No dose-limiting toxicities have been observed to date in ALX Oncology’s first-in-human study of its EGFR-targeted ADC ALX2004, which has now advanced to a 4 mg/kg third cohort. Separately, the first patient has been dosed in the Phase 2 ASPEN-09-Breast trial of the company’s CD47 inhibitor evorpacept combined with trastuzumab and physician’s choice chemotherapy in HER2-positive metastatic breast cancer post–trastuzumab deruxtecan. An interim analysis for ASPEN-09-Breast is planned for Q3 2026, with initial ALX2004 safety data expected in 1H 2026.
The core move is twofold: ALX is opening a post–T-DXd therapeutic lane in HER2-positive metastatic breast cancer with a single-arm, multicenter trial of 80 patients, while progressing dose escalation for its next asset across EGFR-expressing solid tumors. ASPEN-09-Breast will assess overall response rate as the primary endpoint in patients confirmed HER2-positive by ctDNA, with secondary measures including ORR stratified by CD47 expression, CBR, DOR, PFS, OS, and safety. Exploratory analysis will examine outcomes in a ctDNA HER2-negative subgroup. The ALX2004 Phase 1 program spans NSCLC, HNSCC, ESCC, and CRC, with Phase 1a escalation followed by optional exploration and Phase 1b expansion.
Strategically, ALX is positioning evorpacept to address the emerging gap after T-DXd, now approved in the first line. This is an increasingly crowded but still unsettled space with limited prospective data on post-ADC sequencing. Anchoring the regimen on trastuzumab and chemotherapy maintains familiarity for sites while enabling a CD47-targeted macrophage checkpoint approach that ALX has previously associated with broad efficacy signals in HER2-expressing gastric cancer. The trial’s biomarker architecture is notable: ctDNA to confirm HER2 positivity for the primary analysis and CD47 expression as a response modifier. That design aims to de-risk heterogeneity after T-DXd exposure, but it also raises analytical and operational dependencies on assay performance and cutoffs that will need to stand up to regulatory scrutiny in a single-arm setting.
For ASPEN-09-Breast, the choice of a single-arm ORR readout trades speed for interpretability. Physician’s choice of chemotherapy increases real-world relevance but also introduces variability that could complicate cross-trial comparisons, especially as post–T-DXd standards evolve and tucatinib-based regimens and other HER2-targeted options remain in play. Regulators will look for a clear, durable response signal and consistency across biomarker-defined subsets; absent that, the program could be steered toward a randomized design against an accepted regimen. Operationally, the trial will require coordinated ctDNA HER2 testing and CD47 assessment, likely via central labs, which may affect screen failure rates and timelines across community and academic sites.
The ALX2004 update signals preliminary tolerability at increasing doses, an important threshold given class-wide toxicity concerns with EGFR-targeted ADCs, including dermatologic, GI, and pulmonary events. The multicohort, multi-tumor design provides optionality to focus expansion where early activity emerges, but it also demands disciplined assay logistics for EGFR expression and clear, early go/no-go criteria to avoid diffuse development.
Over the next 18 months, watch for the ASPEN-09-Breast interim to define what constitutes a commercially and regulatorily relevant ORR in the post–T-DXd population and whether CD47 enrichment yields a clinically actionable delta. Pay attention to assay concordance between ctDNA and tissue HER2, as discrepancies could complicate labeling and market access. For ALX2004, any early response signals and a clean safety profile will be prerequisites for competitive positioning amid a dense ADC pipeline. The open questions are whether evorpacept can show sufficient depth and durability of response to justify rapid advancement and whether ALX can translate a safe ALX2004 escalation into differentiated efficacy in a space where payload choice and on-target toxicities often set the boundaries.
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.
