ALX Oncology Spotlights Evorpacept HER2 Strategy and EGFR ADC ALX2004 Progress at JPM Conference

ALX Oncology (NASDAQ:ALXO) outlined progress across its two clinical-stage programs—CD47 blocker evorpacept and EGFR-targeted antibody-drug conjugate (ADC) ALX2004—during a presentation at the J.P. Morgan conference led by CEO Jason Lettmann and Chief Medical Officer Barbara Klencke.

Management highlighted what it described as an “incredible year” of multiple data readouts and said it is now focusing evorpacept development in HER2-positive breast cancer and multiple myeloma, while advancing ALX2004 through early dose escalation in a first-in-human Phase 1 study.

Evorpacept: mechanism and differentiation in CD47

Lettmann framed CD47 as an important but historically difficult immuno-oncology target, noting that many prior programs were discontinued due to therapeutic window challenges. He said ALX Oncology’s approach is differentiated because evorpacept blocks the “don’t-eat-me” signal (CD47) while relying on a separate Fc-active antibody (such as a standard anticancer antibody or a bispecific) to provide the “eat-me” signal. According to the company, this bifurcated mechanism avoids activating macrophages against red blood cells, enabling higher dosing without the on-target toxicities that affected earlier CD47 approaches.

Klencke added background supporting CD47’s relevance, citing a meta-analysis across 38 cohorts in 17 published studies covering 7,000 patients, which concluded that CD47 overexpression correlates with lower survival across multiple tumor types.

Aspen-06 gastric cancer: subset data and biomarker focus

Klencke reviewed results from Aspen-06, a randomized Phase 2 study in second- and third-line gastric cancer patients previously treated with HER2-targeted therapy. The trial enrolled 127 patients and randomized trastuzumab, ramucirumab, and paclitaxel (TRP) with or without evorpacept. She said 75% of patients (95) were confirmed to have retained HER2 status based on fresh biopsy following prior HER2 therapy or circulating tumor DNA (ctDNA).

In the retained HER2-positive group (95 patients), Klencke reported an overall response rate of 49% for the evorpacept arm versus 25% for control. She said a pre-specified analysis further enriched outcomes in patients with CD47 overexpression and retained HER2 positivity, where the response rate was 65%, which she characterized as nearly a 40% delta from the control arm.

Klencke also cited durability and time-to-event metrics in the CD47-high subset, including a 25.5-month duration of response for the evorpacept combination, a progression-free survival hazard ratio of 0.39, and an overall survival hazard ratio of 0.63. On safety, she said adverse events were comparable between arms in Aspen-06 and described evorpacept’s profile across more than 750 treated patients as generally manageable and reversible.

Breast cancer strategy: post-Enhertu opportunity and Q3 interim data

The company positioned HER2-positive breast cancer after Enhertu as an area of unmet need. Klencke said multiple real-world evidence datasets suggest response rates in the post-Enhertu setting are generally in the 15% to less than 20% range, with progression-free survival around four to five months at best. She said ALX Oncology believes replicating activity observed in gastric cancer or in a zanidatamab combination study could be meaningful for patients.

ALX Oncology is enrolling an 80-patient, single-arm trial in HER2-positive breast cancer patients who previously received HER2-targeted therapy, including Enhertu, with response rate as the primary endpoint. Klencke said the trial will assess retained HER2 positivity via ctDNA and will evaluate response rates in patients with CD47 overexpression as a key secondary endpoint. The company expects interim data in the third quarter of the year.

In Q&A, the company acknowledged that the study is single-arm and said it will interpret outcomes versus published benchmarks and real-world evidence in the post-Enhertu setting. Lettmann said the study design includes CD47-high and CD47-low groups as well as patients who retain HER2 and those who do not, which he said should be instructive when comparing outcomes across groups.

Looking beyond the single-arm study, management said its assumption is that a Phase 3 randomized comparative trial would likely be needed. Klencke said the company is preparing for a potential CD47-selected strategy and that one objective of the current trial is to generate evidence to define a cut point for patient selection that the FDA would require for a future Phase 3.

ALX2004: EGFR ADC design, preclinical findings, and Phase 1 dose escalation

Lettmann described ALX2004 as an internally developed EGFR-targeted ADC designed to address safety and efficacy limitations seen in the EGFR ADC class. He said the program uses the Matuzumab antibody—an epitope the company said is unique among EGFR ADCs in development and was designed to reduce known on-target toxicities while retaining EGFR binding and activity.

Management also emphasized linker-payload optimization using a topoisomerase 1 (Topo 1) payload. Lettmann said ALX Oncology synthesized more than 60 different linker-payload constructs and used Enhertu/deruxtecan as comparators during optimization. He suggested earlier EGFR ADC setbacks in the field reflected differences in both linker design and epitope choice.

Klencke presented preclinical data intended to support claims of improved delivery, bystander effect, and tolerability. She said non-human primate pharmacokinetic work showed reduced payload release in circulation, supporting the aim of delivering more payload to tumors and less to peripheral tissue. In mouse models, she said ALX2004 matched or exceeded a DXd comparator in complete tumor eradication across models with varying EGFR expression and outperformed in a bystander model mixing EGFR-high and EGFR-ultra-low cells.

In toxicology, Klencke said findings in non-human primates were minimal to moderate and fully recoverable, supporting a 1 mg/kg starting dose in the first-in-human Phase 1 study. She said the company has escalated from 1 mg/kg to 2 mg/kg and then to 4 mg/kg every three weeks, and is actively enrolling at 4 mg/kg. The Phase 1 includes dose escalation and dose expansion in four tumor types: non-small cell lung cancer, head and neck cancer, colorectal cancer, and squamous esophageal cancer.

Multiple myeloma collaboration and 2026 catalysts

On partnerships, Lettmann highlighted collaborations with Jazz and Sanofi and said combination studies have helped validate evorpacept’s activity not only with antibodies but also with bispecifics such as zanidatamab. Regarding Sanofi specifically, he discussed a multiple myeloma program combining evorpacept with Sarclisa as part of a basket study called Umbrella. He said the company communicated over the summer that the program met Sanofi’s criteria to move to the next phase and described multiple myeloma as a large commercial opportunity.

Looking ahead, Lettmann said the company plans to share interim breast cancer data for evorpacept in Q3 and to continue ALX2004 dose escalation while aiming to share data in the first half of the year to further characterize the safety profile. He said ALX Oncology’s goal is to have both programs “heading on registrational paths” by year-end.

About ALX Oncology (NASDAQ:ALXO)

ALX Oncology, Inc is a clinical-stage biopharmaceutical company headquartered in Redwood City, California, focused on developing next-generation immuno-oncology therapies. The company’s mission is to harness and amplify both innate and adaptive immune responses to improve outcomes for patients with a range of solid tumors and hematologic malignancies.

The lead candidate in ALX Oncology’s pipeline is evorpacept (ALX148), a high-affinity CD47-blocking Fc-silenced fusion protein designed to enhance macrophage-mediated phagocytosis of cancer cells when combined with standard therapeutic antibodies or immune checkpoint inhibitors.