ALX Oncology has initiated a Phase 1 trial of ALX2004, an epidermal growth factor receptor (EGFR) antibody-drug conjugate (ADC), in patients with advanced or metastatic EGFR-expressing solid tumors. Initial safety data are anticipated in the first half of 2026. The open-label, multicenter study will include dose escalation and exploration phases, followed by dose expansion. The initial cohort will focus on non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC), and colorectal cancer (CRC).
This first-in-human trial represents a crucial step for ALX Oncology as it seeks to expand its pipeline beyond its lead immunotherapy candidate, evorpacept. The company is betting on ALX2004’s differentiated design, highlighting the “optimized” antibody, linker, and payload as key to overcoming the toxicity hurdles that have plagued earlier EGFR-targeted ADCs. This strategic focus on improved tolerability reflects a broader trend in oncology drug development, as the push for maximal efficacy increasingly confronts the practical limitations of combination regimens and their cumulative toxicity burden.
ALX Oncology emphasizes the preclinical data supporting ALX2004’s enhanced linker stability, dose-dependent anti-tumor activity, and favorable safety profile. The company claims the preclinical models showed no EGFR-related skin toxicity or payload-related interstitial lung disease at clinically relevant doses. However, translating these preclinical findings into clinical benefit remains a significant challenge. The field is littered with promising preclinical ADC candidates that ultimately failed to deliver on their early potential in human trials.
The success of ALX2004 will depend on demonstrating a clear clinical advantage over existing EGFR-targeted therapies, including tyrosine kinase inhibitors (TKIs) and other ADCs. This will require not only confirming a tolerable safety profile but also showing efficacy in patients who have progressed on or are intolerant to standard treatments. Furthermore, the company will need to navigate the complex regulatory landscape for ADCs, including rigorous characterization of the drug-antibody ratio, payload distribution, and potential off-target effects.
Looking ahead, ALX Oncology faces the challenge of balancing its investment in ALX2004 with the ongoing development of evorpacept. The competitive landscape for both immunotherapy and targeted oncology therapies is intensely crowded, and the company will need to secure sufficient resources and strategic partnerships to advance both programs effectively. The initial safety data from the Phase 1 trial will be a crucial inflection point, determining whether ALX2004 can live up to its preclinical promise and justify further investment in this increasingly competitive space. The trial will also be a test case for whether “optimized” design truly translates into a wider therapeutic window and improved patient outcomes.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
