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Roche, BMS Hope to Improve Outcomes in BRAF-Mutated Melanoma Patients with Dual Treatment Regimen

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Originally published June 6.

By Turna Ray

CHICAGO — By exploring a treatment strategy that involves Roche/Plexxikon's investigational pharmacogenomically targeted drug vemurafenib and Bristol-Myers Squibb's newly approved melanoma treatment Yervoy, two large drug developers are hoping to further improve outcomes for a genomically defined patient population.

Roche and BMS announced last week that they would together study the effectiveness of a treatment regimen combining Yervoy and vemurafenib. The US Food and Drug Administration approved Yervoy, or ipilimumab, in late March when it was shown to extend survival in unselected late-stage melanoma patients by 10 months. Roche's vemurafenib, or PLX 4032, is undergoing review by the FDA, but in a late-stage clinical trial, researchers have shown that metastatic melanoma patients with BRAF mutations have significantly better survival outcomes compared to those treated with chemotherapy.

“We have made significant progress in treating metastatic melanoma and hope to further improve outcomes by combining two agents that target this deadly disease in different ways,” Hal Barron, Roche's chief medical officer, said in a statement.

There were 68,000 new cases of melanoma and 8,700 deaths related to the disease last year in the US, according to the American Cancer Society, and the Skin Cancer Foundation estimates that the survival rate for patients with advanced disease is around 15 percent. So far, Yervoy is the only drug that has been shown to significantly improve survival for the disease, and researchers are working to identify other compounds that could benefit melanoma patients. If the companies are successful at developing a combination regimen showing that Yervoy doesn't have poor outcomes in BRAF-mutated advanced melanoma patients, then they may be able to market the dual therapy to a subpopulation of melanoma patients at a premium price.

The companies announced their plans to explore the combination regimen right before the start of the American Society of Clinical Oncology's annual meeting this week in Chicago. The effort is in line with a key trend at the conference in which researchers studying and developing personalized cancer treatments are moving away from the one-drug, one-gene-target model and are attempting to stave off disease relapse and metastasis in molecularly targeted cancer populations with combination therapies that simultaneously attack different markers and pathways.

According to an independent review of both melanoma drugs at the ASCO meeting, the vemurafenib/Yervoy combination may be most appropriate for BRAF-mutated patients with a low tumor burden who wish to achieve stable management of their disease with an immune potentiator, such as Yervoy. Conversely, patients who aren't responding well to Yervoy and develop BRAF mutations can also be treated with vemurafenib as a follow-on drug.

Yervoy and BRAF Mutations

For the time being, BMS and Roche are keeping a tight lid on the design of the Phase I/II trial combining their two drugs. "The scientific information available today supports a hypothesis that Yervoy could be successfully combined with BRAF inhibitors and further addresses an unmet need in the treatment of metastatic melanoma," a BMS spokesperson told PGx Reporter. "The collaborative study will be designed to test that hypothesis."

The spokesperson added that the Phase I/II study will be conducted at sites in the US and in Europe. BMS will manage the operational and regulatory aspects of the trial, which will assess the safety and efficacy of the combination drug. "We will submit the protocol synopsis to FDA for its input. Further details about this study will be posted to clinicaltrials.gov at the initiation of the trial," the company representative said. Roche and BMS are hoping to start the trial in the third quarter of this year.

At the ASCO meeting, investigators from BMS and other research institutions presented data from a study that hypothesized that Yervoy would not yield differential responses in metastatic melanoma patients with and without BRAF mutations. The researchers conducted a retrospective study of a randomized, double-blind Phase II trial of 82 patients with treated or untreated stage III/IV melanoma to try to tease out whether BRAF mutation status impacts the efficacy of Yervoy.

In the study, patients received Yervoy 3 mg/kg or 10 mg/kg doses every three weeks for a total of four doses. Through PCR-based assays, BMS researcher Jeffrey Jackson and colleagues determined the BRAF mutation status of 80 patients' tumor biopsies, and disease control data was available in this subset for 69 patients.

Objective responses and stable disease were similar for patients with BRAF V600E mutations and those with wild-type tumors.

"Eleven patients displayed durable disease control," comprising patients who saw a complete response, partial response, or had stable disease of 24 weeks or more, the researchers reported in the abstract. Of this group, six patients, or 55 percent, had BRAF V600E mutation positive tumors and five patients, or 45 percent, did not. "In the 48 patients showing no durable disease control, the mutation frequency was 50 percent," the abstract states.

In this study, Jackson et al. did not find any associations between BRAF V600E mutation status and durable disease after melanoma patients were treated with ipilimumab at either the 3 mg/kg or 10 mg/kg dose.

The safety of Yervoy was not analyzed in BRAF-mutated patients in this study. Yervoy treats cancer by activating the body's innate immune system, and as a result, in clinical trials the drug caused common side effects such as colitis and diarrhea, and more serious adverse reactions such as hepatitis, endocrine dysfunction, and skin reactions. Around 13 percent of patients treated with Yervoy in the registration trial for the drug suffered severe or fatal autoimmune reactions.

An independent review of new clinical data on vemurafenib and Yervoy presented at the ASCO meeting by Kim Margolin of the Seattle Cancer Care Alliance observed that vemufarenib and Yervoy may be a good combination treatment strategy in certain BRAF-mutated melanoma patients, but the decision as to when to give the drugs and in what succession has to be carefully considered. Margolin noted that vemurafenib has a rapid onset, but has "potentially limited duration of control," whereas the CTLA-4 blocking monoclonal antibody Yervoy has a slower mechanism of onset but has a more stable disease control.

