On June 7, 2021 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported in an oral presentation at the 57th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, updated results from a Phase II study of the MDM2-p53 inhibitor alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic melanoma or advanced solid tumors that have progressed on prior immuno-oncologic (IO) drugs (Press release, Ascentage Pharma, JUN 7, 2021, View Source;ascentage-pharma-presents-updated-results-of-mdm2-p53-inhibitor-alrizomadlin-apg-115-demonstrating-an-orr-of-24-1-including-complete-response-in-combination-with-pembrolizumab-in-patients-with-advanced-mel-301307261.html [SID1234583679]).

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As a leading Chinese biotechnology company with progressive visibility at international scientific congresses in recent years, Ascentage Pharma’s clinical study results have been selected for presentations at the ASCO (Free ASCO Whitepaper) Annual Meeting for the fourth year. This year, results from four of its studies clinical studies were selected for presentations at the meeting, including two oral presentations. The clinical study data from the on-going Phase II study of alrizomadlin have demonstrated a manageable safety profile and meaningful clinical antitumor activity, including one patient with a complete response (CR), an objective response rate (ORR) of 24.1% and a disease control rate (DCR) of 55.2% in the PD-1/PD-L1 inhibitor-resistant melanoma cohort. In addition, partial responses (PRs) were reported in enrolled patients with other tumor types.

"The clinical data of alrizomadlin presented in our oral presentation are encouraging, as they suggest clinical activity in hard-to-treat tumor types across multiple indications, including several without currently available standard of care, such as relapsed or refractory melanoma subtypes," said Dr. Anthony W. Tolcher, Founder and CEO of NEXT Oncology, Director of Clinical Research at Texas Oncology, and the Global Principal Investigator of the study. "Our data provide a clinical validation of the recently published paper in Nature Immunology demonstrating that alrizomadlin synergizes with immunotherapy by sustaining STAT5 stability and controlling T-cell-mediated antitumor immunity via the novel pathway of MDM2 inhibition. This seminal publication elucidates why patients who previously failed to respond to IO therapy may derive clinical benefit from the addition of alrizomadlin to the IO agent pembrolizumab."

"This study of alrizomadlin in combination with pembrolizumab offers a clinical validation of the therapeutic synergy between MDM2-p53 inhibitors and existing immuno-oncologic drugs and shows the potential as a new treatment option that could bring renewed hope for patients with solid tumors," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "At this year’s ASCO (Free ASCO Whitepaper) Annual Meeting, we have announced results from multiple studies, including that of Alrizomadlin, in two oral presentations and two poster presentations. I am very proud of these advances, which attest to Ascentage Pharma’s robust capabilities in global innovation. Moving forward, we will remain committed to our mission of addressing unmet clinical needs in China and around the world, and strive to accelerate our clinical programs in the hope of soon benefitting patients."

An overview of the four abstracts presented at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting:

Drug Candidate

Abstract Title

Abstract #

Format

Lisaftoclax

(APG-2575)

First-in-human study of lisaftoclax (APG-2575), a novel Bcl-2 inhibitor (Bcl-2i), in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs)

7502

Oral

Presentation

Alrizomadlin

(APG-115)

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

2506

Oral

Presentation

Trial in progress: A phase I/II trial of novel MDM2 inhibitor alrizomadlin (APG-115), with or without platinum chemotherapy, in patients with p53 wild-type salivary gland carcinoma

TPS6094

Poster

Presentation

Pelcitoclax

(APG-1252)

Trial in progress: A multicenter phase Ib/II study of pelcitoclax (APG-1252) in combination with paclitaxel in patients with relapsed/refractory small-cell lung cancer (R/R SCLC)

TPS8589

Poster

Presentation

Highlights of the oral presentation on alrizomadlin at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting:

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

Abstract: #2506

This open-label, multicenter Phase II study in the US assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of alrizomadlin in combination with pembrolizumab in patients with advanced solid tumors.
As of April 15, 2021, 102 patients had been enrolled in the Phase II part of the study and treated with alrizomadlin at the recommended Phase II dose (RP2D) of 150 mg every other day, in combination with pembrolizumab. This study has 6 cohorts, including patients with: PD-1/PD-L1 inhibitor-resistant melanoma, non-small cell lung cancer (NSCLC), and urothelial carcinoma; or malignant peripheral nerve sheath tumor (MPNST), liposarcoma, and ATM mutant solid tumors.
Antitumor Effects:
In the PD-1/PD-L1 inhibitor-resistant melanoma cohort (n=29), there was 1 confirmed partial response (PR) out of 7 patients with uveal (ocular) melanoma; 2 PRs (1 confirmed + 1 unconfirmed) out of 5 patients with mucosal melanoma; and 1 complete response (CR, confirmed) and 3 PRs (2 confirmed + 1 unconfirmed) out of 15 patients with cutaneous melanoma. The ORR and DCR in the melanoma cohort were 24.1% (7/29) and 55.2% (16/29), respectively.
In the MPNST cohort (n=6), 1 PR (unconfirmed).
In the liposarcoma cohort (n=16), 1 PR (unconfirmed) and 12 stable diseases (SDs), at a DCR of 81.2% (13/16).
In the PD-1/PD-L1 inhibitor-resistant NSCLC (n=15) and urothelial carcinoma (n=8 evaluable) cohorts, 1 patient in each cohort achieved confirmed PR.
Common treatment-related adverse events (TRAEs) observed in more than 10% of patients were nausea, thrombocytopenia, vomiting, fatigue, decreased appetite, diarrhea, neutropenia, and anemia.
In conclusion, alrizomadlin combined with pembrolizumab is well tolerated, and did not exhibit any overlapping toxicity. These preliminary results have established proof of concept clinically that the combination regimen has antitumor activity in patients with IO relapsed/refractory metastatic melanoma, (including uveal melanoma, mucosal melanoma, or cutaneous melanoma). In addition, this combination therapy also showed promising antitumor activity in patients with MPNST or liposarcoma for which pembrolizumab has no approved indications.