NEW YORK – ALX Oncology has brought its second candidate therapy into the clinic, a potential first-in-class EGFR-targeted antibody-drug conjugate (ADC) that could help reduce toxicity for patients with EGFR-mutant tumors.
The US Food and Drug Administration cleared the firm's investigational new drug application this week, allowing ALX to begin a Phase I trial of the drug, dubbed ALX2004, in EGFR-expressing solid tumors. ALX CEO Jason Lettmann said the firm expects to begin the trial mid-year.
Some of the resources that contributed to ALX's development of this drug were gained from the company's acquisition of ScalmiBio in 2021, including an antibody drug conjugate development platform of cytotoxic payloads and linkers.
The market is crowded with treatment options for EGFR-mutant cancers, including EGFR-targeting monoclonal antibodies like Amgen's Vectibix (panitumumab) and Eli Lilly's Erbitux (cetuximab) and small molecule EGFR inhibitors like AstraZeneca's Tagrisso (osimertinib) and Johnson & Johnson's Lazcluze (lazertinib), as well as earlier-generation EGFR inhibitors. Also approved for EGFR-mutant cancers are J&J's bispecific antibody Rybrevant (amivantamab-vmjw) and AstraZeneca and Daiichi Sankyo's Trop-2-directed ADC Datroway (datopotamab deruxtecan). There are not yet any EGFR-targeted ADCs on the market.
ALX's potential EGFR-targeted ADC, Lettmann said, is designed to target an established biomarker and is using a known payload, topoisomerase I or topo-1. ALX's team is taking inspiration from the anti-HER2 therapy space, where ADCs like AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) have outshined the older HER2-directed antibodies.
"If you look at the successes with Enhertu, … that's been all topo-1-based," Lettmann said. "[AstraZeneca and Daiichi] have proven [that the HER2 ADC] is significantly better than a HER2 antibody like trastuzumab, for example. We see the same opportunity [with ALX2004 in EGFR] and are leveraging a lot of the learnings of those approaches in HER2."
The firm also hopes that ALX2004 will have less toxicity for these patients. EGFR inhibitors can cause significant toxicity for some patients, particularly skin-related or ocular toxicity.
"One of the things that has hampered development of EGFR-targeted ADCs has been safety, and that's where the class has really struggled," Lettmann said. "What is needed is certainly better safety."
AXL is expecting initial safety data readouts from the Phase I trial of single-agent ALX2004 in the first half of 2026.
Patients with any type of EGFR-expressing solid tumor can enroll in the trial, but Lettmann anticipates that the company will likely focus ALX2004's development in colorectal, lung, and head and neck cancers after safety data is reported. ALX has already established relationships with clinical trials sites and key opinion leaders for testing its lead candidate, the CD47 immunotherapy evorpacept, in these tumor types that it hopes to leverage for ALX2004.
For example, the firm is currently studying evorpacept in combination with other targeted therapies, immunotherapies, and ADCs in gastric, breast, colorectal, head and neck, and bladder cancers.
"There is a lot of overlap with where we're already going from a patient perspective," Lettmann said. "We have ongoing studies [for evorpacept] in head and neck cancer and in colorectal cancer, [which] would be a fit for an EGFR-targeted ADC. We see a pretty strong strategic fit with what we're already doing."
There's also the potential to combine evorpacept with ALX2004 in the future, Lettmann said. The firm is already testing evorpacept in ongoing trials with two ADCs: with Enhertu in HER2-positive breast cancer and with Pfizer's Padcev (enfortumab vedotin) in urothelial cancer.
In preclinical studies, ALX2004 has demonstrated anti-tumor activity across several xenograft models for triple-negative breast, nasopharyngeal, pancreatic, non-small cell lung, and colorectal cancer. The drug also produced a bystander effect, which means it can kill not only targeted tumor cells with the payload but also neighboring tumor cells, regardless of their expression status. This is the feature that has allowed Enhertu's expansion into treating breast cancers with lower levels of HER2 expression.
"We're excited about having a known pathway paired with a validated payload to go after a field that needs better options for patients," Lettmann said. "In ADCs, most of the targets that are well validated like HER2 are very competitive now. We saw and identified this opportunity early and put ourselves in a position to potentially be first-to-market with an EGFR-targeted ADC."