Trametinib phase III study: Where does the MEK era clinically begin?
Trametinib is the first compound to demonstrate improved survival with MEK inhibition in BRAF-mutated melanoma
- Date : 17 Jul 2012
- Topic : Melanoma
Trametinib, a novel oral MEK inhibitor, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation, according to phase III study published on 12 July 2012 in The New England Journal of Medicine. Dr Keith Flaherty of the Massachusetts General Hospital Cancer Center, Boston, USA and Dr Caroline Robert from the Institute Gustave Roussy, Villejuif, France contributed equally to this article, on behalf of the METRIC Study Group. The article was published first online on June 4, coincidentally with the study presentation at the 48th Annual Meeting of the American Society of Clinical Oncology in Chicago, USA.
Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma and less frequently in a variety of other cancers. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
Characteristics of trametinib
Tumour growth factor receptors activate RAS oncoproteins, which subsequently activate a kinase cascade that includes RAF, MEK, and ERK kinases. This pathway is mutated in at least 20% of cancers. The RAS–MEK–ERK pathway is thus a focus of intense interest for the development of cancer drugs, but the identification of drug targets downstream has proved to be a formidable challenge. Although a number of MEK inhibitors have emerged, initial studies in patients with tumours that were not selected for a mutation in the pathway had relatively little clinical effect.
The preclinical evaluations of trametinib, an oral selective MEK inhibitor, revealed a molecule with very desirable mechanistic and pharmacologic attributes. It is an allosteric non-ATP site inhibitor that decreases both activation of MEK by BRAF and the capacity of MEK to act on downstream substrates. Its pharmacology in animals and in initial reports in humans shows a long half-life and a lack of oscillation between substantially different peak and trough levels.
In this phase III open-label study, the researchers randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, or chemotherapy in a 2:1 ratio. Patients received trametinib, 2 mg orally once daily or intravenous dacarbazine or paclitaxel every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Thus, all patients entering the trial could ultimately receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (p < 0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group. The difference in overall survival was apparent at this early time point despite the trial design that allowed for crossover to receive trametinib among patients with tumour growth while receiving chemotherapy.
Rash, diarrhoea, and peripheral oedema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction. Asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. There have been no reports of second skin neoplasms, which have been associated with BRAF inhibitor treatment and potentially represent activation of resistance mechanisms for BRAF.
The study was funded by GlaxoSmithKline (GSK).
Maximising the promise of MEK inhibition in combination with other pathway inhibitors
In accompanied editorial Dr Edward Sausville from the University of Maryland in Baltimore discussed on trametinib promises in RAF active tumours. He wrote that despite a decreased rate of melanoma progression and improved survival, only 22% of patients had a complete or partial response to trametinib, as compared with the expected rate of less than 10% for chemotherapy. This fact highlights that the presence of BRAF mutations clearly indicates the importance of the RAS–RAF–MEK pathway, but how that pathway connects to the maintenance of tumour-cell viability, and potential for tumour shrinkage is unclear and should be further investigated. He further discussed that the mere fact that a BRAF mutation is detected in a tumour specimen does not indicate its prevalence throughout the tumour.
There is a need to maximise the promise of MEK inhibition by using trametinib in combination with other pathway inhibitors to define its potential value in tumours without BRAF mutation but with MEK activation by other routes. Resources to allow such preclinical studies may entail large panels of genetically annotated cell lines to avoid blind empiricism in the development of subsequent clinical trials.
Besides studying trametinib as a single cancer drug, GSK is also planning the combination trials. BRAF inhibitor, dabrafenib is another GSK product in pipeline that showed in phase III study progression-free survival of 5.1 months, compared to 2.7 months in the dacarbazine arm.
The pharmaceutical company announced the start of a phase III trial that will evaluate the combination drugs against a placebo and as well as head-to-head against BRAF inhibitor vemurafenib. The rationale behind is expectation that the combination of a MEK inhibitor with a BRAF inhibitor may delay resistance. Trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial. GSK plans a drug application for melanoma treatment.
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