Preoperative pembrolizumab (Pembro) with radiation therapy (RT) in patients with operable triple-negative breast cancer (TNBC)

Background: Radiation therapy (RT) induces immune-mediated cell death. If administered pre-operatively, RT could also generate a rich supply of tumor antigens. The addition of PD-1 mediated checkpoint blockade to pre-operative RT could thus, generate robust anti-tumor immune responses, induce long-term tumor-specific memory, and ultimately, improve cure rates. This study aims to establish the safety of pre-operative pembrolizumab (pembro)-mediated immune modulation with a RT "boost" equivalent in patients with operable triple negative breast cancer (TNBC) for whom lumpectomy and adjuvant RT are planned (NCT03366844). Serial research biopsies will permit interrogation of conventional biomarkers including tumor infiltrating lymphocytes (TILs) and novel immune correlates as potential predictors of response to pembro alone versus pembro with RT. Trial design: Women with operable, primary TNBC >2cm for whom breast-conserving therapy is planned are enrolled in this single-institution pilot study. Study treatment consists of 1 cycle of pre-operative pembro (200 mg IV) alone, followed 3 weeks later by a RT boost (24 Gy/3 fractions) to the primary breast tumor concurrently with pembro (+/- 5 days). Curative-intent, standard-of-care, neoadjuvant chemotherapy or breast-conserving surgery is then undertaken within 8 weeks of study enrollment (i.e. within 5 weeks of pembro #2). Adjuvant RT is administered per standard-of-care after surgery, but without a boost dose. Research blood and fresh tumor biopsies are obtained at baseline and after cycles 1 and 2 of pembro. Correlative analysis will include single-cell RNA sequencing of the tumor immune infiltrate and multispectral immunohistochemistry. Co-primary endpoints are: 1) safety/tolerability, as defined by the number of patients who do not necessitate a delay in standard-of-care chemotherapy or surgery and 2) change in TIL score. Secondary endpoints include safety/toxicity up to 19 weeks after study enrollment and disease-free survival. Legal entity responsible for the study: Heather McArthur. Funding: Has not received any funding. Disclosure: H.L. McArthur: Advisory boards: Amgen, Celgene, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Roche, Peregrine, Calithera, Eli Lilly, TapImmune; Research support: Bristol-Myers Squibb, Eli Lilly, MedImmune, LLC/AstraZeneca, Merck. All other authors have declared no conflicts of interest.