Increased activation of cell survival signaling cascades helps tumor cells grow and makes cancer cells difficult to kill. Inhibiting proteins involved in those survival pathways is a useful strategy for selectively destroying such cells. The mitogen-activated protein kinase (MAPK) pathway is one such signaling cascade. Preclinical research finds that it is activated in most melanomas. One key kinase involved has become the focus of some targeted melanoma therapies. MAPK/ERK kinase (MEK), also known as MAPKK, has several known isoforms that play different roles. Two of those (collectively “MEK1/2”) are associated with MEK’s ability to promote cell survival.

Another oncogenic perturbation to cellular signaling cascades is hyperactivation of BRAF kinase. Genetic mutations causing the BRAF protein to be unusually active are found in 60% of melanomas. Roche/Genentech and Plexxikon (part of Daiichi Sankyo) have together developed and commercialized a targeted therapy (vemurafenib) for metastatic melanoma with the V600E BRAF mutation. Although BRAF is a hotly pursued target, savvy pharmaceutical companies recognize the potential benefits of attacking multiple signaling pathways at once. Unfortunately, preclinical data show that inhibiting BRAF can promote MEK-MAPK signaling. By shutting down that pathway, MEK inhibitors could help combat resistance to BRAF inhibitors.

In 2012, GlaxoSmithKline presented data from a phase 1–2 clinical trial combining its BRAF inhibitor (dabrafenib BRAFi) with the oral MEK1/2 inhibitor trametinib for V600 BRAF–mutant solid tumors. Among 77 BRAFi-naïve melanoma patients, the combination therapy evoked a confirmed overall response rate of 56%. Patients taking that combination had a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions than did those taking either agent alone. Supporting a hypothesis that the two drugs target different pathways, these data suggest that some adverse events associated with one monotherapy may be mitigated by the other.

Some serious adverse events occurred, however: squamous-cell carcinoma in two patients and actinic keratosis in two others. Such effects also occurred with vemurafenib treatment alone, so they may not preclude regulatory approval of the combination. The overall progression-free survival of patients taking any dose combinations was 7.4 months, although the trial had no control arm for comparison. GSK is currently sponsoring phase 3 clinical trials trials evaluating the efficacy of dabrafenib–trametinib therapy for treating unresectable or metastatic BRAF V600E/K-positive melanoma. Meeting the primary endpoint of overall survival would be definitive proof of clinical benefit.

Trametinib is also in development as a monotherapy. Data presented from a phase 3 clinical trial show that it demonstrated better efficacy than two other drugs for treating metastatic BRAF V600E/K–positive melanoma. BRAFi- and MEKi-naïve patients treated with trametinib had a median progression-free survival of 4.8 months compared with 1.4 months observed for dacarbazine or paclitaxel. Current trends suggest an overall survival benefit too. But I believe that the greatest efficacy benefits of MEK inhibitors will come from combination therapies.

Under the agreement with Plexxikon, Genentech (Roche) has developed and commercialized vemurafenib under the name Zelboraf for treatment of metastatic melanoma with the V600E BRAF mutation. Not to be outdone by GSK, the two companies are now developing their own MEK1/2 inhibitor. Genentech is currently sponsoring a phase 1 clinical trial investigating its safety and pharmacokinetics when combined with vemurafenib for metastatic melanoma patients whose cancer has progressed following initial Zelboraf treatment. But that combination therapy lags behind GSK’s on the clinical path.

Combination therapies are also in development to inhibit MEK and non-BRAF cellular signaling targets. One target is the PI3K-AKT pathway, which promotes cancer cell survival and is overactive in a broad spectrum of cancers. Genetech is evaluating combinations of its MEK1/2 inhibitor combined with PI3k inhibitors for treating advanced solid tumors (including melanoma). Those combinations are in early stages of development, with limited efficacy data. But 26 of 46 evaluable patients receiving MEK1/2 and class 1 PI3K inhibitors showed a partial metabolic response. A major concern with combination therapies is whether targeting multiple pathways will compound the side effects of each drug. But toxicities observed in phase 1 with this combination were comparable to those of monotherapy treatment.

Use of MEK inhibitors both alone and in combination therapies is a strategy with strong preclinical roots and growing clinical support. GSK will probably be the first company to seek regulatory approval for such a treatment of metastatic melanoma (trametinib). Although data are promising, regulatory approval will ultimately depend on positive phase 3 results with increased overall patient survival (especially considering the potentially serious side effects). Combination therapies designed to synergistically target multiple signaling pathways hold great promise for cancer treatment, with abundant evidence showing that suppression of one single cascade can increase signaling through related survival pathways. These treatments are not without their pitfalls: Correct dosing and safety profiles can be major issues. But I believe that those can be resolved using intelligently designed clinical trials. In the future, targeted combination therapies could greatly advance the treatment of melanoma and other solid tumors.

About the Author

Author Details
Cheryl Strelko, PhD, is an oncology analyst for GlobalData, 16 New England Executive Park, Burlington, MA 01803; 44-1204-543537; [email protected]. Clinical data cited here were presented at the annual meeting of the American Society of Clinical Oncology held in Chicago, IL, on 1–5 June 2012 (http://chicago2012.asco.org).