Avacta Reports Clinical Proof of Mechanism for FAP-Activated Exatecan PDC AVA6103 in Phase 1 FOCUS-01
核心洞察
Avacta reported clinical proof of mechanism for AVA6103, a FAP (搜索)-activated peptide-drug conjugate delivering exatecan, in the Phase 1 FOCUS-01 trial across the first three dose levels.
Nineteen heavily pretreated patients received AVA6103 at 1.5, 3 and 4.5 mg/m2, with no neutropenia and one case each of thrombocytopenia and nausea or vomiting.
Plasma pharmacokinetics showed rapid clearance of intact AVA6103 with low levels of cleaved pre|CISION peptide and free exatecan detectable up to 48 hours after dosing.
Avacta Therapeutics (搜索) has reported clinical proof of mechanism for AVA6103, its next-generation controlled-release pre|CISION peptide-drug conjugate (PDC) carrying the topoisomerase I (搜索) inhibitor exatecan, in the ongoing Phase 1 FOCUS-01 trial. The preliminary Phase 1a data, announced September 16, 2026, cover the first three dose levels in patients with select solid tumors and show a clean safety profile alongside pharmacokinetic behavior that matched preclinical predictions.
AVA6103 is designed to exploit fibroblast activation protein (搜索) (FAP (搜索)), a protease highly expressed in the tumor microenvironment, to release exatecan preferentially within tumors rather than systemically. The approach differs from antibody-drug conjugates such as Enhertu and Datroway, which use tumor-associated cell-surface antigens to deliver topoisomerase I (搜索) inhibitor payloads. Avacta is pursuing FAP-triggered cleavage and sustained intratumoral release to widen the therapeutic window of exatecan, whose conventional development was limited by systemic toxicity. AVA6103 is the second clinical program from the pre|CISION platform and the first using its sustained-release design, following AVA6000 (FAP-Dox), a FAP-activated form of doxorubicin.
Trial Design and Dosing
FOCUS-01 is enrolling patients with locally advanced or metastatic disease across six indications: colorectal cancer (搜索), pancreatic ductal adenocarcinoma (搜索), gastric or gastroesophageal junction cancers, cervical cancer (搜索) and small cell lung cancer (搜索). The first three dose levels have completed enrollment of 19 patients in two parallel arms, with dosing every two weeks (Q2W) or every three weeks (Q3W), assessed for safety and tolerability, pharmacokinetics and pharmacodynamics, and preliminary efficacy.
The dose levels were 1.5 mg/m2, 3 mg/m2 and 4.5 mg/m2, selected to allow comparison with both the Phase 1 trial of Enhertu (Doi et al. 2017) and conventional exatecan. The first three dose levels are similar to the absolute payload dose levels in the published Enhertu Phase 1 trial; dose level 2 is similar to the maximum tolerated dose (MTD) of conventional exatecan (Rowinsky et al. 2000); and dose level 3 represents an approximate 50% increase over that MTD. Screening is ongoing for enrollment into both the Q2W and Q3W arms at dose level 4.
Safety Compared With Enhertu and Conventional Exatecan
Avacta compared the safety profile of AVA6103-derived exatecan at the first three dose levels with published data for Enhertu, which releases the highly similar payload deruxtecan (搜索), and with conventional exatecan given once daily for five days. The company reported minimal toxicity with AVA6103 at equivalent and escalated doses of the conventional exatecan MTD in heavily pretreated patients.
Neutropenia occurred in 0% of AVA6103-treated patients, versus 22% with similar doses of Enhertu and 64% at the MTD of conventional exatecan, which is equivalent to the 3 mg/m2 dose of AVA6103. Thrombocytopenia was reported in 5% (1/19) with AVA6103, 11% with Enhertu and 43% with conventional exatecan. Anemia occurred in 16% (3/19) with AVA6103, 11% with similar Enhertu doses and 43% with conventional exatecan. Nausea and vomiting were reported in 5% (1/19) with AVA6103, 44% with Enhertu and 67% with exatecan across all dose levels in that trial.
Pharmacokinetics Support a Tumor Drug Reservoir
Plasma pharmacokinetic data across the first three dose levels showed a rapid reduction in the plasma level of intact AVA6103, with prolonged low-level release of both products of the cleavage reaction, the pre|CISION peptide and released exatecan. Low levels of the cleaved peptide and free exatecan remained detectable for up to 48 hours after dosing.
Because the released peptide has a very short half-life of 2 to 3 hours, as demonstrated in the AVA6000 program, its detection in plasma up to 48 hours after dosing indicates that the PDC is retained in the tumor in a drug reservoir that is slowly cleaved to release the peptide and exatecan, as the mechanism was designed to do. Avacta said the consistency of these results with predictive PK modeling based on preclinical studies increases confidence that AVA6103 is performing as intended and that the preclinical data will translate to the clinic.
Preclinical Head-to-Head Comparison With Enhertu
The company also reported a head-to-head preclinical comparison of AVA6103 and Enhertu in a gastric cancer (搜索) patient-derived xenograft model that is HER2 (搜索)-positive and FAP (搜索)-positive by immunohistochemistry. When tumors reached 100 to 200 mm3, animals were randomized to AVA6103 on a weekly times three dose-dense regimen or Enhertu at a dose with evidence of activity.
Enhertu treatment slowed growth compared with vehicle control, with two animals showing small tumor reductions and 1 of 6 with progression as best response. AVA6103 treatment produced deep and prolonged partial responses in 6 of 6 animals treated.
"We are thrilled to report the proof of mechanism data with our first Next-Generation pre|CISION molecule in the clinic, which continues to underscore the potential of our platform to make a significant difference to cancer patients," said Christina Coughlin, CEO of Avacta. She noted that AVA6103 moved from candidate status to Investigational New Drug application in less than a year and has now reached an initial clinical readout with safety and PK data showing it is performing as expected from preclinical studies.
"Our head-to-head comparison with the marketed ADC Enhertu shows better activity in a HER2 (搜索)+ preclinical model even at low FAP (搜索) levels, with the dose-dense regimen demonstrating advantages of AVA6103 over traditional dosing of ADCs," Coughlin said. She added that FAP expression in approximately 90% of solid tumors provides a gateway for Avacta to link multiple payloads and access previously unaddressable markets.
Next Readouts
The FOCUS-01 design and preclinical updates will be presented in Trials in Progress presentations at the American Association for Cancer Research Conference on Pancreatic Cancer, held September 25 to 28, 2026, and at the European Society for Medical Oncology Congress, held October 23 to 27, 2026.
First efficacy data from FOCUS-01, including clinical tumor biopsies anticipated to confirm that AVA6103 is retained in a drug reservoir in the tumor, are expected in the first half of 2027. Selection of payloads and data supporting clinical candidate selection for the Dual Payload Next Gen Program (AVA6207 (搜索)) will be presented in the fourth quarter of 2026, alongside clinical data from the first-generation faridoxorubicin (AVA6000) program at the ESMO Congress.