Preclinical data demonstrate tumor response with AVA6103 in the setting of Enhertu^®-resistance

Potential for prolonged responses with increased FAP+ fibroblasts recruited to the tumor during treatment with AVA6103

LONDON and PHILADELPHIA, Oct. 23, 2026 (GLOBE NEWSWIRE) -- Avacta Therapeutics (AIM: AVCT, “the Company”, “Avacta”), a life sciences company developing innovative, targeted oncology drugs, today announces the presentation at the European Society for Medical Oncology (ESMO) Congress of the FOCUS-01 Phase 1 clinical trial design and substantial progress in the preclinical arena. AVA6103 is the first Next-Generation pre|CISION^® controlled-release peptide-drug conjugate platform (PDC), a fibroblast activation protein (FAP)-activated exatecan (Exd) PDC, designed to deliver payload to tumors with similar kinetics of antibody drug conjugates (ADCs) using small molecule chemistry.

AVA6103 is designed to significantly increase the therapeutic window of its highly potent payload, exatecan, a topoisomerase 1 inhibitor (TOP1i) similar to the deruxtecan payload of Enhertu^®. The Company highlights preclinical data demonstrating superior disease control by AVA6103 compared with Enhertu^® in a patient-derived xenograft (PDX) mouse model with HER2+/FAP+ gastric tumors that progressed after initial treatment with Enhertu^®, resulting from enhanced cleavage potential with recruitment of FAP+ fibroblasts during treatment with AVA6103.

Dave Liebowitz, Chief Medical Officer of Avacta, commented:

“AVA6103’s continued ability to shrink HER2+ gastric tumors after progression on Enhertu^® demonstrates the potential of pre|CISION^® PDCs to deliver sustained antitumor activity in preclinical models, well beyond the time points achievable with ADCs, showing the potential to improve outcomes for patients with aggressive cancers.

These results add to a growing body of evidence suggesting that pre|CISION^® PDCs are not vulnerable to antigen loss, a phenomenon known to limit the efficacy of ADCs such as Enhertu^® over time, which is demonstrated here in our results. We observed persistent expression of FAP in the tumor through fibroblast recruitment, which is most likely mechanism for increased payload delivery over time on treatment.”

“These findings build further on our initial Phase 1a data with AVA6103 demonstrating proof of mechanism, with a clean safety profile thus far and exceptional alignment between preclinical modeled and clinical pharmacokinetic data, with controlled exatecan release evident in patients for days after dosing. The FOCUS-01 trial continues to progress well towards tumor PK in late Q4 2026 or early Q1 2027 and the first efficacy data, which we expect in H1 2027.”

Alexander Spira MD, PhD, FACP, FASCO, Lead author at ESMO, Co-Director, Virginia Cancer Specialists (VCS) Research Institute and one of the lead investigators of the trial, commented:

“The FOCUS-01 trial is moving rapidly and we are happy to partner with Avacta on this exciting new drug. The preclinical and translational data we have seen thus far reinforce our excitement around this mechanism of action.”

Key Preclinical and Translational Findings with AVA6103

Preclinical data demonstrate that AVA6103 is shows better antitumor activity than Enhertu^® in FAP-positive / HER2-positive disease, including in advanced and resistant tumors.

• In an early stage model (animals randomized once tumors reach 100-200mm³), all AVA6103-treated animals achieved partial responses, with tumor growth inhibition more than double that of Enhertu^®
• In animals with large established tumors (randomized at 400-500mm³), AVA6103 inhibited tumor growth and achieved partial responses, while Enhertu^® demonstrated limited activity
• All AVA6103-treated animals that had previously progressed on Enhertu achieved stable disease, while all animals retreated with Enhertu^® progressed
  
  

Tumor tissue studies from this experiment demonstrate that tumors treated with AVA6103 have increased FAP expression over time via immunohistochemistry, with recruitment of FAP+ fibroblasts over the course of treatment. Transcriptomic analysis via RNA seq studies revealed that AVA6103 induced a coordinated inflammatory, wound-healing response, with an upregulation of pathways involved with damage repair, cell cycle arrest, and extracellular matrix (ECM) reorganization.

