“Data from a phase 3 trial demonstrate combination dabrafenib and trametinib was superior to dabrafenib plus placebo for improved PFS in patients with BRAFV600-positive metastatic melanoma, according to data presented here at the ASCO Annual Meeting.
“ ‘This is the first melanoma trial, phase 3, to have an active control arm,’ researcher Georgina V. Long, BSc, PhD, MBBS, FRCP, oncologist at Melanoma Institute Australia at the University of Sydney, said of the COMBI-D trial.”
Editor’s note: This story describes the results of a clinical trial, in which volunteer patients are help test a new treatment. The treatment consists of a combination of the targeted therapy drugs dabrafenib and trametinib. Patients treated with the combination lived longer without progression of their cancer than patients who received dabrafenib plus a non-active placebo. Importantly, these results are specific to patients whose tumors have “BRAF V600E” mutations, which doctors can detect via molecular testing.
“Accounting for approximately half of all cancers in the United States, skin cancer is widely recognized as the most common cause of cancer nationwide. More than 3.5 million cases of skin cancer are diagnosed each year, and according to the Skin Cancer Foundation, incidences of skin cancer outnumber all combined cases of breast, colon, lung and prostate cancers.
“With the month of May designated as National Skin Cancer Awareness Month, HemOnc Today highlights 10 issues for oncologists and dermatologists to consider for their patients, as well as the new guideline revisions and research regarding the identification, treatment and management of patients with melanoma and skin cancer.”
“Patients with metastatic melanoma treated with dabrafenib demonstrated improved quality of life compared with those who received dacarbazine, according to phase 3 study results.
“Initial analyses of the BREAK-3 trial indicated dabrafenib (Tafinlar; GlaxoSmithKline) prolonged median PFS compared with dacarbazine (DTIC) in patients with BRAFV600E-mutant metastatic melanoma (5.1 months vs. 2.7 months; HR=0.30; 95% CI, 0.18-0.53).”
“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.”
“Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.
“Now, a new preclinical study published online ahead of print in the Journal of Clinical Investigation from Penn Medicine researchers found that in many cases the root of the resistance may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors vermurafenib and dabrafenib. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine [sic] (HCQ), the authors found, and the BRAF inhibitors will be able to do their job better…
“Based on these promising preclinical results, Dr. Amaravadi and his team have already launched a clinical trial for patients with advanced BRAF mutant melanoma to see how well-tolerated HCQ is with the BRAF inhibitor vemurafenib. ‘So far,’ he said, ‘we are seeing a benefit to patients and low toxicity.’ “
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.
The application for dabrafenib (Tafinlar) as a treatment for certain lung cancer cases has been given a boost with the U.S. Food and Drug Administration (FDA) designating it a breakthrough therapy. Tafinlar is being investigated as a therapy for patients with non-small cell lung cancer (NSCLC) who have a mutation called BRAF V600E in the BRAF gene and have received at least one previous round of chemotherapy. In a recent clinical trial, Tafinlar exhibited antitumor activity in such patients. The breakthrough therapy designation provides increased drug development guidance from the FDA and accelerated approval for drugs that treat serious or life-threatening conditions and that provide a substantial improvement over currently available treatments. Tafinlar is already approved for use in certain types of skin cancer.