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"Vemurafanib is appropriate for patients who have symptoms and need to respond fast. It remains to be seen whether a smaller disease burden at the time of relapse with excellent response to vemurafenib will have an advantage for the next therapy, which could very well be [Yervoy]," she said. Additionally, "the definition of progression has also gotten a lot trickier with the advent of [Yervoy]," she said. "And the decisions about when to offer a different therapy to patients who progress on [Yervoy] may differ with patients who have BRAF-mutated melanoma, who may have the opportunity to go on vemurafenib after having been on [Yervoy]."

Yervoy costs $120,000 for a complete course of the drug at 3 mg/kg; a full treatment schedule involves four infusions at $30,000 over three months.

BRIM3

Also at ASCO's annual meeting, researchers from Memorial Sloan Kettering, Roche, Genentech, and Plexxikon reported interim Phase III results from the BRIM3 study, in which metastatic melanoma patients with BRAF mutations were randomized to receive either vemurafenib or dacarbazine.

In the study, Roche researcher Paul Chapman and colleagues enrolled nearly 700 patients with untreated, unresectable stage IIIC or stage IV melanoma who had BRAF V600E mutations assessed by Roche's Cobas 4800 BRAF V600 Mutation Test. Final analysis was planned for when 196 patients had died in the trial. Patients were recruited from more than 100 sites across the world between January and December 2010.

However, after patients received six months of treatment, researchers reported that 84 percent of study participants who received vemurafenib were alive compared to 64 percent who received chemotherapy. An independent data monitoring board recommended that because of the marked benefit seen in the vemurafenib arm, patients in the chemo arm should be crossed over to receive the newer drug.

At the pre-planned interim analysis, there was a 63 percent decrease in the hazard of death and a 73 percent decrease in the hazard of tumor progression favoring vemurafenib. For the 65 percent of study participants who could be evaluated for a response, more than 48 percent of vemurafenib-treated patients had a response to the drug while less than 6 percent of chemotherapy-treated patients had a response.

At the time of data analysis, 66 percent of patients on vemurafenib and 25 percent of chemo-treated patients were still on treatment. "The median length of time patients lived (median OS) cannot be reliably estimated at this time because of the small number of patients in long-term follow-up," Roche said in a statement. "Median OS estimates when BRIM3 met this co-primary endpoint in January 2011 were 9.2 months in patients receiving vemurafenib and 7.8 months in those receiving chemotherapy; an additional two months of follow-up showed an estimated median OS of 10.5 months for patients receiving vemurafenib, while the median OS estimate for patients receiving chemotherapy remained at 7.8 months."

In the study, the most common Grade 3 or higher adverse events were keratoacanthomas, rash, joint pain, sensitivity to the sun, and fatigue. Squamous cell carcinoma, a common type of skin cancer, was reported in 12 percent of patients, but in these cases, the lesions were resected and patients were able to continue with vemurafenib treatment. Patient discontinuations due to drug-related toxicities were 6 percent in the vemurafenib arm and 4 percent in the decarbazine arm.

Based on interim analysis, "vemurafenib is associated with significantly improved OS and PFS compared to DTIC in patients with previously untreated, V600E BRAF-mutated metastatic melanoma," Chapman et al. reported.

While Roche is taking vemurafenib as a single agent through the FDA, the company intends to study the drug in combination with other treatments, such as Yervoy, and is investigating its efficacy in different cancer indications (PGx Reporter 05/18/2011).

For example, Roche is currently studying vemurafenib in metastatic or unresectable papillary thyroid cancer patients whose tumors test positive for BRAF V600 mutations and are resistant to radioactive iodine therapy. Roche recently launched a Phase II trial to study the safety and efficacy of vemurafenib in papillary thyroid cancer. Between 30 percent and 70 percent of thyroid cancer patients have BRAF mutations.

While vemurafenib is undergoing regulatory approval, Roche subsidiary Genentech and Plexxikon are making the drug available to patients with BRAF V600 mutation-positive melanoma through a global patient access program.

Pricing Concerns

Given the price of Yervoy as single agent, industry observers have expressed concern that a BMS/Roche combination regimen may be prohibitively expensive.

"We price our medicines based on a number of factors including the value they deliver to patients, the scientific innovation they represent, and the cost to develop them," the BMS spokesperson said, adding that the premium pricing reflects the fact that Yervoy "is the first and only approved medicine proven to significantly extend the lives of patients with metastatic melanoma."

The BMS representative noted that the drug firm offers patient assistance to help manage the cost of the drug for 98 percent of uninsured patients. The company also has a program that assists patients with private insurance with their co-pay or co-insurance costs related to Yervoy.

The spokesperson pointed out that Yervoy is currently approved for the 3 mg/kg dose. However, in the study presented at ASCO looking at Yervoy in BRAF-mutated patients, researchers administered both the 3 mg/kg and 10 mg/kg doses. Potentially, if a Yervoy/vemurafenib combination product involving Yervoy at 10 mg/kg successfully clears FDA, the dual treatment may be an expensive option.

"While we do not comment specifically on future pricing for any of our products, we are actively evaluating potential ways to address price in the context of ensuring that patients who need Yervoy will have access to this medicine," the spokesperson said.


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