Introduction: TNBC is a mutationally complex breast cancer subtype with poor prognosis and no current targeted therapy options. Compared with other intrinsic breast cancer subtypes, TNBC has higher programmed death-ligand 1 (PD-L1) expression levels, which may hinder antitumor T-cell responses. MPDL3280A is a monoclonal anti-PDL1 antibody, engineered for optimized efficacy and safety, that blocks signaling through the PD-L1/PD-1 and PD-L1/B7.1 pathways.
Methods: MPDL3280A was tested in a metastatic TNBC expansion cohort as part of a multicenter Phase Ia study. Pts received MPDL3280A at 15 mg/kg, 20 mg/kg or 1200 mg flat dose IV q3w. AEs were summarized for the safety follow-up duration from the first dose to 30 days after the last dose before the clinical cutoff on Sept 2, 2014. Responses were assessed by RECIST v1.1 criteria in pts who received MPDL3280A by Jul 21, 2014, evaluable for efficacy (≥ 6-wk follow-up). PD-L1 expression on tumor-infiltrating immune cells (ICs) at baseline was centrally evaluated by IHC in archival or fresh biopsies, and pts were scored as PD-L1 IHC (IC) 0, 1, 2 or 3. Peripheral biomarkers were assayed using FACS and multiplex immunoassays.
Results: In the TNBC cohort, 27 pts were selectively enrolled. These pts had a median age of 48 y (29-82 y) and were evaluable for safety; 52% had ECOG PS 0 and 44% had ECOG PS 1. Visceral and bone metastases were present at baseline in 59% and 11% of pts, respectively. In addition, 85% received ≥ 4 prior systemic regimens (neoadjuvant, adjuvant or metastatic), including anthracyclines (78%), taxanes (82%) and platinum agents (15% cisplatin, 41% carboplatin). All-grade treatment-related AEs occurred in 67% of pts, most frequently fatigue (22%), pyrexia (15%), neutropenia (15%) and nausea (15%). 11% of pts experienced a Grade 3-5 related AE (5 Grade 3 events: adrenal insufficiency, neutropenia, nausea, vomiting, decreased WBC count; 1 Grade 5 pulmonary hypertension event in a pt with an atrial septal defect). Among 21 efficacy-evaluable PD-L1 IHC 2 or 3 pts (13 IHC 2 and 8 IHC 3), the unconfirmed RECIST ORR was 24% (95% CI, 8% to 47%); 3 PRs and 2 CRs were observed. Response duration ranged from 0.1+ to 41.6+ wks, with the median not yet reached. Pts with evidence of durable nonclassical responses suggestive of pseudoprogression were also observed. Overall, the 24-wk PFS rate was 33% (95% CI, 12% to 53%). Biomarker analysis revealed transient elevation of plasma cytokines and proliferating CD8 cells following MPDL3280A treatment. Updated clinical data, including PD-L1-negative pts, will be presented.
Conclusions: MPDL3280A was generally well tolerated and demonstrated promising efficacy in pretreated metastatic PD-L1 IHC 2 or 3 TNBC pts. Furthermore, circulating biomarker analyses revealed pharmacodynamic responses to MPDL3280A. Clinical evaluation of MPDL3280A in metastatic PD-L1 IHC 0 or 1 TNBC is ongoing (NCT01375842).
Citation Format: Leisha A. Emens, Fadi S. Braiteh, Philippe Cassier, Jean-Pierre Delord, Joseph Paul Eder, Marcella Fasso, Yuanyuan Xiao, Yan Wang, Luciana Molinero, Daniel S. Chen, Ian Krop. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2859. doi:10.1158/1538-7445.AM2015-2859