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ASCO Abstracts Shining a Light on Cancer Immunotherapy

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By Marie Powers
Staff Writer

The American Society of Clinical Oncology (ASCO) released the first of more than 4,700 abstracts late Wednesday in anticipation of its 2013 annual meeting, scheduled to attract more than 30,000 participants to Chicago from May 31 to June 4.

Early abstracts highlighted by ASCO at a Wednesday afternoon press conference suggested a significant focus this year will be advances in cancer immunotherapies, including inhibitors of PD-L1 and PD-1.

Roy S. Herbst, professor of medicine at Yale University Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale-New Haven, summarized a Phase I expansion study of MPDL3280A, a human monoclonal antibody currently in development at Genentech Inc., a unit of Roche AG, of Basel, Switzerland.

PD-L1 is a protein frequently overexpressed on the surface of cancer cells that binds either to the PD-1 or B7.1 receptor cells and acts as a disguise, allowing cancer cells to evade the immune system. When MPDL3280A attaches to the PD-L1 protein, however, it blocks PD-L1 expressed by the tumor so the cancer can no longer hide from the immune system, allowing T cells to do their job. MPDL3280A was engineered to enhance safety and efficacy compared to earlier PD-L1 or PD-1 targeted agents.

The Phase I trial enrolled 171 patients across all dose cohorts with locally advanced or metastatic solid tumors whose disease had progressed despite prior therapies. MPDL3280A was delivered intravenously every three weeks, with response assessed by CT scan.

In terms of safety, no maximum tolerated dose was seen, and there were no dose-limiting toxicities or treatment-related deaths, with the majority of adverse events (AE) considered transient. Although 43 percent of patients had a Grade 3/4 AE, only 13 percent of those were believed drug-related. Only one patient withdrew from treatment due to an immune-related AE, according to Herbst.

In 140 patients evaluated for efficacy, the overall response rate was 21 percent (29/140). Although researchers have not yet established how PD-L1 expression affects response to MPDL3280A, Genentech is developing a companion diagnostic to the drug. Using the investigational test, researchers analyzed archived tumor tissue from 103 patients and found that tumor shrinkage occurred in 36 percent of patients with PD-L1 positive tumors (13/36) and in 13 percent of patients with PD-L1 negative tumors (9/67). Because the diagnostic test for PD-L1 is still in development, a negative result on the PD-L1 test could simply mean the tumors had less PD-L1 than the test currently detects, Herbst suggested.

The highest response was observed in non-small-cell lung cancer and melanoma, but tumor shrinkage also was observed in kidney cancer, colorectal cancer and gastric cancer.

"Importantly – and I've seen this in my own patients – these responses have tended to occur quickly in many cases, and also they're quite durable," he added. Data showed that 26 of 29 responders continue to respond, some for more than 15 months.

The study has been expanded to include a larger range of solid tumors and blood cancers, with more than 275 patients currently enrolled. A number of additional Phase II and Phase III studies are planned to confirm the drug's anticancer activity and further validate the diagnostic test. Genentech also is looking at ways to combine MPDL3280A with other anticancer therapies.

Early evidence of efficacy using MPDL3280A across a wide swath of solid tumors is especially encouraging given that Phase I studies traditionally focused on safety, said Clifford A. Hudis, president-elect of ASCO, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University.

The fact that the drug prompted the greatest response in patients whose tumors tested positive for the PD-L1 marker "suggests that, maybe in the near future, we'll be able to develop a biomarker that identifies tumors that are more responsive to this particular approach," Hudis said.

Daniel S. Chen, associate group director and global development team leader for the anti-PD-L1 program at South San Francisco-based Genentech, agreed that targeting PD-L1 represents cutting-edge cancer therapeutic development.

"We chose PD-L1 as a specific target for therapy because it's what we see human cancers up-regulating in what appears to be an attempt to escape from a patient's immune response," Chen told BioWorld Today. "We believe the biology for PD-L1 is very broad, and we've seen responses in many cancer types. That makes sense, because the human immune system can interact with almost any kind of cancer."

Nonetheless, it makes sense to identify the patients most likely to benefit from cancer immunotherapy, he added, noting that development of a companion diagnostic is an equally important component of the PD-L1 program.

Nivolumab Wows as Companion to Yervoy

Jedd Wolchok, medical oncologist at the Memorial Sloan-Kettering Cancer Center and the study lead on clinical trials that led to the approval of Yervoy (ipilimumab, Bristol-Myers Squibb Co.), provided the overview of a second ASCO abstract focusing on cancer immunotherapy, sponsored by BMS. Wolchok and colleagues studied the clinical activity and safety of nivolumab, an anti-PD-1 currently in clinical trials, in combination with the anti-CTLA-4 ipilimumab, in patients with inoperable Stage III and Stage IV melanoma.

The rationale for the combination study was that "neither medicine produces complete responses or disappearance of all melanoma tumors from CT scans in more than 3 percent of patients," Wolchok explained. However, both block pathways that are essentially "molecular breaks," preventing T cells from achieving "a full and persistent state of activation," he added. Animal studies suggested the combination would produce better results than either compound alone.

In fact, the ongoing Phase I study, which included six different arms of concurrent or sequenced cohorts, suggested the combination regimen led to an objective response rate of 53 percent in the largest group of patients on concurrent therapy. In other words, "more than half of patients had at least a 50 percent reduction of the measurable tumors on their CT scans," Wolchok said.

The findings were based on 52 patients in three completed treatment arms in which patients received concurrent treatment with the two drugs.

"What was unique in our experience was that most of these responding patients had rapid and deep regressions, with many showing more than 80 percent tumor regression by the time of the first scans," Wolchok added. When all of the concurrent cohorts were combined, 40 percent showed an objective response.

Two of the remaining three arms enrolled patients who had undergone prior ipilimumab treatment, and those patients received only nivolumab. Preliminary data suggested that even patients who initially had little benefit from ipilimumab saw significant tumor shrinkage after subsequent treatment with nivolumab.

Side effects were manageable and did not affect the therapeutic benefits for most patients in the analysis, and no treatment-related deaths were reported, according to Wolchok. A randomized Phase III of the nivolumab/ipilimumab combination as first-line therapy for patients with advanced melanoma is scheduled to begin in June.

The nivolumab findings reinforced promising data about the compound presented at ASCO 2012 and earlier this year at the American Association for Cancer Research annual meeting. (See BioWorld Today, June 4, 2012, and April 15, 2013.)

The Street took notice, too, sending BMS shares (NYSE:BMY) up 5 percent Wednesday even before ASCO abstracts were released. The stock gained $2.13, closing at $44.34.