322 - Phase 1b Trial of Berzosertib as a Radiosensitizer in the Post-Neoadjuvant Treatment of Chemotherapy-Resistant HER2-Negative Breast Cancer
Presenter(s)
R. W. Mutter1, P. J. Dizona2, J. Allred3, L. A. Vallow4, K. V. Giridhar3, P. N. Barry5, A. M. Brufsky6, C. Omene7, B. M. Anderson8, K. J. Ruddy9, L. N. Francis1, K. S. Corbin1, D. Shumway1, A. E. Garda10, G. Shapiro11, M. M. Poppe12, B. A. Costello13, A. Wahner Hendrickson3, R. Leon-Ferre14, M. Goetz3, and J. N. Sarkaria1; 1Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 2Department of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, 3Mayo Clinic, Rochester, MN, 4Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, 5Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, 6Division of Hematology Oncology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, 7Rutgers Cancer Institute, Rutgers, NJ, 8University of Wisconson School of Medicine and Public Health, Madison, WI, 9Department of Medical Oncology, Mayo Clinic, Rochester, MN, 10University of Pittsburgh Medical Center, Pittsburgh, PA, 11DFCI, Boston, MA, 12Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 13Division of Medical Oncology, Mayo Clinic, Rochester, MN, 14Comprehensive Cancer Center Oncology (Medical), Mayo Clinic, Rochester, MN
Purpose/Objective(s): Patients with locally advanced breast cancer and high residual cancer burden (RCB) after neoadjuvant systemic therapy (NAST) face increased risk of breast cancer recurrence and mortality. Our preclinical data suggested that ATR inhibition may be a tumor-specific radiosensitizing approach.
Materials/Methods: This was a multicenter, dose-finding phase 1b trial to assess safety and establish the recommended phase 2 dose (RP2D) of berzosertib combined with conventionally fractionated breast/chest wall plus regional nodal irradiation. Eligible patients were age = 18 years with recurrent or residual hormone receptor (HR)-positive, HER2-negative or triple negative breast cancer (TNBC) after anthracycline and/or taxane-based NAST. All underwent axillary surgical staging and margin-negative resection with lumpectomy or mastectomy (with or without reconstruction). Berzosertib was given intravenously twice weekly for 5 weeks at escalating doses (60 mg/m2, 120 mg/m2, 180 mg/m2, or 240 mg/m2, the single-agent RP2D) alongside radiotherapy. Once the RP2D was determined, 12 additional patients were treated at that dose.
Results: Among 27 patients (median age 51), 26% had HR+ and 74% had TNBC. Mastectomy was performed in 89%, and 85% had RCB class III. Eight TNBC patients (30%) received neoadjuvant pembrolizumab. Berzosertib was escalated to 240 mg/m2 without dose-limiting toxicities. The RP2D of berzosertib with radiation was therefore 240 mg/m2, which is also the single-agent RP2D, and no dose limiting toxicities were observed in the 12-patient expansion cohort. Most common grade =3 toxicities were hematologic (30%; 7 lymphopenia and 1 anemia) and dermatologic (7%). There was no reported late grade =2 fibrosis. At a median follow-up of 32 months (IQR 26 – 39), the 3-year DFS was 58% (95% CI, 41-80%), with rates of 86% for ER+ and 48% for TNBC. In TNBC patients, 3-year DFS was 57% with pembrolizumab vs 42% without. Compared to baseline, study treatment increased HLA-DR+ dendritic cells in the peripheral blood; additional correlative studies are ongoing and will be presented.
Conclusion: Berzosertib combined with radiotherapy was well tolerated and associated with promising disease control outcomes in an extremely high-risk population. Further evaluation of ATR inhibition with contemporary radiotherapy plus pembrolizumab in TNBC with high RCB after NAST is warranted. (NCI10291)