FOCUS-01: Trial in Progress

The FOCUS-01 Phase 1a trial is a first in-human, multicenter dose escalation trial of AVA6103 and is enrolling patients with select tumor types predicted to be sensitive to the payload exatecan, based on co-expression of FAP and SLFN11, a gene known to predict response to the Topoisomerase 1 inhibitor mechanism.

Preliminary safety and pharmacokinetic (PK) data from the first three dose levels of the FOCUS-01 trial, reported in September, demonstrated proof of mechanism in patients treated in the first three cohorts in the trial. AVA6103 demonstrated a favorable safety profile and was well tolerated through the first three dose levels up to a payload dose approximately 50% higher than the maximum tolerated dose (MTD) of conventional exatecan.

The pharmacokinetic data of the PDC, released peptide and released exatecan patients were remarkably consistent with predictive PK modelling based on preclinical data, greatly increasing confidence that the safety profile, tumor selectivity and antitumor efficacy observed in the preclinical studies of AVA6103 will translate into the clinic.

Enrollment is ongoing in both arms of the study, with enrollment completed at dose level 4, representing an absolute dose of payload that is more than double the maximum tolerated dose (MTD) of conventional exatecan and approaches the equivalent topoisomerase I inhibitor payload dose of the approved dose of Enhertu^® in breast cancer.

Details of the poster presentation

A phase I trial of FAP-Exd (AVA6103), a Fibroblast Activation Protein (FAP)-enabled pre|CISION^® peptide-drug conjugate delivering sustained tumor microenvironment (TME) release of exatecan in patients with FAP-positive solid tumors
Authors: Alexander I. Spira, Nehal J. Lakhani, Judy S. Wang, Muhammad R. Khawaja, Ruairidh Edwards, Karen Campbell, Curtis Rink, Christiana Nikolova, David Liebowitz
Poster number: 1134eTiP

The poster can be found on Avacta’s website here.

Enhertu^® (trastuzumab deruxtecan; T-DXd) is a protease cleavable-linker ADC, approved for both breast cancer and gastric cancer indications (an AstraZeneca/Daiichi Sankyo product). Enhertu^® is a registered trademark of Daiichi Sankyo Company, Limited and AstraZeneca.

For further information from Avacta, please contact:

About Avacta - https://avacta.com/

Avacta Therapeutics is a clinical-stage life sciences company expanding the reach of highly potent cancer therapies through its proprietary pre|CISION^® platform. pre|CISION^® is a payload delivery system based on a tumor-specific protease (Fibroblast Activation Protein or FAP) that is designed to concentrate highly potent payloads in the tumor microenvironment while sparing normal tissues. Avacta's innovative pre|CISION^® peptide drug conjugates (PDC) are a novel entry to the XDC drug class, leveraging the success of antibody drug conjugates with alternative methods of delivery beyond antibodies.

Our pre|CISION^® PDCs leverage this tumor-specific release mechanism in a small molecule format to provide unique benefits over traditional antibody drug conjugates (ADC), releasing active payload in the tumor and reducing systemic exposure and toxicity which enables dosing to be optimized to deliver the best outcomes for patients. The lead clinical program is AVA6103, a Next Generation FAP-enabled controlled release pre|CISION^® version of exatecan that delivers the payload directly in the tumor with limited peripheral blood exposure and is currently in clinical development as a treatment for tumor types sensitive to exatecan including cervical cancer, HR+ breast cancer, small cell lung cancer, gastric cancer, colorectal cancer and pancreatic cancer.

About FAP-Exd (AVA6103)

AVA6103 is the second clinical candidate and is the first asset in the pipeline based on the Next Generation innovative pre|CISION^® controlled release mechanism that provides for prolonged release of payload directly in the tumor, minimizing systemic exposure. AVA6103 is being evaluated in the FOCUS-01 Phase 1 trial (FAP-Exd in Oncologic Cancers with Unmet needS). Preclinical data suggest this approach has optimized payload delivery with a high intratumoral concentration and prolonged exposure of released payload in the tumor, coupled with limited systemic exposure to the released payload. 

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