PD-1 Agent 'Breaks Ceiling' in Cancer Immunotherapy

Predictive Biomarker Possibly Identified

Nick Mulcahy

June 02, 2012

June 2, 2012 (Chicago, Illinois) — A new immune-targeted approach to cancer treatment is being heralded as the next big thing in oncology after 2 investigational agents (BMS-936558 and BMS-936559, Bristol-Myers Squibb) produced unprecedented durable tumor response rates in 3 cancers in early trials.

The phase 1 results are so promising that Bristol-Myers Squibb will move directly into phase 3 trials of their novel agents for lung cancer, melanoma, and renal cancer, according to a media report.

The approach uses monoclonal antibodies to neutralize the programmed death 1 (PD-1) protein and its partner molecule (PD-L1), elements of tumors that enable them to evade their nemesis — the immune system.

This inhibition of PD-1 with antibodies "may meet the expectations" of the "next frontier in the treatment of cancer," according to an editorial published online June 2 in the New England Journal of Medicine to coincide with the presentation of the studies here. It accompanies the publication of the phase 1 studies of BMS-936558 and BMS-936559.

Editorialist Antoni Ribas, MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, writes that together, the studies show that the new immunotherapy agents have "broken the ceiling of durable tumor response rates of 10% to 15%."

This ceiling of 15% has existed for the past 30 years, a period in which many immunotherapies for cancer have shown limited benefit and high toxicity, he noted.

The antibodies that block PD-1 and PD-L1 are "likely to provide a new benchmark for antitumor activity in immunotherapy," according to Dr. Ribas.

The 2 studies caused quite a stir at the here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO), where they are being presented. Although the data are still very early, the results created a buzz after being highlighted at a press conference and making it to the front pages of several leading American newspapers, including the Wall Street Journal.

Responses Described as "Remarkable"

In a phase 1 trial of BMS-936558, an injectable antibody that blocks PD-1 and enhances antitumor immunity, American researchers enrolled 296 patients with advanced melanoma, colorectal cancer, nonsmall-cell lung cancer (NSCLC), prostate cancer, and renal cancer that had progressed despite standard therapies.

Objective responses were observed in 26 of 94 patients (28%) with melanoma, in 9 of 33 patients (27%) with renal cancer, and in 14 of 76 patients (18%) with NSCLC; all were treated for at least 6 months. The responses were "very durable"; 20 patients had responses lasting 1 year or more (of the 31 who had 1 year or more follow-up), said lead author Suzanne Topalian, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland.

There were no objective responses in patients with advanced colorectal or prostate cancer.

However, the agent was effective in both the squamous and nonsquamous NSCLC. The lung cancer findings were unexpected because lung cancer patients have been historically unresponsive to immune-based therapies, Dr. Topalian explained.

"It's a remarkable result," she said. "I have been in the field of cancer immunotherapy since 1985, and this was a genuine surprise."

Another prominent oncologist echoed that sentiment.

"The top news [from the study] is that an immune-targeted approach is working for lung cancer," said Sunil Verma, MD, from the Sunnybrook Odette Cancer Centre and the University of Toronto in Ontario, Canada, who was not involved with the study.

"This is one of the first trials to show benefit in lung cancer with an immune-targeted approach," Dr. Verma told Medscape Medical News.

BMS-936559 is a separate antibody that targets the PD-L1 partner molecule. This anti-PD-L1 antibody has patterns of clinical activity similar to those of the anti-PD1 antibody, the researchers report.

Predictive Biomarker Possibly Found

The phase 1 trial of BMS-936558 provides some evidence that just such a predictive biomarker has been found.

A subanalysis of data from the trial suggests that PD-L1 could help predict which patients will respond to BMS-936558, said Dr. Topalian during the press conference.

The researchers used immunohistochemistry to analyze tumor samples obtained from 42 patients prior to treatment initiation. They sought to assess the role of the expression of PD-L1 in the modulation of the PD-1/PD-L1 pathway. In correlating the results with response data, the team found that 9 of 25 patients (36%) with PD-L1-positive tumors responded to BMS-936558, whereas none of 17 patients (0%) with PD-L1-negative tumors did.

Additional studies are planned to assess the potential role of PD-L1 as a predictive marker of response to anti-PD-1 therapy, said Dr. Topalian.

Less Toxicity

The antibodies that block PD-1 and PD-L1 are not the first agents to block immune system "checkpoints" that are "hijacked" by tumor cells, writes Dr. Ribas.

Blockade of the CTLA4 (cytotoxic T-lymphocyte-associated antigen 4) checkpoint with ipilimumab (Yervoy, Bristol-Meyers Squibb) improved overall survival in metastatic melanoma. However, therapy with ipilimumab resulted in objective responses in only 10% to 15% of patients, and the "glass ceiling" held. At the same time, responses were associated with clinically significant autoimmune or inflammatory toxic effects in 20% to 30% of those patients.

Dr. Ribas further explained to Medscape Medical News how the new BMS antibodies are different from ipilimumab.

"Blocking PD-1 may be more targeted to cancer-specific T cells, whose function is blocked directly by the tumor. Therefore, it predicts that blocking PD-1 may result in higher response rates and fewer side effects than blocking CTLA4," he said.

The study results appear to reinforce this point.

Dr. Topalian reported that the anti-PD-1 antibody BMS-936558 was generally well tolerated. Serious toxic effects (grade 3 or 4) were observed in 14% of patients, and there were 3 deaths from pulmonary toxicity. In the 207-patient study of the other antibody for anti-PD-L1 (BMS-936559), treatment-related serious toxic effects occurred in 9% of patients.

Adverse events that are "consistent" with immune-related causes were seen, but overall, the adverse-event profile "does not appear to preclude its use," Dr. Topalian and her coauthors write. They predict that the therapy could be delivered in an outpatient setting with "minimal supportive care."

At the press conference, Dr. Topalian reported that fatigue was the most common adverse effect (24%) seen by her team, and that only 5% of participants discontinued treatment in the trial.

More PDI-1 Study Details

The antibody was administered as an intravenous infusion every 2 weeks of each 8-week treatment cycle. Response was assessed after each treatment cycle and patients received treatment for up to 2 years (12 cycles) or until they had a complete response or progressive disease.

The trial was a dose-escalation study; after 3 different planned doses (0.3 to 10.0 mg/kg body weight), no maximum tolerated dose was observed, the researchers report.

The patients were "heavily pretreated," with 47% having had at least 3 previous regimens, including immunotherapy and BRAF inhibitors in some melanoma patients.

The surprising responses seen in lung cancer "underscore the possibility that any neoplasm could be immunogenic with proper immune activation," write the researchers.

The studies were funded by Bristol-Myers Squibb (BMS). Dr. Topalian reports being a consultant/advisor to BMS and Amplimmune; and receiving research funding from BMS. Some of her coauthors report financial disclosures related to BMS or are employees of the company. Dr. Ribas reports financial ties to Plexxikon. Dr. Verma reports being a consultant/advisor to and receiving honoraria from GlaxoSmithKline and Roche Diagnostics; and receiving research funding from Roche Diagnostics.

N Engl J Med. Published online June 2, 2012. BMS-936558 Abstract, BMS-936559 Abstract, Editorial

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA2509. To be presented June 2, 2012.

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