Hutchmed advances ATTC platform with first-in-human trial of EGFR-targeted PI3K/PIKK conjugate

China-based biopharma HutchMed (Nasdaq/AIM:HCM;HKEX:13) announced the clinical debut of pipeline candidate HMPL-A580, an antibody-targeted therapy conjugate (ATTC) designed to deliver a PI3K/PIKK inhibitor payload via an anti-EGFR antibody. The molecule has entered a Phase I/IIa first-in-human clinical trial in patients with unresectable, advanced, or metastatic solid tumors, with a first patient dosed. The multicenter, open-label study is being held across sites in China and the United States.; AllSci trial listing

HMPL-A580 is the second clinical candidate from Hutchmed’s next-generation ATTC platform, which conjugates proprietary small-molecule inhibitor payloads to monoclonal antibodies using cleavable linkers. The first is HMPL-A251, a which also uses a PI3K/PIKK inhibitor payload but conjugated to a humanized anti-HER2 IgG1 antibody and entered the clinic in December 2025.

The two-part trial for HMPL-A580 includes a dose-escalation phase to establish maximum tolerated and recommended expansion dosages, followed by Phase IIa expansion to characterize safety, tolerability, and preliminary anti-tumor activity. The trial (NCT07396584) will enrol 186 patients with primary completion forecast by December 2028.

Research context

No approved therapy currently combines EGFR targeting with intracellular PI3K pathway inhibition within a single conjugate molecule. Most programs aimed at the PI3K/AKT/mTOR (PAM) pathway rely instead on systemic small-molecule inhibitors engineered for mutant selectivity or isoform specificity to improve tolerability.

Relay Therapeutics is advancing RLY-2608, a mutant-selective PI3Kα inhibitor, in a Phase II pivotal study in PIK3CA-mutated breast cancer. Eli Lilly is developing STX-478, a mutant-selective PI3Kα inhibitor acquired through its purchase of Scorpion Therapeutics, in early clinical studies. Taiho Oncology is evaluating TOS-358, a covalent PI3Kα inhibitor, in Phase I/Ib trials. Celcuity and Pfizer are also advancing gedatolisib, a dual pan-PI3K/mTOR inhibitor, which has reached late-stage development in breast cancer.

These programs deliver pathway inhibition through systemic oral or intravenous small molecules. HMPL-A580 represents a divergent strategy: using antibody-directed delivery to restrict pathway inhibition to EGFR-expressing tumor cells, potentially widening the therapeutic index relative to conventional systemic PI3K inhibitors.

The antibody-drug conjugate field has also explored EGFR-targeted delivery, though typically using cytotoxic payloads rather than targeted pathway inhibitors. For example, MRG003, an EGFR-directed ADC developed by Lepu Biopharma, carries a monomethyl auristatin payload and is being evaluated in clinical studies in solid tumors. In contrast, Hutchmed’s ATTC platform attaches a targeted therapy payload — in this case a PI3K/PIKK inhibitor — rather than a conventional cytotoxic warhead.