KEY TAKEAWAYS
- The Phase 1 trial, guided by B7-H4 expression, explores XMT-1660’s potential to overcome resistance and improve outcomes in breast cancer.
- The primary endpoints are safety, RP2D, ORR, DCR, and DOR, and the secondary endpoints are pharmacokinetic analysis, anti-drug antibody assessment, and tumor tissue evaluation for B7-H4 expression.
- This trial is currently evaluating XMT-1660 as a potential treatment for breast, endometrial, and ovarian cancers.
Breast cancer (BC) is the most usually diagnosed cancer and one of the major causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard-of-care (SOC) therapies. High B7-H4 expression, observed in cancers like breast, endometrial, and ovarian, with limited presence in normal tissue, promotes tumorigenesis by suppressing anti-tumor immunity as a CD28/B7 family member. XMT-1660 is a precise B7-H4-directed ADC with an optimized drug. Models with higher B7-H4 expression showed more excellent anti-tumor activity, supporting the development of a Phase 1 clinical trial. The study explored the anti-tumor activity of XMT-1660 in preclinical models of TNBC and ER-positive/HER2-negative breast cancer, including tumors from heavily pretreated patients.-to-antibody ratio and DolaLock microtubule inhibitor payload for controlled bystander effect.
In this Phase 1 trial, a first-in-human open-label dose escalation (DES) portion was conducted, followed by dose expansion (EXP) to evaluate XMT-1660 in patients with BC, EC, and OC after progression on applicable SOC treatments (e.g., CDK4/6i + ET; platinum-based chemotherapy). The Bayesian Optimal Interval (BOIN) design was employed in the DES to determine the MTD. XMT-1660 was administered to patients intravenously every three weeks.
Primary endpoints in the DES aimed to assess safety, determine a recommended phase 2 dose (RP2D), and evaluate preliminary efficacy as a secondary endpoint. Simultaneously with the DES, optional backfill cohorts enrolled patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a chosen dose level from DES, and initiation could occur at multiple dose levels concurrently. In the EXP portion, planned cohorts enrolled TNBC, ER+/HER2- BC, EC/OC, and additional patients could be enrolled based on emerging data. The primary endpoint of EXP was to evaluate safety and tolerability, overall response rate, disease control ratio, and duration of response. Secondary endpoints included pharmacokinetic analysis and assessment of anti-drug antibodies. Patients were not chosen based on B7-H4 status, but baseline tumor samples were collected for retrospective tumor tissue evaluation.
This Phase 1 trial of XMT-1660 is currently enrolling patients to access the safety and efficacy of the drug in patients with breast, endometrial, and ovarian cancers.
Source: https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS3154
Clinical Trial: https://www.clinicaltrials.gov/study/NCT05377996
Erika P. Hamilton, Arvind Chaudhry, Alexander I. Spira, Sylvia Adams, Nour Abuhadra, Antonio Giordano, Ritesh Parajuli, Hyo S. Han, Amy M. Weise, Aubri Marchesani, Divya Gupta, Kate Josephs, Kevin Kalinsky. DOI 10.1200/JCO.2023.41.16_suppl.TPS3154, J Clin Oncol 41, 2023 (suppl 16; abstr TPS3154).
