13:10 Onyx's Nexavar likely to join graveyard of failures in melanoma, physicians say
Story Onyx Pharmaceuticals' (NASDAQ:ONXX) Nexavar (sorafenib) will likely fail in melanoma, physicians said.
There has been a graveyard of failures in melanoma, from CTLA-4 inhibitors like Pfizer's (NYSE:PFE) tremelimumab and Medarex's (NASDAQ:MEDX) ipilimumab, to Genta's (OTC:GNTA) Genasense. More recently, Synta suspended development of elesclomol due to serious safety concerns.
Dr Salvatore Del Prete, director of clinical research at the Bennett Cancer Center, Hematology Oncology Associates, said it would be a "leap of faith" to say that Nexavar can be used in melanoma, even though it works in kidney cancer. But he acknowledged, "Other drugs that have worked in renal cell carcinoma, like IL-2 and interferons, happened to work in melanoma."
"It doesn't seem like a big step forward any way we look at it," said Dr Antoni Ribas, an associate professor of hematology and oncology and a researcher at UCLA's Jonsson Cancer Center.
Ribas explained that Nexavar was first developed as a c-Raf inhibitor. In 2002, a discovery was made that melanoma patients have a mutation in BRAF - but later studies found that Nexavar does not block mutated BRAF in melanoma. "Most of its effect is not through the c-Raf pathway in patients, but through blocking VEGF kinases for blood vessel formation," he added.
BRAF mutations occur in 60-70% of melanoma patients, according to Ribas. "It's a high percentage of melanoma patients, and more frequent in younger patients," he added.
The mutation renders the BRAF protein constantly active, which implies that this pathway could be a viable target for drug development.
New drugs in development by Novartis (NYSE:NVS), Roche (OTC:RHHBY) and Plexxikon block BRAF specifically, said Ribas. Novartis is developing RAF265, which targets the BRAF protein kinase, and Roche and Plexxikon have PLX5568 in the pipeline.
"Those drugs will tell us whether blocking BRAF is what we anticipated, and is a way of treating melanoma," Ribas said. The preclinical data suggests BRAF is important, but whether it's a viable target will depend on the data unveiled at ASCO, he said.
Dr Anna Pavlick, director of New York University's Langone Medical Center's melanoma program, said the current first-line treatment in metastatic melanoma is to enroll patients in a clinical trial, since nothing else works better. She explained that a lot of patients make it to second-line therapy and there is supportive care. "Most patients are diagnosed when they are asymptomatic and are not losing weight," she said.
The Phase III Eastern Cooperative Oncology Group (ECOG) trial is testing Nexavar in combination with carboplatin and paclitaxel in patients with unresectable stage III or stage IV melanoma. Data from this trial is likely expected in 2Q09, according to analyst reports.
"There is a tremendous unmet need for new therapies in melanoma, a historically difficult tumor to treat," an Onyx spokesperson said. "We are looking forward to data from the Phase III melanoma study sponsored by a cooperative group in the U.S. to understand if Nexavar can provide a new option to help these patients and their families."
Pavlick questioned the trial design, explaining that paclitaxel is not the standard of care in melanoma. "What if we are using all of these patients' lives to find that the carbo-taxol design is a bust?" she said in an interview. The best cytotoxics for use when designing a trial for melanoma have yet to be determined, and the company is trying combination this based on a single Phase I/II study, she added.
Pavlick had previously expressed doubts about Nexavar's success in melanoma on a recent panel. "I don't think the randomized Phase III trial will be positive," she said at the time.
Synta's SYMMETRY trial, which tested elesclomol in combination with paclitaxel in chemo-naive patients with stage IV metastatic melanoma, was recently suspended due to an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol with paclitaxel) compared to the control arm (paclitaxel alone).
Dr Gary Schwartz, chief of the melanoma and sarcoma service at Memorial Sloan Kettering Cancer Center, said Nexavar and carboplatin are poor inhibitors of MAP kinase, which is part of the same pathway as BRAF. But in combination with the right drug, there may be some hope there, he said.
Yet Schwartz added that he has reservations at this point regarding Nexavar's success in melanoma. He added that KIT mutations may be another tumor type to target in the future.
Onyx has a market cap of USD 1.85bn.
by Kimberly Ha and Elizabeth Krutoholow
