MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors
- 987 Downloads
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.
The authors extend special thanks to Alessandra Trocino for providing excellent service and assistance.
Antonio M. Grimaldi and Paolo A. Ascierto prepared the manuscript collaboratively, with input from and approval of all co-authors. All authors read and approved the final manuscript.
Compliance with Ethical Standards
No funding was received for the preparation of this review.
Conflict of interest
Antonio M. Grimaldi has received honoraria from BMS, MSD, Novartis, and Roche Genentech, and had consultant/advisory roles for MSD and Novartis. Ester Simeone has received honoraria from BMS, Novartis, and Roche Genentech, and had a consultant/advisory role for BMS. Paolo A. Ascierto received research founding from BMS, Roche Genentech, and Array Biopharma, and had consulting/advisory roles for BMS, Roche Genentech, MSD, Novartis, Array Biopharma, Amgen, Merck Serono, and Pierre Fabre. Lucia Festino, Vito Vanella, and Martina Strudel declare no conflicts of interest.
- 17.Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16:1389–98.CrossRefPubMedGoogle Scholar
- 26.Flaherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: a phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J Clin Oncol. 2016;34(Suppl). Abstract No. 9502.Google Scholar
- 28.Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Ann Oncol. 2016;27(Suppl 6):LBA40.Google Scholar
- 29.Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34(Suppl). Abstract No. 107.Google Scholar
- 31.Johnston S. XL518, a potent selective orally bioavailable MEK1 inhibitor, down-regulates the RAS/RAF/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. In: 19th AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics. San Francisco, CA; 2007. p.Abstract C209.Google Scholar
- 32.LoRusso P, Shapiro G, Pandya SS, et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors. J Clin Oncol. 2012;30(15 Suppl). Abstract No. 2566.Google Scholar
- 34.McArthur G, Dreno B, Atkinson V et al. Efficacy of long-term cobimetinib + vemurafenib in advanced BRAFV600-mutated melanoma: 3-year follow-up of coBRIM (Phase 3) and 4-year follow-up of BRIM7 (Phase 1b). Poster at Society for Melanoma Research 2016 Congress, 6–9 Nov 2016, Boston, MA.Google Scholar
- 35.Winski S, Anderson D, Bouhana K, et al. MEK162 (ARRY-162), a novel MEK 1/2 inhibitor, inhibits tumor growth regardless of KRas/Raf pathway mutations. In: Proceedings of the 22nd EORTC–NCI–AACR symposium on molecular targets and cancer therapeutics. Berlin, Germany; 2010. Nov 16–19.Google Scholar
- 36.Bendell JC, Papadopoulos K, Jones SF, et al. A phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors. Mol Cancer Ther. 2011;10(Suppl 1). Abstract No. B243.Google Scholar
- 39.Dummer R, Schadendorf D, Ascierto PA, et al. Results of NEMO: a phase III trial of binimetinib (BINI) vsdacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. J Clin Oncol. 2016;34(Suppl). Abstract No. 9500.Google Scholar
- 40.Dummer R, Ascierto PA, Gogas H et al. Results of COLUMBUS Part 1: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in BRAF-mutant melanoma. Presented at the Society for Melanoma Research annual meeting, 6–9 Nov 2016, Boston, MA.Google Scholar
- 41.Van Herpen C, Postow MA, Carlino MS, et al. A phase 1b/2 study of ribociclib (LEE011; CDK4/6 inhibitor) in combination with binimetinib (MEK162; MEK inhibitor) in patients with NRAS-mutant melanoma. Presented at the 2015 European Cancer Congress, 25–29 Sep 2015, Vienna. Abstract No. 3300.Google Scholar
- 43.Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(Suppl). Abstract No. 3003.Google Scholar
- 44.RibasA, Hodi S, Lawrence DP, et al. Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: phase 1 KEYNOTE-022 study. J Clin Oncol. 2016;34(Suppl). Abstract No. 3014.Google Scholar
- 45.Hwu P, Hamid O, Gonzalez R. Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma. Ann Oncol. 2016;27(Suppl 6):vi379–400.Google Scholar
- 46.Infante J, Kim TM, Friedmann J, et al. Safety and clinical activity of atezolizumab combined with cobimetinib in metastatic melanoma. Presented at the Society for Melanoma Research annual meeting, 6–9 Nov 2016, Boston, MA.Google Scholar
- 47.Bendell JC, Kim TW, Goh BC, et al. Clinical activity of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(Suppl). Abstract No. 3502.Google Scholar