“Emerging data showing improved survival with targeted and immunotherapeutic approaches are rapidly altering the standard of care for patients with melanoma. For BRAF-positive patients with metastatic or unresectable melanoma, the standard of care includes a BRAF inhibitor in combination with a MEK inhibitor. For patients with or without BRAF mutations, there are immunotherapeutic options available in frontline and in resistant disease settings.
“Questions remain, however, in terms of how to optimally sequence and/or combine both targeted agents and immunotherapies. And, for BRAF-mutant disease, when is it appropriate to switch from a targeted approach to an immunotherapeutic one?”
Large numbers of immune cells (T cells in particular) are frequently found within or adjacent to melanoma tumors, indicating that the tumors attract the attention—if not the action—of the immune system. True to its reputation as one of the most ‘immunogenic‘ cancers, melanoma now has more U.S. Food and Drug Administration (FDA)-approved immunotherapy (immune system-targeting) drugs than any other cancer type. As a consequence, metastatic melanoma is no longer the universally fatal disease it was even just 3 or 4 years ago. Continue reading…
“The FDA has expanded the approval for single-agent pembrolizumab (Keytruda) to include the frontline treatment of patients with advanced melanoma regardless of BRAF status, based on a substantial improvement in progression-free and overall survival compared with ipilimumab (Yervoy) in the phase III KEYNOTE-006 trial.
“In the study, which compared 2 pembrolizumab regimens with ipilimumab, the PD-1 inhibitor reduced the risk of disease progression by >40% and the risk of death by >30%.
“ ‘As recently as five years ago, there were few treatment options for patients suffering from advanced melanoma,’ Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, the developer of the PD-1 inhibitor, said in a statement. ‘Today’s news is another exciting milestone for Keytruda and for patients with this disease.’ “
“Omid Hamid, MD, Chief, Translational Research and Immunotherapy, Director, Melanoma Therapeutics, The Angeles Clinic, discusses a recent trial investigating the combination of vemurafenib and atezolizumab in melanoma in patients with previously untreated BRAF-positive unresectable or metastatic melanoma.
“The targeted therapy vemurafenib has a great initial response rate and palliative benefit, but does not have long-term durability. Atezolizumab, an immunotherapy, has a low initial response rate, but has the ability to have a high long-term durability, says Hamid.
“With the combination, the toxicities of elevated liver enzymes and rash were initially seen, however the regimen became more tolerable after it was adjusted, says Hamid.”
“Combinations of targeted therapies continue to advance toward full regulatory approval for patients with metastatic or unresected melanoma, given the substantial benefits seen with these agents. At this time, the FDA is considering two applications for separate combinations of BRAF and MEK inhibiting agents for patients with unresectable or metastatic BRAFV600 mutation-positive melanoma.
“ ‘The future of the treatment of melanoma is clearly going to be in combinations, both for targeted therapy and for immunotherapy,’ said Jeffrey S. Weber, MD, PhD, who recently joined the NYU Langone Medical Center. ‘Already, there is an FDA-approved combination therapy that is targeted; that is dabrafenib and trametinib. There are new combinations coming up, mainly concerning CDK 4/6 and MEK inhibitors in NRAS-mutated but BRAF wild-type melanoma, which is an unmet medical need.’ “
“Exelixis, Inc.EXEL, -1.02% today announced positive overall survival (OS) results from coBRIM, the phase 3 pivotal trial evaluating cobimetinib, a specific MEK inhibitor discovered by Exelixis, in combination with vemurafenib in previously untreated patients with unresectable locally advanced or metastatic melanoma carrying a BRAF V600 mutation. Exelixis’ collaborator Genentech, a member of the Roche Group, informed the company that coBRIM met its secondary endpoint of demonstrating a statistically significant and clinically meaningful increase in overall survival for patients receiving the combination of cobimetinib and vemurafenib, as compared to vemurafenib monotherapy. Ongoing study monitoring did not identify any new safety signals. Long-term safety data are expected later this year. These data will be the subject of a presentation at an upcoming medical meeting.”
“Latest results from a trial of a combination of two targeted therapies (dabrafenib and trametinib) to treat advanced melanoma have shown that patients are living significantly longer on the combined therapy than patients treated with another drug, vemurafenib, when used alone.
“Professor Caroline Robert, of the Institut Gustave Roussy, Paris, France, will tell the 2015 European Cancer Congress today (Monday) that not only is the median overall survival time longer for patients receiving the combination treatment, but also that 51% of patients receiving the combination treatment are alive after two years, compared to 38% of patients receiving vemurafenib alone.
“Analysis of data up to 13 March 2015 showed that the median overall survival time among patients with metastatic melanoma harbouring V600 mutations in the BRAF gene who received the combination treatment was 25.6 months. Among patients receiving vemurafenib alone, it was 18 months. On the basis of this finding, the European Commission approved the combination of dabrafenib and trametinib for use in Europe for these patients on 1 September 2015.”
“Patients with advanced melanoma skin cancer survive for longer without their disease progressing if they have been treated with a combination of two drugs, nivolumab and ipilimumab, than with either of these drugs alone. New results show that these patients also do better regardless of their age, stage of disease and whether or not they have a cancer-driving mutation in the BRAF gene.
“Dr James Larkin, a Consultant Medical Oncologist at The Royal Marsden, London, UK, told the 2015 European Cancer Congress, that results from the CheckMate 067 phase III clinical trial had already shown that the combination of the two drugs, which target two different pathways that regulate the immune system, improved the progression-free survival in patients with melanoma who had not received any other treatment. However, until now it was not known whether this remained the case when the results were analysed according to genetic status, age and how advanced was their disease.
“Nivolumab is an inhibitor of the programmed cell death protein 1 (known as PD-1), which functions as an immune checkpoint, playing an important role in the immune system. Ipilimumab inhibits the CTLA-4 checkpoint, which also plays a role in the immune system.”
“A new kind of cancer study supports the idea that traditional treatment can be turned on its head, with patients given targeted therapy based not on where their tumors started but on their own genetic mutations.
“Researchers used a targeted melanoma drug to treat patients with a range of cancers, from lung cancer to brain cancer, who weren’t being helped by traditional chemotherapy any more. Even though they had many different types of tumors, they all had one thing in common — a genetic mutation called BRAFV600.
“It’s a mutation familiar to doctors who treat melanoma, the deadliest form of skin cancer. It’s seen in about half of melanoma cases. A pill called vemurafenib, sold under the brand name Zelboraf, specifically targets the mutation. It helps about half of patients with melanoma who have the mutation.
“The same mutation is sometimes seen in colon cancer, lung cancer, thyroid cancer, brain tumors and some blood cancers.”