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ASCO Presentations on PGx Melanoma Drugs Portend Crowded Market for BRAF-Mutated Tumors

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Originally published June 5.

CHICAGO – Roche's personalized melanoma drug Zelboraf (vemurafenib) – the first BRAF inhibitor to enter the market and one of the few drugs to significantly improve survival in patients with advanced disease – is likely to face significant competition in coming years from next-generation agents that will attempt to mirror or improve upon the agent's efficacy and safety against skin cancer.

At the American Society of Clinical Oncology's annual meeting here this week, researchers presented data on several investigational agents that target BRAF mutations using a variety of molecular pathways. In a Phase III trial, GlaxoSmithKline's BRAF inhibitor dabrafenib appeared similar to the efficacy profile of Zelboraf. Meanwhile, trametinib – another GSK drug being investigated as a treatment against BRAF-mutated melanoma tumors – inhibits the MEK kinase, which plays a role in cancer growth and metastasis.

The compounds are being studied as single agents and as a combination therapy.

In addition to drugs targeting BRAF mutations, which comprise around 60 percent of melanomas, researchers are exploring other gene alterations in the same pathway in order to characterize treatment for other molecularly defined patient subsets. Another MEK inhibitor, called MEK-162, developed by Array Biopharma and licensed to Novartis, is being studied in melanoma patients with BRAF and NRAS mutations.

At the meeting, investigators from Novartis and elsewhere reported data from a Phase II study on MEK-162. They said the inhibitor represents the first targeted agent that has shown activity against melanoma tumors with NRAS mutations, which are found in 18 percent of metastatic skin cancer patients.

For sponsors developing these new personalized agents for melanoma patients, Roche's Zelboraf and Bristol-Myers Squibb's CTLA-4 blocking monoclonal antibody Yervoy are the drugs to beat in terms of safety and efficacy. Before the approval of Yervoy and Zelboraf last year, the typical survival rate for a patient with Stage IV melanoma was between six to 10 months, and most treatments did not have a significant impact on extending patients lives.

In one clinical trial reported at last year's ASCO meeting, patients treated with Yervoy in combination with chemotherapy experienced median overall survival of more than 11 months while patients receiving just chemotherapy lived for a median of around 9 months. At the meeting this year, researchers from Roche and elsewhere presented final data form the BRIM3 trial, a Phase III study comparing Zelboraf against dacarbazine, which showed that patients on the BRAF inhibitor were alive for a median of 13.6 months compared to 9.7 months on chemotherapy.

Despite the survival advantage seen with Zelboraf, patients eventually relapse. As such, researchers are working to characterize the resistance mechanisms in BRAF-mutated melanoma.

At this week's ASCO meeting, investigators led by Jeffrey Alan Sosman of the Vanderbilt-Ingram Cancer Center, analyzed patient tumor samples by immunohistochemistry for signaling molecules in the MAPK, PI3K/AKT, and cell cycle pathways. They analyzed gene signaling by Sequenom MassArray genotyping and direct DNA sequencing.

"Resistance to BRAF inhibition is an overwhelming problem," Sosman said at the meeting. He and his research team reported that BRAF-mutant melanoma escapes BRAF inhibition mainly by activating the MAP kinase pathway.

"NRAS mutations appear to be a mechanism of acquired resistance in a few [tumor samples], while the role of MEK1 mutations in resistance is less clear," the researchers concluded. Sosman highlighted NRAS Q61 mutations as one escape route for BRAF-mutated tumors.

One presenter at the conference, Michael Atkins, an onocologist at Beth Israel Deaconess Medical Center, reflected that the variety of ASCO presentations on personalized treatment strategies for melanoma indicated that researchers had moved the "bar up a little" in this diseases setting.

Nevertheless, "despite these recent advances, metastatic melanoma is still a bad disease. We may have postponed, but we have not prevented, the tragedy of this disease," Atkins said. "There is much work to be done to raise the bar even higher."

