CHICAGO – GlaxoSmithKline PLC is getting ready to file both its BRAF inhibitor dabrafenib and its MEK inhibitor trametinib as single agents and start a Phase III trial of the two agents in combination against BRAF V600 mutation-positive metastatic melanoma.

The company presented the BREAK3 study of dabrafenib and the METRIC study of trametinib June 4 at the American Society of Clinical Oncology annual meeting in Chicago. Both trials showed a statistically significant benefit in progression-free survival compared to chemotherapy. Trametinib showed a survival advantage in METRIC; overall survival data from BREAK3 are not yet mature.

Both targets, BRAF and MEK, are part of the MAP kinase pathway. But whereas BRAF inhibitors will eventually succumb to resistance and cause serious side effects in many patients, MEK inhibitors could meet the need for new therapies. MEK is part of a kinase cascade involved in 20% of cancers, according to an editorial accompanying the same-day publication of METRIC in the New England Journal of Medicine.

Dabrafenib would join Roche’s Zelboraf (vemurafenib),which cleared FDA last year. Vemurafenib was the first BRAF inhibitor to reach the market, and it has shown a survival advantage in metastatic melanoma Also see "First-Line Market For Melanoma Not A Lock For Bristol Or Roche" - Pink Sheet, 5 June, 2011.. METRIC is the first Phase III trial of a MEK inhibitor.

The monotherapy filings will be the backbone for the program, Kiran Patel, medicine development leader for GSK’s MEK inhibitor program, said in an interview. But the “data clearly show you should combine two drugs early instead of waiting for progression,” he said, so the combination “is the right way forward.” But GSK is confident both drugs have high value as monotherapy as well.

Could Dabrafenib Break Zelboraf’s Hold?

Dabrafenib had a 50% response rate in the BREAK3 study, compared to 6% for the comparator chemotherapy dacarbazine. The trial enrolled 250 patients with previously untreated, inoperable Stage III or IV melanoma who had the BRAF V600 mutation. For the primary endpoint of PFS, the dabrafenib arm had a median of 5.1 months versus 2.7 months for dacarbazine – a 70% reduction in the risk of disease progression or death. There were 118 events at the time of the primary analysis.

Overall survival data are not mature, but patients who progressed on dacarbazine were allowed to cross over to dabrafenib, so it will be difficult to assess.

The drug was well-tolerated, investigators reported, with dacarbazine having a higher incidence of decreased blood counts and dabrafenib having a higher frequency of mild to moderate skin reactions, joint pain and fever.

Still, dabrafenib has the potential to be the preferred BRAF partner in combination therapy. It appears to have less of the toxicity associated with vemurafenib, which is linked to sensitivity to the sun and secondary skin tumors (mild). Dabrafenib showed low rates of both of those: photosensitivity occurred in 3% of patients and Grade 3 squamous cell carcinomas in 5% of patients.

During the presentation of the study results, Dana Farber’s Michael Atkins expressed excitement that with BREAK3, dabrafenib becomes the second BRAF inhibitor with proven efficacy and tolerability. With FDA approval, “this means there is competition in the BRAF inhibitor field and this is good for patient and for investigators.”

Adopting The METRIC System

The METRIC study of trametinib also selected patients with V600E or V600K BRAF mutations, who had had one prior regimen of chemotherapy. The 322-patient trial showed a 55% reduction in the risk of progression for the MEK inhibitor over the chemotherapy arm, either dacarbazine or paclitaxel, with PFS of 4.8 months versus 1.5 months. The response rate was 22% versus 8% for chemo, a finding that Edward Sausville, University of Maryland, calls out in the NEJM editorial as odd given the strength of benefit in PFS and survival. Zelboraf had an objective response rate of 48%.

“Although the response rate associated with trametinib appears to be inferior to that with vemurafenib, the two agents appear to provide similar improvements in progression-free and overall survival, as compared with chemotherapy,” lead author Keith Flaherty, Massachusetts General Hospital, Boston, et al. note in the NEJM write-up. “For both progression-free survival and overall survival, vemurafenib had a numerically greater effect than dacarbazine. Trametinib and vemurafenib would have to be directly compared in a randomized trial to definitively determine whether one drug is superior to the other.”

Though survival is not yet mature, at six months of follow up, 81% of the trametinib patients were alive compared to 67% of patients on chemotherapy, a statistically significant 46% reduction in the risk of death. Patients who progressed on chemo were allowed to cross over to the trametinib arm, per a protocol design that maintained power for overall survival. “It is possible that the between-group difference in overall survival might have been even more significant in the absence of crossover,” the article states.

Side effects were generally deemed manageable. The most common were hypertension (12%), reduced heart function (7%), skin rash (7%) and eye problems (less than 1%).

In the editorial, Sausville lauded the safety profile, noting that the majority of patients did not limit their dose of trametinib because of side effects. “To date, there have been no reports of second cutaneous neoplasms, which have been associated with BRAF inhibitor treatment and potentially represent activation of resistance mechanisms for BRAF,” he noted. Vemurafenib caused squamous cell carcinomas in 18% and 26% of patients in its clinical trials.

That sets trametinib up as an appealing candidate for combination therapy. “We … need to maximize the promise of MEK inhibition by using trametinib perhaps in combination with other pathway inhibitors to define its potential value in tumors without a BRAF mutation but with MEK activation by other routes,” Sausville concluded.

There is some indication that adding a MEK inhibitor to BRAF inhibition could mitigate some of the cutaneous squamous cell carcinoma seen with vemurafenib, Flaherty et al. comment. In addition to the potential for lessened toxicity, the combination strategy is also expected to produce synergistic effects on efficacy.

“Although further study will be needed to understand the individual role of BRAF inhibitors versus MEK inhibitors in patients who have melanoma with a V600E or V600K BRAF mutation, both classes of drugs appear to be capable of substantially altering the natural history of metastatic melanoma,” the authors state. Additional clinical work should also explore the potential sequencing of therapy.

The combination of dabrafenib and trametinib has already been tested in a Phase I/II trial, also presented at ASCO.

GlaxoSmithKline Deals One-Two Punch With BRAF/MEK Pair

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