follows:

Newly updated activity results of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, plus pembrolizumab: Phase 2 study in adults and children with various solid tumors.

Abstract: #9517

This US/Australian multicenter trial evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of alrizomadlin in combination with pembrolizumab in patients with advanced solid tumors.

As of March 1, 2022, 150 patients had been enrolled in the Phase II study. Alrizomadlin was orally administered QOD at the recommended Phase II dose (RP2D) of 150 mg in combination with intravenously administered pembrolizumab. This study consists of 6 cohorts: PD-1/PD-L1-refractory melanoma (n=60), non-small cell lung cancer (NSCLC, n=19)/STK-11-mutant lung adenocarcinoma (n=7), ATM-mutant solid tumors (n=20); liposarcoma (n=17), urothelial cancer (n=13), and MPNST failed prior standard-of-care therapies (n=14).

Efficacy Results:
In the 46 efficacy evaluable (EE) patients with melanoma progressed on PD-1/PD-L1 inhibitors, the confirmed ORR was 10.9% (2CRs+3 partial responses [PRs]/46EEs). In the cutaneous and uveal melanoma sub-cohorts, confirmed ORRs were 20% (2CRs+2PRs/20EEs) and 6.7% (1PR/15EEs), and DCRs (including confirmed PR, CR, and stable disease ≥ 4 cycles) were 55% (2PRs+2CRs+7SDs/20EEs) and 73.3% (1PR+10SDs/15EEs), respectively.
In the MPNST cohort, the DCR was 50% (6SDs/12EEs).
The PD-1/PD-L1-refractory NSCLC, urothelial, and liposarcoma cohorts each reported 1 confirmed PR.

Common treatment-related adverse events (TRAEs; ≥ 10%) of any grade were nausea, thrombocytopenia, vomiting, fatigue, decreased appetite, diarrhea, neutropenia, and anemia.

Conclusions:
This Phase II study showed that alrizomadlin in combination with pembrolizumab was well tolerated.
Preliminary and interim results of the combination therapy demonstrated clinical benefit for patients with relapsed/refractory melanoma and high DCRs in the cutaneous and uveal melanoma sub-cohorts.
Alrizomadlin combined with pembrolizumab demonstrates clinical benefit in patients with MPNST,with a 50% DCR, an orphan pediatric indication with no effective standard of care.