Anti-PD-L1 Agent Induces Durable Responses in Several Advanced Cancer Tumor Types

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CHICAGO—The engineered anti-PD-L1 antibody MPDL3280A produced durable responses in patients with locally advanced or metastatic lung cancer, melanoma, and renal, colorectal, and gastric cancers, some within days of treatment initiation, a phase 1 expansion study reported at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.

The agent also improved cancer-related symptoms, such as no longer requiring oxygen supplementation or decreased need for narcotics to control pain.

“The fact that this drug was active in such a variety of tumors suggests that PD-L1 is part of a universally or generally important immune mechanism,” said ASCO President-Elect Clifford A. Hudis, MD. “Over the next few years, drugs that target and help activate and direct the immune system will likely take on a growing role in patient care, and it's particularly exciting to see strong effects in patients whose cancer has progressed despite all other standard therapies.”

The agent was administered intravenously every 3 weeks; as of February 1, 2013, 171 patients were evaluable for safety, said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine at Yale Cancer Center and Chief of Medical Oncology at Smilow Cancer Hospital at Yale-New Haven, CT.

No maximum tolerated dose, dose-limiting toxicities, or treatment-related deaths were observed. A total of 43% of patients had a grade 3/4 adverse event (AE), but no grade 3-5 pneumonitis was seen. One immune-related AE (elevated alanine aminotransferase and aspartate aminotransferase) led to discontinuation of MPDL3280A.

Of the 140 patients evaluable for efficacy, overall response rate (ORR) was 21% (24-week progression-free survival [PFS], 45%), with the highest number of therapy responses occurring in those with lung cancer (n=41; ORR 22%; 24-week PFS, 46%), melanoma (n=38; ORR 29%; 24-week PFS, 43%), and renal cell carcinoma (n=47; ORR 13%; 24-week PFS, 53%). Therapy responses are still ongoing, with 26 of 29 responders continuing to respond (time on study of responders 3 to 15+ months), and additional delayed responses are not reflected in the ORR.

“We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors. So far, almost none of the patients that have had tumor shrinkage have progressed,” noted Dr. Herbst.

More than 275 patients are currently enrolled in the expanded study, which includes a larger range of solid tumors and hematologic cancers. Further MPDL3280A monotherapy and combination studies have been initiated, and clinical registration trials of the agent at a dose of 1,200 mg administered intravenously every 3 weeks in patients with NSCLC are planned.

In a separate presentation by John D. Powderly, MD, of the Carolina BioOncology Institute, Huntersville, NC, preliminary biomarkers data suggest tumor PD-L1 IHC status in the tumor microenvironment may be associated with anti-tumor response to MPDL3280A in that “patients with higher baseline expression of cytotoxic Th1 T-cell markers appear to respond favorably.” He reported that MPDL3280A therapy appears to restore anti-tumor immunity in responders, with evidence of adaptive PD-L1 tumor expression and active immune infiltration, providing mechanistic insights into anti-PD-L1 biology and immunotherapy. The relationship between PD-L1 status and overall survival in patients administered MPDL3280A is under prospective evaluation.

This study was supported by Genentech, Inc.

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