TPS1102 Background: While immunostimulatory therapies have shown great success, a major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The DNA repair proficiency of a tumor may impact its potential for immune recognition and sensitivity to immune checkpoint blockade. Preclinically, PARP inhibition in HDR-deficient tumors has been shown to trigger antitumor immunity through a STING-dependent antitumor immune response. Effects of PARP inhibitors were augmented when combined with PD-1 blockade. We hypothesize that enhanced DNA damage and cell death induced by PARP inhibition in tumors with homology directed repair (HDR) deficiency will enhance adaptive anti-tumor immune responses and increase sensitivity to PD-1 axis blockers. Methods: This is a randomized, open-label phase II clinical trial exploring the PARP inhibitor olaparib either alone or in combination with the anti-PD-L1 human monoclonal antibody atezolizumab in BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. HDR deficiency is defined as the presence of deleterious BRCA 1/2 mutations. Randomization occurs in a 1:1 fashion to two arms: (1) olaparib 300 mg PO bid continuously in 21-day cycles or (2) olaparib 300 mg PO bid continuously in combination with atezolizumab 1200 IV every 3 weeks in 21-day cycles. Patients undergo baseline evaluations and pre-treatment biopsy within 2 weeks of starting therapy. Repeat biopsies are required at the time of first tumor assessment scan (6 weeks from the start of treatment) and in the event of disease progression. Correlative studies, including detailed analysis of the genomic profile and tumor immune contexture, will be performed at each biopsy time point. The primary objective is to compare progression free survival between the study arms. If progression occurs on the olaparib monotherapy arm, cross-over to the combination arm is allowed. This study began enrolling in August 2018; 47 of the planned 72 patients have been registered. Clinical trial information: NCT02849496 .
Neoadjuvant Pyrotinib plus Trastuzumab and Chemotherapy for Stage I–
III HER2‐Positive
Breast Cancer: A Phase
II
Clinical Trial