FDA Advances ALX2004 to Phase 1 Trials in EGFR+ Solid Tumors

US FDA

• The FDA has cleared the investigational new drug (IND) application for ALX2004 for the treatment of epidermal growth factor receptor (EGFR)-expressing solid tumors.
• ALX2004 is a first-in-class antibody-drug conjugate (ADC).
• A single-agent, dose-escalation and dose-expansion, phase 1 trial assessing ALX2004 in EGFR-positive solid tumors is expected to begin mid-2025.

The FDA has granted clearance to the IND application of ALX2004, a potential best- and first-in-class ADC for the treatment of EGFR-expressing solid tumors.¹

Phase 1 trials plan to assess ALX2004 in solid tumors that express EGFR mutations and will begin mid-2025. Initial safety data are expected to be available in the first half of 2026.

“Clinical advancement of our first ADC and the first drug candidate developed on our proprietary linker-payload platform is an important milestone in our mission to deliver breakthrough therapies that will help transform the future of cancer treatment,” said Jason Lettmann, chief executive officer at ALX Oncology, in a press release.

ALX2004 is designed to optimize ADC-based mechanisms of antitumor activity. The ALX2004 molecule is made of an antibody backbone that works to optimize anti-EGFR activity and utilizes ALX Oncology’s proprietary, highly differentiated topoisomerase I inhibitor payload platform.¹

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In multiple clinically relevant xenograft models, the agent has been shown to have potent antitumor activity.²

“We meticulously designed all aspects of ALX2004 – the antibody backbone, linker and payload – to optimize the targeted delivery of a powerful chemotherapy payload to tumor cells while minimizing systemic toxicity. The resulting, highly differentiated molecule has demonstrated potent anti-tumor activity in preclinical models and is a strategic addition to our clinical pipeline, which also includes multiple trials evaluating our lead therapeutic candidate, evorpacept [ALX148],” added Lettmann in the press release.¹

In addition to ALX2004, ALX Oncology is developing evorpacept, a CD47 myeloid checkpoint inhibitor, for the treatment of a variety of HER2-positive cancers.² Most recently, evorpacept given with trastuzumab (Herceptin), paclitaxel, and ramucirumab (Cyramza; TRP) resulted in favorable survival outcomes and responses vs TRP alone when used for the treatment of patients with HER2-positive gastric or gastroesophageal junction cancer. These findings come from the phase 2/3 ASPEN-06 trial (NCT05002127) which were presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.³

New trials plan to evaluate evorpacept in combination with trastuzumab for the treatment of patients with HER2-positive breast cancer and in combination with cetuximab (Erbitux) in patients with colorectal cancer. Both are expected to begin in the first half of 2025.²

References:

1. ALX Oncology receives IND clearance from U.S. FDA for ALX2004, a novel EGFR-targeted antibody-drug conjugate. News release. ALX Oncology Holdings Inc. April 7, 2025. Accessed April 7, 2025. https://tinyurl.com/2k7tdd8n

2. ALX Oncology highlights focused evorpacept development plan, clinical progress and corporate updates at R&D day webcast event. News release. ALX Oncology Holdings Inc. March 5, 2025. Accessed April 7, 2025. https://tinyurl.com/yckb5ruv

3. Shitara K, Wainberg Z, Tabernero J, et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2–overexpressing gastric/gastroesophageal cancer (GC). J Clin Oncol. 2025;43(suppl 4):332. doi:10.1200/JCO.2025.43.4_suppl.332