Anti-PDL1 Agent Promising in Advanced Breast Cancer Immunotherapy with monoclonal antibody proves safe in phase Ia trial. 4.22.2015by Kay JacksonContributing Writer, MedPage Today PHILADELPHIA -- In patients with metastatic triple-negative breast cancer, immunotherapy with the monoclonal antibody MPDL3280A appeared to be safe, tolerable, and capable of durable clinical activity, according to results from an ongoing multicenter phase Ia study. "The latest analysis of our data revealed a 24-week progression-free survival rate of 27% with an objective response rate of 19%, and three of four responses are ongoing," reported Leisha A. Emens, MD, PhD, of Johns Hopkins University, and colleagues in a press release at the American Association for Cancer Research annual meeting."MPDL3280A was generally well tolerated and demonstrated promising efficacy in pretreated metastatic PD-L1 IHC 2 or 3 TNBC patients," she added. "Furthermore, circulating biomarker analyses revealed pharmacodynamic responses to MPDL3280A." The triple-negative breast cancer cohort is part of an ongoing trial into the efficacy and safety of MPDL3280A in a number of advanced solid tumors. Triple-negative breast cancer has higher programmed death-ligand 1 (PD-L1) expression levels than other breast cancers and this can inhibit T-cell antitumor responses, Emens noted. MPDL3280A is an engineered anti-PDL1 antibody that inhibits the binding of PD-L1 to PD-1 and B7.1. "Inhibiting PD-L1/PD-1 and PD-L1/B7.1 interactions can restore antitumor T-cell activity and enhance T-cell priming," Emens said. "MPDL3280A leaves the PD-L2/PD-1 interaction intact, maintaining immune homeostasis and potentially preventing autoimmunity." The high mutation rate of triple-negative breast cancer, which can produce neoantigens that induce an immune response, makes it a candidate for cancer immunotherapy, in particular PD-L1-targeted therapies. In addition, patients with triple-negative breast cancer with high levels of tumor-infiltrating lymphocytes (TILs), have improved outcomes, Emens said. The TNBC cohort enrolled 54 patients (median age 48), both PD-L1-negative and PD-L1-positive. The key eligibility criteria were measurable disease per RECIST v1.1 and ECOG PS 0 or 1; 52% had ECOG PS 0 and 44% had ECOG PS 1. At baseline, visceral metastases were present in 59% of patients and bone metastases in 11%. In addition, 85% received four or more prior systemic regimens, neoadjuvant, adjuvant, or metastatic. Patients received MPDL3280A at 15 mg/kg, 20 mg/kg or 1,200 mg flat dose IV q3w. Treatment-related adverse events, summarized for the safety follow-up from the first dose to 30 days after the last dose, were seen in 63% of patients. The most common included fatigue (22%), pyrexia (15%), neutropenia (15%) and nausea (15%). Some 11% of patients experienced grade 3 to 5 treatment-related adverse events. The grade 3 adverse events included adrenal insufficiency, neutropenia, nausea, vomiting, and decreased white blood cell count. There were two deaths, which are currently under investigation, the authors stated. The median duration of response has not yet been reached (range: 18 to 56-plus weeks). Patients with evidence of durable nonclassical responses suggestive of pseudoprogression were also observed. The median duration of survival follow-up is 40 weeks. Emens pointed out that while bevacizumab (Avastin) is approved in more than 80 countries worldwide for the treatment of metastatic triple-negative breast cancer, there are no targeted therapies in the U.S. for metastatic triple-negative breast cancer, which has a worse prognosis than other breast cancer subtypes. Clinical evaluation of MPDL3280A in metastatic PD-L1 IHC 0 or 1 triple-negative breast cancer is ongoing.
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