Nick Mulcahy

May 16, 2013

Another experimental agent that employs "immune checkpoint blockade" and improves the immune system's ability to combat tumors has shown efficacy in multiple cancers, according to phase 1 clinical trial data.

The agent, a human monoclonal antibody known as MPDL3280A, is Genentech's entry into this new class of cancer drugs. It produced an overall response rate of 21% (29 of 140 patients) in this early trial.

The best responses were seen in patients with nonsmall-cell lung cancer, kidney cancer, and melanoma, said Roy Herbst, MD, from the Yale Cancer Center in New Haven, Connecticut. Lesser responses were seen in patients with colon, stomach, head and neck, and bladder cancers.

All of the patients had metastatic or incurable solid tumors.

Dr. Herbst spoke during presscast held in advance of the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO). The data he presented are the first ever for MPDL3280A.

Therapy responses were durable, with 26 of 29 responders continuing to respond (responders' time on study drug, 3 - 15 months), he noted.

The overall response rate seen with MPDL3280A is in the same ballpark as that seen with another immune checkpoint blockade agent, nivolumab (Bristol-Myers Squibb), in a phase 1 trial of patients with a variety of cancer types. Those results were presented last year at the ASCO annual meeting, as reported by Medscape Medical News.

Since then, high overall response rates (41%) with nivolumab have been reported in patients with melanoma.

The response rate with MPDL3280A was higher in patients with tumor expression of PD-L1 than without (36% vs 13%). This makes sense because MPDL3280A blocks PD-L1, a protein that cancer cells express to evade the immune system, Dr. Herbst explained.

These study data are evidence that MPDL3280A can "productively manipulate the immune system," said presscast moderator Clifford Hudis, MD, from the Memorial Sloan-Kettering Cancer Center in New York City. He pointed out that phase 1 studies have traditionally been used to assess safety and establish dosing. In this trial, however, "we already have evidence of efficacy," he said, some of it out to 1 year.

"The fact that MPDL3280A is active in such a variety of tumors suggests that PD-L1 is part of a universally or generally important immune mechanism," Dr. Hudis noted in a press statement.

The study has been expanded to include blood cancers and a larger range of solid tumors, and now has enrolled 275 patients. MPDL3280A combination studies, including with targeted therapies, have also been initiated, said Dr. Herbst.

Well Tolerated

Intravenous MPDL3280A was administered every 3 weeks in the clinical trial. Patients received MPDL3280A for a median duration of 127 days (range, 1 - 330).

The overall response rate was assessed with RECIST criteria and includes confirmed and unconfirmed complete and partial responses. Response was assessed with computed tomography scans every 6 weeks for 6 months, and every 12 weeks thereafter.

No dose-limiting toxicity was observed with any of the 6 doses tested. "This is good news," said Dr. Herbst. There were also no maximum tolerated dose and no treatment-related deaths.

There were more patients who were evaluable for safety than for efficacy (171 vs 140).

According to Dr. Herbst, the majority of adverse events were transient grade 1/2. A total of 43% of patients had a grade 3/4 adverse event. However, the investigators determined that only 13% of these were related to the drug; the remainder were due to disease or other factors.

There was no grade 3 to 5 pneumonitis, which is a "concern" with immune checkpoint blockade, said Dr. Herbst.

Immune-related grade 3/4 adverse events are another concern; however, the investigator-assessed rate of these was only 2% (n = 4). They included increased levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), colitis, and hyperglycemia. There was only 1 immune-related adverse event that led to treatment discontinuation (elevated ALT and AST levels). "Immune-related adverse events were uncommon," Dr. Herbst reported.

This study was funded by Genentech. Dr. Herbst reports receiving research funding from Genentech. Some of the study coauthors are employees of Genentech.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract 3000. To be presented June 3, 2013.

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