Similar to Zelboraf

In the Phase III BREAK-3 trial, researchers from GSK and multiple institutions compared dabrafenib against the standard chemotherapy dacarbazine in 250 patients with Stage III or Stage IV melanoma and BRAF V600E mutations. At the meeting, study leader Axel Hauschild from Universitaetsklinikum Schleswig-Holstein in Germany reported that patients on the BRAF inhibitor lived two more months without their disease advancing than patients on the control arm, amounting to a 70 percent lower risk of disease progression or death.

Patients in the dacarbazine arm were allowed to cross over to dabrafenib after they progressed on chemotherapy. Their overall survival data in this study is not yet mature, however.

"Dabrafenib is the second BRAF inhibitor with proven efficacy and tolerability. In my opinion, [US Food and Drug Administration] approval should happen," Atkins said in reviewing the data from the BREAK-3 trial. "This will mean there will be competition in the BRAF inhibitor field and this is good for patients and [researchers] as a whole."

Although the crossover design will make it difficult to discern the extent to which dabrafenib improves survival compared to chemo, the overall survival profile of the new BRAF inhibitor will likely be very similar to Zelboraf, according to Atkins and other presenters. He pointed out, however, that although dabrafenib was well tolerated, causing few serious adverse events and treatment-related discontinuations in patients, "the toxicity profile seemed to be different than vemurafenib."

Patients treated with dabrafenib experienced common adverse reactions, such as hyperkeratosis (37 percent), headache (32 percent), pyrexia (28 percent), arthralgia (27 percent), and skin papillomas (24 percetn). Serious adverse events related to dabrafenib included pyrexia (4 percent), squamous cell carcinomas (6 percent), and new primary melanomas (2 percent). Atkins pointed out that there appears to be a lower incidence of squamous cell carcinomas and photosensitivity with dabrafenib than with Zelboraf, while pyrexia was less frequent in Zelboraf-treated patients than for those receiving the newer drug.

"The mechanisms for these differences are worth investigating and, given similar efficacy, toxicity differences might alternately determine which drugs get utilized," Atkins said.

Interim data from BREAK-MB – a Phase II trial assessing the safety and efficacy of dabrafenib in 127 melanoma patients who had BRAF V600E or V600K mutation-positive tumors and whose disease has spread to the brain – suggested that GSK might be able to further differentiate dabrafenib from Zelboraf. At the meeting, lead author John Kirkwood of the University of Pittsburgh Cancer Institute noted that melanoma patients with V600E mutations and brain metastases appeared to have an overall response rate to dabrafenib that was similar to patients in the BREAK 3 trial whose skin cancer hadn't spread to the brain.

In BREAK-MB, researchers split BRAF-mutated melanoma patients into two arms by whether they were treatment naïve for the brain metastases or if they had received treatment. The unconfirmed overall response rate in the untreated V600E mutation group was 53 percent and 20 percent in the V600K group. The interim objective response rate was 40 percent for previously treated patients with V600E mutations and 50 percent for patients harboring V600K mutations.

Overall survival in the V600E population was 31 weeks for treatment-naïve patients and 33 weeks for those previously treated for brain metastases. Progression-free survival was around 16 weeks in both groups. The researchers only reported survival data in the V600E population.

The data "support consideration of this agent as first-line therapy for [melanoma patients with BRAF V600E mutations and] with brain disease," Kirkwood said. However, in reviewing the study, Atkins pointed out that the BREAK-MB data showed that the brain metastases of melanoma patients with V600E and V600K BRAF mutations respond differently to dabrafenib. Noting that the drug could potentially be less active for patients with V600K mutations, Atkins observed that that the responses of patients in this subgroup weren't as bad as might have been expected based on previous findings.

Overall, BREAK-MB shows that "there is no reason to preclude dabrafenib in patients with BRAF V600E or V600K melanoma and brain metastases," he added. Based on the presented data, Atkins thought that dabrafenib treatment might be able to replace whole-brain radiation and perhaps even reduce the need for surgeries in melanoma patients with brain metastases.

