Thomas Powles, MD
An investigational immunotherapy, MPDL3280A, reduced tumors in 43% of patients with previously treated metastatic urothelial bladder cancer (UBC) whose tumors were characterized as positive for the programmed death ligand-1 (PD-L1), and the drug has received the first Breakthrough Therapy Designation from the FDA for bladder cancer, according to information released May 31, 2014 at the 50th Annual Meeting of ASCO.
“Really there has been no FDA-approved therapy for these patients with relapsed disease after platinum-based therapy, which is extraordinary when we consider the frequency of this group of patients, and their life expectancy is short, at only 7 months,” said presenter Thomas Powles, MD, clinical professor of Genitourinary Oncology, Barts Cancer Institute at the Queen Mary University of London, United Kingdom. “It is a challenging population to treat.”
The phase I single-arm, multicenter, open-label trial of MPDL3280A included 67 patients with previously treated, metastatic bladder cancer who had limited treatment options and an ECOG performance status of 0 to 1. There were visceral metastases evident in 75% of patients. Seventy-nine percent of patients were previously treated with cisplatin therapy, and 34% of patients were previously exposed to carboplatin therapy. Over a third of the patients had regressed within 3 months of therapy. Thirty patients in the study were identified as PD-L1 positive.
Dose was given at 15 mg/kg and was administered intravenously every 3 weeks for up to 16 cycles. After 6 weeks of follow-up, the objective response rate (ORR) as measured by RECIST criteria was 43% (13/30), and after 12 weeks, ORR was 52% (13/25) in patients with PD-L1–positive tumors.
“This is early rapid responses in quite refractory disease, which we think is encouraging,” Powles said.
Complete response was observed in 7% patients with PD-L1-positive tumors (2/30), and interestingly, the ORR was 11% (4/35) in patients whose tumors were identified as PD-L1 negative. The median time to response was 42 days.
Treatment-related grade 3 adverse events (AEs) occurred in 4% (3/68) of patients and included weakness (asthenia; 2%), low platelet count (thrombocytopenia; 2%), and low phosphate levels (blood phosphorus decrease; 2%). “In bladder cancer the important issue is that there is no renal toxicity reported in the study,” said Powles “Because, as we know, many of these patients have problems with renal function,” he said.
The most common AEs observed to date that occurred in more than 5% of patients in the study were decreased appetite (12%), fatigue (12%), nausea (12%), fever (pyrexia; 9%), and weakness (asthenia; 7%).
Metastatic UBC has traditionally shown poor prognosis, and limited treatment options have been available. The American Cancer Society estimates that approximately 15% of people with advanced bladder cancer (stage IV) will live for 5 years.
“Bladder cancer is the ninth most common cancer worldwide, for which there have been no new treatment advances in nearly 30 years, so we are pleased the FDA has granted breakthrough designation for MPDL3280A in metastatic bladder cancer,” said Sandra Horning, MD, chief medical officer and head of Global Product Development in a Genentech press release.
The anti-PD-L1 agent MPDL3280A is an engineered monoclonal antibody designed to interfere with the PD-L1 protein. The drug is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to both PD-1 and B7-1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells. The study authors concluded that treatment resulted in transient increases in circulating CD8+Ki-67+ T cells and plasma proteins (eg, IL-18) upstream of IFNγ signaling, representing pharmacodynamic biomarkers of activity, which will be further explored. Gene expression data from pretreatment tumors showed that patients who progressed had a proportionally higher myeloid gene signature (eg, IL8, CCL2).
"We are evaluating MPDL3280A in a broad range of tumors, and have begun pivotal studies that include a companion diagnostic test in lung and bladder cancers,” Horning said.
Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). Presented at the Annual Meeting of the American Society of Clinical Oncology, May 31, 2014. J Clin Oncol 32:5s. Abstract #5011.
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