FDA Fast Tracks Ipilimumab for Metastatic Melanoma

Nick Mulcahy

August 19, 2010

August 19, 2010 — Bristol-Myers Squibb (BMS) has announced that its Biologics License Application for ipilimumab for metastatic melanoma has been accepted for filing by the US Food and Drug Administration (FDA) and that it has been granted a priority review designation.

Ipilimumab — the first agent ever proven to improve survival in advanced melanoma — will be indicated for second-line use in adult patients.

A priority review designation is granted to agents that either offer major advances in treatment or provide a treatment where no adequate therapy exists.

The projected FDA action date is December 25, 2010, which is a timeline based on the FDA's 6-month goal for completing priority reviews, according to a press statement from BMS.

The company previously reported that it has also submitted regulatory filings for ipilimumab with the European Medicines Agency.

Pivotal Study Published

The news of the FDA's fast-tracking of ipilimumab comes at the same time as the results of the pivotal trial upon which the filing is based appear in print — in the August 19 issue of the New England Journal of Medicine.

The results were first presented at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting; they were published online simultaneously in the journal.

At ASCO, the ipilimumab data generated extensive media coverage, as well as a prediction of great patient demand, as reported by Medscape Medical News at the time.

An editorial by Patrick Hwu, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, accompanies the print edition of the study.

"Dramatic" Reponses

Dr. Hwu comments on the specifics of the phase 3 trial of ipilimumab and the evolving universe of treatment for metastatic melanoma. He highlights the fact that the response to ipilimumab can be "dramatic."

Ongoing complete responses in some patients with metastatic melanoma can continue past 6 years.

Follow-up from the earliest cohort of patients who received ipilimumab "shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years," he says.

However, on the downside of the data from the 676-patient study, the "best overall response rate" (patients with a complete or partial response) was limited to 10.9% of the ipilimumab recipients.

The majority of patients with metastatic melanoma do not respond to this agent.

"The majority of patients with metastatic melanoma do not respond to this agent," writes Dr. Hwu.

Given the fact that only a minority of patients in the study responded to ipilimumab, Dr. Hwu says that "it will be critical to determine biomarkers that will predict this outcome."

More patients might have been found to have a complete or partial response rate if the criteria were different, suggested Dr. Hwu.

"Classic response criteria developed for chemotherapy, such as the criteria of the World Health Organization and the Response Evaluation Criteria in Solid Tumors (RECIST), may need to be reevaluated for immunologic agents," he writes.

He explained that the "development of immune responses against self-antigens, such as those expressed by tumors, can take time, and the clinical experience with anti-CTLA-4 drugs clearly shows that clinical responses can take months to develop."

New Class of Drug "Validation"

The phase 3 trial was cosponsored by BMS, which is marketing ipilimumab, and Medarex, the company that developed the agent and that was eventually bought by BMS.

In the study, patients receiving ipilimumab plus a peptide vaccine (glycoprotein 100) had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001). Patients receiving ipilimumab alone had a nearly identical median survival —10.1 months — in the 3-group clinical trial (P < .003).

All of the study participants had undergone previous treatment for the disease. Ipilimumab, at a dose of 3 mg/kg of body weight, was administered with or without the peptide vaccine every 3 weeks for up to 4 treatments (induction).

Ipilimumab is another targeted therapy for cancer but represents a new class of drug, known as a targeted T cell antibody, said Stephen O'Day, MD, one of the study authors, in his presentation of the data at ASCO.

Ipilimumab is directed against an antigen on the surface of T cells. The antigen, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), acts as a brake on the T cell, explained Dr. O'Day, who is from the University of Southern California Keck School of Medicine in Los Angeles. By blocking the brake, the T cell goes into attack mode and kills cancer cells.

The pivotal study shows that this blocking of the immune system has an impact on the cancer, Dr. Hwu notes.

"The current work is perhaps most significant because it provides validation of the blockade" as an "important therapeutic strategy against cancer," he writes.

Big Picture

"The ultimate role" of anti-CTLA-4 drugs such as ipilimumab in the therapy of patients with metastatic melanoma is "still unclear," says Dr. Hwu. That's because the treatment of metastatic melanoma is "rapidly changing," he adds.

After a 10-year dry spell of no FDA approvals, there are now a host of potential new treatments.

"For example, 50% of metastatic melanomas express a mutated BRAF gene, and the use of BRAF inhibitors to treat patients who have this mutated gene has resulted in clinical response rates higher than 50%," he writes.

Future research efforts should include the "rational combination of anti-CTLA-4 agents" or other immune system inhibitors with targeted therapies or other immune agents, Dr. Hwu proposes.

With these comments, Dr. Hwu echoes experts who spoke at ASCO about ipilimumab.

Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida, who acted as a discussant of the study at ASCO, said that "improvements" will be needed "if this drug is going to be a success."

"We think they'll come from combinations," he continued, saying that potential agents for combinations include chemotherapy, vaccines, other immunotherapies, and investigational agents.

Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, who moderated an ASCO press conference on ipilimumab, said the "next step" in improving treatment outcomes might be found by combining ipilimumab, a targeted T cell antibody, with the investigational PLX4032 (Plexxicon Inc), which is a molecularly targeted therapy that was first reported on at ASCO.

PLX4032 is one of the aforementioned BRAF inhibitors and is an oral agent. Overall survival data are not yet available for PLX4032, but will be published soon in the New England Journal of Medicine.

PLX4032 has "unbelievably dramatic responses in terms of tumor shrinkage," said Dr. Schuchter.

Dr. Schuchter said that the Melanoma Research Foundation is in the planning stages of a study that combines ipilimumab and PLX4032 in patients with metastatic melanoma.

Like Dr. Hwu, she said that there will be other possible combinations as more agents are evaluated, including the investigative agent tremelimumab (Pfizer).

Dr. O'Day reports serving in a consultant or advisory role for and receiving honoraria and research funding from Bristol-Meyers Squibb, and receiving research funding from Medarex. F. Stephen Hodi, MD, lead author of the study, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports receiving consulting fees from Bristol-Myers Squibb–Medarex, Novartis, and Genentech. Dr. Sondak reports being a speakers bureau member and providing consulting and expert testimony for Merck/Schering-Plough; he is also on advisory panels for Bristol-Myers Squibb, Genzyme, GlaxoSmithKline, Pfizer, and Provectus. Dr. Hwu has disclosed no relevant financial relationships.

N Engl J Med. 2010;363:711-723, 779-781. Abstract

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