April 3, 2012 9:22 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Roche’s (PINK:RHHBY) Zelboraf has been steadily adopted as a personalized treatment for patients with late stage melanoma since gaining approval last year, with benefits that have surpassed expectations, oncologists told Biopharm Insight. However, the notoriously difficult to treat cancer has seen a recent increase in treatment options and resistance issues have left room for others in the field.
Most notably, Bristol Myers Squibb’s (NYSE:BMY), Yervoy, which was approved by the FDA in March 2011 and by the EMA in July 2011, has made a significant impact on the disease, particularly in patients who do not qualify for Zelboraf on the basis of their genetic makeup.
Zelboraf is specifically approved for patients who have a tumor with a specific marker, known as BRAF V600E that is identifiable by the cobas 4800 BRAF V600 Mutation Test.
The drug has changed the field as many did not expect to see such a dramatic effect on Stage IV, or late stage melanoma patients, Keiran Smalley, assistant member, Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute said. The increase in survival has been impressive to date and there is hope it can be increased even further, he explained.
In patients without the marker, Yervoy is a first-line therapy, Smalley explained, since the drug works by simply activating a patient’s immune system.
However, treatment is not as straightforward as it may appear, oncologists said.
Only about half of patients with the marker meet the criteria for clinical response to Zelboraf, Smalley explained. It is not entirely clear why some patients with the mutation do not respond, Channing Der, Sarah Graham Kenan Distinguished Professor, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill said.
Furthermore, a large percentage of patients that do respond to therapy ultimately develop resistance within two to 18 months after initial treatment, Der said.
Patients will progress on Zelboraf, it is really a matter of time, Dr Keith Flaherty, director, Developmental Therapeutics, MGH Cancer Center said. If there are no alternatives, many community oncologists want to keep patients on therapy even when the drug is no longer working. If a patient has already received Yervoy, alternatives are limited, he explained. Yervoy could be used if not previously tried, but it takes some time before it works while the immune system ramps, he said.
There is also no agreement on when treatment with immunotherapy should begin since response can be slow, Smalley noted.
Since Yervoy is an option for patients regardless of BRAF status, it is difficult to determine whether to start treating with Yervoy or Zelboraf in patients with a BRAF mutation, Dr Frances Collichio, clinical Professor, Division of Hematology and Oncology, University of North Carolina explained. Patients with a good performance status or stronger immune system should start therapy on Yervoy, she said.
Progression on Zelboraf is too rapid for some patients to successfully switch to treatment with Yervoy, but it is difficult to stop therapy when it is working, Collichio said.
A recently published Phase II trial showed targeted therapy aimed at the BRAF mutation induced responses in half the patients with a median survival of 16 months (N Engl J Med 2012; 366:707-714).
Responses with Zelboraf are short-lived but this survival is better than previously seen, said Flaherty, creating a challenge for clinicians. The National Cancer Institute (NCI) hopes to answer these questions and a study will test upfront therapy with Yervoy or Zelboraf in a randomized fashion and then switch patients to test which sequence is better, he said.
The resistance to Zelboraf is not fully understood from a biological standpoint and is not easy to predict, said Der.
Yet a solution may not be too far away, oncologists said, pointing to GSK’s (NYSE:GSK) GSK2118436, which has the same target as Zelboraf but is being testing in combination with GSK1120212 that has a target called “MEK.” Melanoma may try to outsmart Zelboraf and continue to grow by sending a signal through MEK, Der explained.
There are additional mechanisms of resistance, but this approach may prove to be more efficacious in preventing the onset of resistance, Der said.
GSK is planning to start a Phase III trial of the combination in 2012, according a spokesperson.
So far, the data shows the combination is at least as good as Zelboraf alone, Flaherty said.
Data presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) will indicate whether the combination will replace the latter, he said. An ongoing Phase I/II trial has an estimated primary completion date of April 2012, a GSK spokesperson confirmed. The meeting is scheduled to take place 1-5 June 2012, in Chicago.
The combination seems to also block the appearance of squamous tumors, a common side effect seen with Zelboraf, Smalley added.
However, the side effects of Zelboraf are not terrible, and are therefore not a limiting factor, Flaherty said. GSK would need to show an improvement in efficacy and toxicity for FDA approval, he noted.
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