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CHICAGO, IL USA (UroToday.com) - Dr. Thomas Powles presented an exciting phase I clinical trial evaluating the safety and early efficacy data of MPDL3280A, a human anti-PD-L1 monoclonal antibody, in patients with treatment-refractory, metastatic urothelial carcinoma. PD-L1 is a transmembrane protein that acts to downregulate T-cell immune function. MPDL3280A is a monoclonal antibody against PD-L1 that contains an engineered Fc-domain constructed to maximize patient safety and therapeutic efficacy.

asco xThis study is especially interesting, as therapeutic options for metastatic urothelial cancer remain limited, particularly when patients have poor renal function and cannot tolerate treatment with cisplatin-based chemotherapy regimens. Previous data suggest that PD-L1 expression occurs regularly in immune cells found in urothelial carcinoma (27% of tumors). Additionally this compound has demonstrated activity in melanoma, renal, and lung cohorts, giving the investigators a solid rationale for using a therapeutic approach that inhibits PD-L1.

This study was a phase I expansion cohort of urothelial bladder patients that included both patients with PD-L1 positive and negative tumors. Included patients had good performance status (ECOG PS 0-1) and limited comorbid illness, but 75% had visceral disease, and 79% had progressed after cisplatin therapy. Only 4% of patients experienced grade 3-4 toxicities, none of which were renal toxicity. The investigators performed a subgroup analysis evaluating tumor-infiltrating cells, a proposed biomarker of response for PD-L1 therapies. There was a 43% response rate at 6 weeks among patients with the highest levels of tumor-infiltrating cells, but even tumors with low levels of tumor-infiltrating cells had an 11% overall response rate. Additionally, there were two complete responses, both in patients who had failed first line gemcitabine/cisplatin chemotherapy, and 16 of 17 responding patients continued to have responsive disease after 12 weeks at the time of data cutoff. The overall response rate at 12 weeks was 52%, indicating some durability of response, even in this heavily pre-treated population. Median time to response was 42 days.

This study demonstrates relatively rapid, durable responses among a population of heavily pre-treated patients with metastatic urothelial carcinoma who otherwise have an expected overall survival of approximately 8 months. The therapy was well tolerated, even among an older patient population with visceral metastases, with only 4% of grade 3 or 4 adverse events, no renal toxicity, and no deaths in the study. MPDL3280A was granted breakthrough therapy designation on 5/31/14 by the FDA. Clinical trials in urothelial carcinoma and other solid malignancies are ongoing.

Presented by Thomas Powles, MBBS, MRCP, MD at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA

Barts Cancer Institute, Queen Mary University Hospital of London

Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com

 

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