BioWorld Insight Contributing Writer

The approval of Bristol-Myers Squibb Co.'s Yervoy (ipilimumab) is the first for the metastatic melanoma space in more than a decade. The New York-based pharma's CTLA-4-blocking antibody also was the first therapy to demonstrate a significant improvement in overall survival, and analysts are estimating the drug will bring in sales of $1 billion in the U.S. alone. (See BioWorld Today, March 28, 2011.)

But whether that approval is a bellwether for a field plagued by failures remains to be seen.

History has not been kind to candidates in the melanoma field. Berkeley Heights, N.J-based Genta Inc.'s Bcl-2-targeting antisense drug Genasense (oblimersen) failed to show a statistically significant benefit first in a Phase III trial, and then missed again in a confirmatory study, showing no improvement in the co-primary endpoint of progression-free survival or on secondary endpoints of overall response rate and disease control rate. (See BioWorld Today, Oct. 30, 2009.)

Emeryville, Calif.-based Onyx Pharmaceuticals Inc. and German partner Bayer AG's tyrosine kinase inhibitor Nexavar (sorafenib) also failed two Phase III trials in melanoma, although the drug is approved to treat advanced liver and kidney cancer. (See BioWorld Today, April 28, 2009, and Dec. 5, 2006.)

Other candidates failing to garner FDA approval for melanoma include Lexington, Mass.-based Synta Pharmaceutical Corp.'s elesclomeol and cancer vaccine Canvaxin from now-defunct CancerVax Corp., of Carlsbad, Calif. (See BioWorld Today, June 8, 2010, and Oct. 5, 2005.)

Yervoy's success where others failed may be due in part to trial design, as well as its mechanism of action, said Donald Morton, chief of the melanoma program at the John Wayne Cancer Institute (JWCI) in Santa Monica, Calif. "This is the first drug that has been approved based upon a randomized trial to show effectiveness vs. other therapies, so it's a major step forward.

"One of the reasons this trial was successful," Morton continued, "was that it contained enough patients so that even though the difference in overall survival was about four months, there was a large enough sample size that it was statistically significant." A subset of patients had durable, long-term remissions as well, Morton said, "which is of course ideal when you're treating malignancy."

Morton added that the mechanism of action is key, and is totally different from other available treatments. "I think there's great potential for using it in combination with other treatments such as surgery or active melanoma agents."

Yervoy's approval was based on the pivotal trial 020, in which 676 previously treated patients with a specific human leukocyte antigen (HLA) genotype were randomized into one of three groups to receive Yervoy at a 3 mg/kg intravenous dose in combination with investigational tumor vaccine gp100, Yervoy without the pg100 vaccine or the gp100 vaccine alone. The HLA genotype "facilitates the immune presentation of the investigational peptide vaccine," according to the Yervoy's label.

The primary outcome measure was overall survival in the Yervoy-plus-gp100 arm compared with the gp100-alone patients. Secondary outcome measures were overall survival in the Yervoy-plus-gp100 arm vs. the Yervoy-only arm, Yervoy alone compared to the gp100-only arm, best overall response rate at week 24 between each of the study arms and duration of response.

Patients treated with Yervoy monotherapy, or with Yervoy plus gp100, lived a statistically significant longer period of time at 10 months, compared with 6.5 months for patients who received only the vaccine. As published in The New England Journal of Medicine, the estimated one-year survival rate was 46 percent for patients in the Yervoy-only arm vs. 25 percent in the gp100 arm, and 24 percent vs. 14 percent, respectively, at the two-year mark.

Yervoy is expensive, about $30,000 per dose with three to four doses expected for induction. Leerink Swann analyst Seamus Fernandez said he predicts peak sales at $850 million for Yervoy. Morton also agreed that the drug is pricey, "but people are excited about it because before there was no alternative."

The Next Wave of Melanoma Candidates

A number of companies, however, are hoping to follow in Yervoy's footsteps.

PLX4032 from Plexxikon Inc. (which is being acquired by Daiichi Sankyo Co. Ltd.) and partner Roche AG is leading the pack. The Phase III-stage BRAF inhibitor showed improved survival over standard-of-care dacarbazine in patients with previously untreated metastatic melanoma with the BRAF mutation. The firms expect to file for regulatory approval this year. (See BioWorld Today, Nov. 8, 2010, and Jan. 20, 2011.)

Leerink's Fernandez said the specific genotype targeting should help PLX4032 succeed in melanoma, where roughly 50 percent of patients have a BRAF mutation. "I think science is catching up with the disease," Fernandez told BioWorld Insight.

JWCI's Morton said targeting drugs to a mutation, as with PLX4032, "is the future not only for melanoma but for all types of cancer." The problem with past trials, Morton said, "is that the drugs were designed for and tested in all patients with melanomas, and they weren't sophisticated enough to select a subtype of patients more likely to respond to that particular drug."

Other drugs in late-stage development include the Phase III cancer vaccine, Allovectin-7, from San Diego-based Vical Inc., in trials as a first-line therapy for patients with Stage III and Stage IV recurrent metastatic melanoma. Allovectin-7 could give Yervoy a run for its money, as the Phase II results showed a median survival of 18.8 months. Data from Allovectin-7's Phase III trial are expected in the second half of 2011.

Then there's BioVex Inc., of Woburn, Mass., which was just acquired by Thousand Oaks, Calif.-based Amgen, which is developing the Phase III oncolytic OncoVex GM-CSF. Pfizer Inc. ran into trouble with its anti-CTLA-4 antibody tremelimumab, after an interim Phase III analysis suggested the drug likely would not meet statistical significance. But Swiss pharma Debiopharm Group revived that drug after Pfizer discovered a biomarker that could better target patients and elicit a response. (See BioWorld Today, Jan. 8, 2010.)

Another drug that hit the skids, but appears to be making a comeback is London-based AstraZeneca plc and Boulder, Colo.-based Array BioPharma Inc.'s selumitinib. The firms halted the Phase II MEK kinase inhibitor, which may be more effective in patients with BRAF mutations, when initial results indicated no difference in efficacy between the two arms in the primary endpoint of progression-free survival. However, AstraZeneca is advancing the compound through a number of redesigned multi-arm Phase II trials. (See BioWorld Today, Dec. 21, 2007.)

Leerink's Fernandez said the future of melanoma drugs will depend on the mechanism of action, but the hurdle will be higher now that Yervoy is approved and likely will become part of the clinical trial comparator group. "The problem is that they're going to face a high hurdle and will have to do head-to-head comparisons, or study a candidate as a second-line treatment." It is similar to when VEGF inhibitor Avastin (bevacizumab, Roche AG) hit the market, Fernandez said. "It's difficult to conduct a clinical trial in colorectal cancer without Avastin on board."

Fernandez added developers also likely will have to incorporate specific genotypes such as the BRAF mutations if PLX4032 is approved. "Development will have to incorporate Yervoy and PLX4032, or both. I view it as a challenge to designing clinical trials at this point."