“Results of a new study by UCLA researchers has found that a groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combos alone, and with increased immune response and fewer side effects.
“An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.
“In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients’ own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance.
“This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.”
The gist: In the U.S. and Australia, oncologists are allowed to prescribe a treatment that combines the drugs Mekinist (trametinib) and Tafinlar (dabrafenib) for people with unresectable or metastatic melanoma whose tumors have a V600E or V600K mutation in the BRAF gene. European regulators would like to see more data on the benefits and risks of the treatment before approving it for European patients. The company that produces the treatment was conducting a clinical trial with volunteer patients to capture that data, but has now decided to halt the trial, which was comparing the combo treatment to the drug Zelboraf (vemurafenib). The trial found that the combo treatment has such a significant improvement on patient survival that the patients who had been taking vemurafenib for comparison should be allowed to switch to the combo treatment, and the trial ended early.
“GlaxoSmithKline has stopped a Phase III study of its combination therapy for advanced cutaneous melanoma ahead of schedule after it showed a significant survival benefit.
“The UK drug giant said an Independent Data Monitoring Committee (IDMC) has made the recommendation as it emerged patients with metastatic melanoma – carrying a BRAFV600 mutation – who took a combo of Mekinist (trametinib) and Tafinlar (dabrafenib) demonstrated an overall survival benefit compared to those taking vemarufenib.
“Safety signals were also good, remaining consistent with that for the MEK inhibitor and BRAF inhibitor observed to date, the firm said.”
“The European Commission has given marketing authorization for trametinib as monotherapy for unresectable or metastatic melanoma in adults with a BRAF V600 mutation, GlaxoSmithKline announced.
“Trametinib (Mekinist), a kinase inhibitor that targets MEK1/MEK2 activation and kinase activity, has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy. Before taking trametinib, patients must have confirmation of a BRAF V600 mutation using a validated test.”
Editor’s note: The European Commission (the executive body of the European Union) has approved the drug trametinib (brand name Mekinist) as a treatment for unresectable or metastatic melanoma in adults whose tumors have a mutation called V600 in the BRAF gene. The approval is based on promising results for the drug in a clinical trial.
Every year, new cancer treatment insights are shared at the American Society of Clinical Oncology (ASCO) Annual Meeting. Here are some of the most notable recent developments in melanoma treatment, gleaned from researchers’ presentations at ASCO last month: Continue reading…
“GlaxoSmithKline’s melanoma drug Mekinist – one of several drugs being sold to Novartis under an asset swap deal – has been recommended for approval by European regulators.
“The European Medicines Agency (EMA) said on Friday its experts had backed the drug, also known as trametinib, as a treatment for unresectable or metastatic melanoma in patients with a mutation of a gene known as BRAF.”
“Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms.”
Editor’s note: We previously covered the benefits of a dabrafenib/trametinib combo for advanced-stage melanoma. However, some patients’ tumors become resistant to this drug combination and new treatment routes need to be considered. This study is exploring how molecular testing of specific genetic mutations in patients’ tumors might be used to help guide treatment decisions after they become resistant to the dabrafenib/trametinib combo.
“In recent years, the FDA has approved new drugs for the treatment of advanced melanoma, which has presented new ways to treat the disease, according to a presentation at the American Academy of Dermatology annual meeting.
“ ‘In the last four years there have been four new drugs that have been FDA-approved for melanoma and what’s even more exciting is that they really speak to two new ways to treating melanoma,’ Allan C. Halpern, MD, MSc, chief of dermatology service at Memorial Sloan-Kettering Cancer Center, told Healio.com.
“The most recent FDA approval, in January, was the combination of a BRAF inhibitor and a MEK inhibitor for treating advanced melanoma.”
“Prior treatment with immunotherapy did not limit response to BRAF inhibitors among patients with metastatic melanoma, according to results of a retrospective study.
“However, patients who underwent initial treatment with BRAF inhibitors and subsequently received immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) demonstrated poorer outcomes, results showed.
“Patients with BRAF-positive metastatic melanoma have several treatment options, including BRAF inhibitors vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib (Taflinar, GlaxoSmithKline), the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline), and the immunotherapy agents ipilimumab and interleukin-2. Yet, there are limited data with regard to optimal sequencing, according to researchers.”
The US Food and Drug Administration just granted accelerated approval for a treatment that combines two drugs that target melanomas with BRAF mutations — but this was contingent on the results of an ongoing phase III clinical trial. The drugs are the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Now the latest results of the trial are in and they look good. This combination treatment is not approved elsewhere in the world, and the trial included 423 people from Australia, Europe, and North and South America. Final results are expected later this year and will be presented at a scientific meeting. In addition, another trial is comparing this combination treatment to the BRAF inhibitor vemurafenib (Zelboraf), which is also FDA-approved.