Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading 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 has been observed in several cancers including endometrial, ovarian, and breast, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4–directed Dolasynthen antibody-drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with a controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2– patient-derived xenograft mouse models, which included tumors from heavily pretreated patients. Antitumor activity tended to be more frequent in models with higher B7-H4 expression, providing a rationale for a Ph1 clinical trial.
The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary end points in DES are to assess the safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary end point. In the EXP portion, cohorts enrolling TNBC, ER+/HER2– BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary end point of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary end points include pharmacokinetic analysis and antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumor samples are collected for retrospective tumor tissue evaluation.
The trial is currently enrolling patients (NCT05377996).
Kevin Kalinsky,1 Alexander Spira,2 Sylvia Adams,3 Nour Abuhadra,4 Antonio Giordano,5 Ritesh Parajuli,6 Heather Han,7 Amy Weise,8 Kate Josephs,9 Erika Hamilton10
1Winship Cancer Institute at Emory University, Atlanta, GA.
2Virginia Cancer Specialists, Fairfax, VA.
3NYU Langone Health, New York, NY.
4Memorial Sloan Kettering Cancer Center, New York, NY.
5Dana-Farber Cancer Institute, Boston, MA.
6University of California Irvine, Orange, CA.
7Moffitt Cancer Center, Tampa, FL.
8Henry Ford Health, Detroit MI.
9Mersana Therapeutics, Inc., Cambridge, MA.
10Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN.