578P - Increased therapeutic index of muzastotug (ADG126), a masked anti-CTLA-4 antibody, in combination with pembrolizumab (pembro) enables significant clinical benefits and supports further clinical development in patients with metastatic MSS CRC

Background

Muza is a fully human anti-CTLA-4 IgG1 SAFEbody® with cleavable masking peptides that is preferentially activated in the tumor microenvironment; it binds to a unique CTLA-4 epitope to prime T cells and deplete Tregs. Previously we presented initial results from dose escalation and the first stage of dose expansion (EXP) in patients (Pts) of MSS CRC without liver metastasis, which makes up ∼30% of 3L MSS CRC population. Here we report safety and activity results from the second stage EXP of the study (NCT05405595).

Methods

In this Phase 1b/2, open-label, multicenter dose escalation and EXP study, Pts received Muza [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per modified RECIST 1.1.

Results

As of April 16, 2024, 60 Pts have been treated including 36 MSS CRC Pts in EXP. Pts details: median age 60 yrs (26-75); 31.7% had ³ 3 prior therapies and 8.3% received prior IO therapies. No DLT or Grade 4/5 TRAE was observed and MTD was not reached. Grade 3 TRAEs at 10 mpk Q3W was 13.5% (5/37); TRAEs of ³ 10% for all grades were pruritis (28.3%), hypothyroidism (15.0%), and diarrhea (13.3%). In MSS CRC EXP, 10 mpk Q3W (Muza)/Pembro treatments resulted in 4 PRs (including 1 initial PR) and 14 SDs (24 evaluable); 10 mpk Q6W treatments resulted in 7 SDs (10 evaluable). The median treatment cycles for both Muza (10 mpk Q3W) and Pembro were 7 (2-16). Subgroup analysis reveals that Pts without liver and peritoneal metastasis (n=17) showed a better response, resulting in 24% ORR and 88% DCR; most updated data for CBR and mPFS, etc., will be presented.

Conclusions

Muza up to 10mpk Q3W in combination with Pembro is well-tolerated with a comparable G3 TRAE rate as Pembro monotherapy. Meaningful clinical benefit and durability have been observed as demonstrated by significantly better ORR and mPFS compared to SOCs in 3L MSS CRC. These data support further evaluation of this combination therapy in the clinic, including with a 20 mpk loading dose regimen, in a randomized Ph2 study in MSS CRC without liver metastasis.

Clinical trial identification

NCT05405595.

Editorial acknowledgement

Legal entity responsible for the study

Adagene Inc.

Funding

Adagene Inc.

Disclosure

D. Li: Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Eisai, Exelixis, Genentech, Ipsen Biopharmaceuticals, Merck, Servier, DelCath, TerSera Therapeutics, Abbvie, Sumitomo, Transthera, Trisalus; Financial Interests, Institutional, Research Grant: AstraZeneca. S.Y. Kim: Financial Interests, Personal, Advisory Board: GUARDANT Health; Financial Interests, Personal, Invited Speaker: LG Chem; Financial Interests, Institutional, Research Grant: Roche. J. Lee: Financial Interests, Personal, Steering Committee Member: AstraZeneca, Seattle Genetics; Non-Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Non-Financial Interests, Personal, Other, AP Council: ASCO; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, BMS, Daichi Sankyo, Leaptherapeutics, Merck MSD; Non-Financial Interests, Institutional, Project Lead: OncXerna, Samsung Bioepis; Non-Financial Interests, Personal, Member: KSMO. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi-Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis, Roche, Pfizer, Daiichi-Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. X.K. She: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc; Non-Financial Interests, Personal, Ownership Interest: Adagene Inc; Non-Financial Interests, Institutional, Leadership Role: Adagene. Y. Li: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc; Non-Financial Interests, Institutional, Member of Board of Directors: Adagene Inc. L.E.C. Chung: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc. P. Xiao: Financial Interests, Personal, Full or part-time Employment: Adagene Inc. G. Liu: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc. S. Zeng: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc. D. HuLowe: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc. M. Chisamore: Financial Interests, Institutional, Full or part-time Employment: Merck & Co. Inc; Financial Interests, Institutional, Stocks/Shares: Merck & Co. Inc. P.P. Luo: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc; Non-Financial Interests, Institutional, Leadership Role: Adagene Inc; Non-Financial Interests, Institutional, Member of Board of Directors: Adagene; Non-Financial Interests, Personal, Ownership Interest: Adagene. J. Zha: Financial Interests, Personal, Full or part-time Employment: Adagene Inc; Financial Interests, Personal, Stocks/Shares: Adagene Inc. M.R. Patel: Financial Interests, Personal, Advisory Board, Financial interest: daiichi, janssen, accutar, Olema, Mitsubishi, Kura, Nurix; Financial Interests, Personal, Advisory Board, Financial Interest: ION; Financial Interests, Institutional, Local PI, institution received research funding: daiichi. All other authors have declared no conflicts of interest.