BRAF and MEK

At the meeting, researchers also presented data involving MEK inhibitors. In the METRIC Phase III trial, researchers from GSK and elsewhere investigated the safety and efficacy of trametinib compared to cytotoxic chemotherapy in 322 patients with BRAF V600E or V600K mutations.

The primary goal for the researchers was to track progression-free survival in 237 patients with V600E mutations. In this regard, they reported that trametinib-treated trial participants experienced about three more months of progression-free-survival than chemo-treated patients. Those on the trametinib arm also experienced a 55 percent lower risk of progression or death compared to melanoma patients treated with chemotherapy.

Lead study author Caroline Robert of Institut Gustave Roussy in France reported at the conference that 24 percent of patients in the trametinib arm responded to the drug while seven percent of patients in the control arm responded to chemotherapy. Overall survival data is not yet mature for this study; patients progressing on chemo are crossed over to the trametinib arm.

"Patients who initially received trametinib had a 14 percent greater chance of being alive after six months," Edward Sausville of the Marlene and Stewart Greenebaum Cancer Center wrote in an editorial in the New England Journal of Medicine this week accompanying the publication of the METRIC data.

"The difference in overall survival was apparent at this early time point despite the humane and highly laudable trial design that allowed for crossover to receive trametinib among patients with tumor growth while receiving chemotherapy," Sausville wrote. "Thus, all patients entering the trial could ultimately receive trametinib."

Common adverse events for patients on trametinib included skin rash, diarrhea, edema, hypertension, and fatigue. Serious adverse reactions included hypertension in 12 percent and rash in seven percent of trametinib treated patients.

In the editorial, Sausville highlighted the need for researchers to better understand the mechanism of action driving the efficacy of MEK inhibitors. "The presence of BRAF mutations clearly indicates that the tumor thinks the RAS–RAF–MEK pathway is important; how that pathway connects to the maintenance of tumor-cell viability (and potential for clinical shrinkage) is unclear and should be the focus of further investigation," he wrote.

When certain proteins, dubbed tumor growth factors, activate RAS proteins, it can set off the kinases RAF, MEK, and ERK, which lie along the same pathway. Defects in these kinases can cause cancer cells to thrive.

For example, studies show that 60 percent of melanoma patients have mutations in the BRAF gene, which is part of the RAF kinase. BRAF inhibitors such as Zelboraf work by inhibiting the abnormal signaling of proteins caused by BRAF mutations that drive cancer. Recognizing that BRAF depends on MEK to bolster its signaling, researchers are hoping drugs that inhibit MEK will further improve survival in melanoma patients.

Another study presented at the meeting showed that combining MEK and BRAF inhibitors may offer advantages in terms of reducing treatment-related toxicities. Updated results from a Phase I/II study showed that when given dabrafenib with trametinib, melanoma patients experienced fewer toxicities than they did with either single agent. In this study, patients who had not been previously treated with a BRAF inhibitor were given increasing doses of the dabrafenib/trametinib combination.

"The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEK inhibitor-related rash and BRAF inhibitor-induced hyperproliferative skin lesions compared with the single agents," study authors, led by Jeffery Weber of Lee Moffitt Cancer Center, concluded. Based on encouraging results form early studies, GSK has launched a Phase III trial to study the safety and efficacy of the combination treatment.

Finally, Paolo Ascierto of Istituto Nazionale Tumori Fondazione Pascale presented data on Novartis' MEK-162 from a prospective, open-label, Phase II study involving 66 patients: 42 with BRAF mutations and 24 with NRAS mutations. BRAF-mutated patients treated with MEK-162 experienced median progression-free survival of 3.55 months and patients with NRAS mutations saw 3.65 months of median progression-free survival, Ascierto reported at the meeting.

Eight patients experienced visual disturbances, but this condition was reversible, according to the study abstract. Serious side effects associated with MEK-162 treatment included diarrhea (4.5 percent) and CK elevation (15.2 percent), and five patients stopped participating in the trial due to drug toxicities.

Reviewing the data on trametinib, Patricia LoRusso of the Karmanos Cancer Institute, concluded that the oncology community is ready to add MEK inhibitors to its armamentarium against advanced-stage melanoma.

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