Please can you give a brief introduction to unresectable melanoma and metastatic melanoma? What makes these conditions difficult to treat?
Melanoma is the most serious and deadly form of skin cancer. Unresectable melanoma is melanoma that has spread locally and cannot be removed by surgery, while metastatic melanoma is melanoma that has spread to other parts of the body. Both are advanced stages of melanoma and have had historically low survival rates.
Prior to 2011, there were no treatments that improved survival for unresectable or metastatic melanoma, making these stages of melanoma difficult to treat. In addition, there were no biomarkers or relevant targeted therapies, which meant that the older therapies (chemotherapy and/or cytokine therapy) were applied more universally.
However, an improved understanding of the molecular basis of the disease has presented great opportunities for more targeted approaches to treatment, reducing the number of patients receiving treatments that may not benefit from them.
What are BRAF V600E or V600K mutations? How common are they and how can they be detected?
Approximately 50% of people with metastatic melanoma have a BRAF mutation in their tumour, which is an abnormal change in a gene that leads to signalling down the mitogen-activated protein kinase (MAPK) pathway. This enhanced activation of the MAPK pathway enables melanoma cells to grow and spread.
V600E and V600K mutations account for 95% of BRAF mutations in metastatic melanoma – approximately 85% and 10%, respectively. These mutations are detected in the tumour using an FDA-approved test. One such test is the THxID® - BRAF, for which GSK collaborated with the in-vitro diagnostic company bioMérieux.
Why are combination treatments needed to manage unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations?
Targeting a key protein in a tumour can be an effective treatment; however, it can also lead to resistance to therapy down the line.
BRAF and MEK are protein kinases that are essential components of the MAPK pathway and play a pivotal role in the progression of BRAF-mutant melanoma. As a result of their enhanced activation in BRAF-mutant melanomas, the MEK and BRAF proteins disrupt the normal regulation of cell growth and death, leading to increased cancer cell production and survival. Therefore, inhibiting the function of the mutated BRAF protein can stop further signals down the MAPK pathway and lead to a clinical response; however, drug resistance inevitably develops as the tumour learns to circumvent this road block.
Many mechanisms of resistance involve reactivation of the MAPK pathway via MEK signalling. Therefore, therapeutic efforts have focused on increased MAPK pathway inhibition through dual therapy with a BRAF inhibitor, Tafinlar® (dabrafenib), and a MEK inhibitor, Mekinist® (trametinib). Together, the combination stops or slows tumour cell growth, and potentially offers patients the opportunity to achieve a more durable response.
How do researchers determine whether different agents target different mechanisms regulating the growth of cancer cells?
Over the past 20 years, the growth in knowledge of molecular biology and genetics of cancer has not only enriched our understanding of how tumours grow, but also taught us that not every tumour is the same. In melanoma alone for example, we can genetically differentiate at least three sub-types, the most common being those with BRAF V600 mutations.
Before a potential therapeutic agent is developed or tested, researchers do extensive pre-clinical work to understand how each sub-type of tumour behaves and what are the critical cellular pathways the tumour needs to survive.
Then, the potential targeted therapeutic agent is tested in these pre-clinical models and the downstream effects on the tumour’s growth are analyzed. This improved understanding coupled with biomarker testing has paved the way for developing more targeted, and effective, approaches to treatment.
How important do you think combining agents that target different mechanisms will be in the future of cancer treatments?
Combining agents that target different mechanisms regulating the growth of cancer cells is one of the most promising and exciting areas in cancer research. Identifying multiple targets that inhibit the survival of cancer cells and testing for clinical synergy is now at the forefront of developing novel therapies to treat many types of cancer.
This approach enables us to design drugs that are more potent and specific for each type of cancer, thereby making it much more difficult for a tumour to develop resistance to treatment.
GSK aspires to be a leader in investigating various combinations of medicines to drive a meaningful and sustained clinical benefit. We have announced a number of combination studies involving collaborations with other pharmaceutical companies.
GSK recently announced that they have received FDA approval for the use of Mekinist® (trametinib) in combination with Tafinlar® (dabrafenib) for patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations. What impact do you think this will have?
As the first approved combination of targeted therapies in metastatic melanoma in the U.S., we hope that that Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) will become the new standard of care for appropriate patients with BRAF V600E or V600K mutation-positive metastatic melanoma.
The combination was approved through the FDA’s Accelerated Approval program, meaning the Agency was able to approve this therapy based on evidence (response rate and median duration of response in a Phase I/II study) that is considered reasonably likely to predict a real clinical benefit.
Naturally, the accelerated approval will be contingent on the results of the ongoing Phase III trial that is comparing combination therapy with Tafinlar® (dabrafenib) and Mekinist® (trametinib) to Tafinlar® (dabrafenib) alone in patients with unresectable and metastatic melanoma.
What do you think the future holds for unresectable and metastatic melanoma treatments?
The treatment landscape for unresectable and metastatic melanoma is rapidly evolving and will be led by combining agents that target different mechanisms regulating the immune system as well as the growth of cancer cells.
Immune checkpoint inhibitors target specific receptors on our T-cells that result in activation of the immune system ultimately resulting in attack of the cancer cells by the activated immune system.
Many of these immune therapies are in various phases of clinical trials (nivolumab, lambrolizumab, PDL-1 inhibitors, etc.) and the first to be FDA approved was Yervoy® (ipilimumab) in 2011.
There is also continued development of targeted therapies, alone or in combination, which block the growth of melanoma cells.
In terms of the future for Tafinlar® (trametinib) and Mekinist® (trametinib), several clinical trials will address the safety and benefit of combining them with immune checkpoint inhibitors as well as other targeted agents.
Where can readers find more information?
For more information about Tafinlar® (trametinib) and Mekinist® (trametinib), including full Prescribing Information, readers can visit: http://us.gsk.com/html/media-news/tafmekpress-kit.html.
For information about melanoma, there are a number of organizations dedicated to fighting this disease. These include: The AIM at Melanoma Foundation, The Melanoma Research Foundation, The Melanoma International Foundation, and the Melanoma Research Alliance.
About Dr. Kiran Patel
Kiran developed the trametinib and dabrafenib programs at GSK for over four years leading to registration and approval of the monotherapies and combination of dabrafenib and trametinib in patients with BRAF V600 mutation positive advanced melanoma.
Prior to GSK, Kiran held senior positions in clinical research and development for companies such as Onyx Pharmaceuticals, ACT Biotech, Telik and Pharmacyclics, Inc. At Onyx, he was a Global Clinical Lead (GCL) responsible for the global clinical development of sorafenib (Nexavar®) and provided a leadership role in the management of registration programs in melanoma and breast cancer.
Kiran has also been responsible for global clinical and regulatory activities for company-sponsored, cooperative groups, NCI/CTEP sponsored and collaborative clinical trials.
Kiran received his medical education and clinical training from the South Gujarat University, Surat, India, where he also completed his internship. He subsequently completed his post doctoral research fellowship in Hematology and Oncology at University of California, San Francisco (UCSF). He also holds an MBA from Golden Gate University, San Francisco, CA.