Combining Two Targeted Therapies Results in Melanoma Patients Living Significantly Longer

“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.”

Long-Term Survival Possible With MAPK Inhibition in BRAF-Mutant Melanoma

“Long-term outcomes for BRAF-mutant melanoma patients treated with BRAF and MEK inhibitors are influenced by a number of baseline factors including BRAF genotype, gender, and serum lactate dehydrogenase (LDH) levels, according to a new study.

“Treatment of V600 BRAF-mutant metastatic melanoma has improved with inhibition of the MAPK pathway with BRAF inhibitors and MEK inhibitors. But ‘the degree of response and the duration of survival are highly variable,’ wrote study authors led by Alexander M. Menzies, MBBS, of the Melanoma Institute Australia in Sydney. ‘Whether clinicopathologic factors can be used to predict the clinical course of these patients is largely unknown, and there have been few studies examining this issue.’

“The study included 142 consecutive immunotherapy- and MAPK inhibitor–naive patients with BRAF-mutant metastatic melanoma. All were treated either with BRAF inhibitors (111 patients) or with a combination of dabrafenib and trametinib (31 patients), and the median follow-up was 15.7 months. Results were published online ahead of print in Cancer.”

ECOG-ACRIN Opens Trial of Treatment Sequencing in Advanced Melanoma

“A new phase III cancer treatment trial has opened for patient enrollment that examines two treatments that work in completely different ways yet have both been shown in previous clinical trials to be effective in treating patients with advanced melanoma, the ECOG-ACRIN Cancer Research Group announced today.

“Half of the patients in the trial will be randomly assigned to begin treatment with an investigational combination of two immunotherapy drugs, given together, that work by unleashing parts of the immune system to kill tumor cells. If the treatment stops working and the disease gets worse, patients will receive a second, different treatment of two other drugs, also given together, that work by blocking molecular pathways that drive tumor cell growth and survival.

“For the other half of the patients in the trial, the scenario will be reversed. They will be randomly assigned to begin treatment with the two molecularly targeted drugs, and if those drugs stop working and the disease gets worse, they will be treated with the investigational immunotherapy combination.

“Researchers in the ECOG-ACRIN Melanoma Committee are conducting trial EA6134 to find out which sequence of treatments provides the best outcome for patients.”

Novartis Presents New Data at ASCO for Zykadia® and Combination of Tafinlar® and Mekinist® in Certain NSCLC Patients with Unmet Needs

“Novartis today announced new data from two Phase II studies of Zykadia® (ceritinib), as well as one Phase II study of Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) in certain patients with non-small cell lung cancer (NSCLC). Data from these studies were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“The results of the Zykadia studies – ASCEND-2 and ASCEND-3 – reinforce the efficacy of the medicine in patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC who had received previous treatment with an ALK inhibitor and in those receiving an ALK-targeted therapy for the first time. Overall response rates (ORR) seen in these trials were 38.6% and 63.7%, respectively, based upon investigator assessment. Comparable ORR results were observed in patients with ALK+ NSCLC who entered the studies with brain metastases (33% and 58%, respectively)[1],[2].

“Separately, the study of dabrafenib in combination with trametinib in patients with metastatic BRAF V600E-mutation positive NSCLC who had failed at least one round of chemotherapy demonstrated an ORR of 63% in this population[3].”

AstraZeneca-Novartis Three-Drug Melanoma Treatment Found Safe

“A first-of-its-kind combination of three drugs to treat a deadly form of skin cancer can be taken safely, passing the first hurdle to regulatory approval for a potentially long-lasting treatment.

“The treatment was tested in an early-stage trial that was a collaboration between AstraZeneca Plc and Novartis AG. Researchers combined two drugs, dabrafenib and trametinib — a so-called doublet therapy that has been proven effective in targeting melanomas with mutations in the BRAF gene — with an immune system-based treatment that may prevent the disease from relapsing.

“Dabrafenib, sold as Tafinlar, and trametinib, sold as Mekinist, were developed by GlaxoSmithKline Plc and acquired by Novartis in March. The immune therapy drug, MEDI4736, is being developed by AstraZeneca.

“Melanoma is a rare but deadly form of skin cancer for which a number of drugs have been approved in recent years. Among them are BRAF inhibitors like dabrafenib, which target mutations found in about half of all melanoma patients, as well as immune therapies like Bristol-Myers Squibb Co.’s Yervoy, which unleash the body’s own immune system. Because the immune system can be trained, those therapies may be more durable than other forms of treatment.”

Dabrafenib plus Trametinib Improves Health-Related Quality of Life in Metastatic Melanoma

“The addition of trametinib to dabrafenib improved health-related quality of life and reduced pain in patients with BRAF V600-mutated metastatic melanoma, according to results of a randomized phase 3 study.

“The combination of dabrafenib (Tafinlar, GlaxoSmithKline) and trametinib (Mekinist, GlaxoSmithKline) received accelerated approval from the FDA in 2014 based on the results of a phase 1/2 study that compared the combination with dabrafenib monotherapy. Results from a phase 3 trial later demonstrated significantly improved PFS and objective rate response with the combination vs. dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.

“In the current analysis, Dirk Schadendorf, MD, of the department of dermatology at the University Hospital Essen in Germany, and colleagues sought to evaluate the effect of the combination on health-related quality of life among patients treated in the phase 3 study.”

Drugs That Work in Melanomas with BRAF Mutation Also Work in Lung Cancers with Same Mutation

“A subset of lung cancer patients can derive important clinical benefits from drugs that are more commonly used to treat melanoma, the authors of a new academic clinical trial in Europe have reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

“Dr. Oliver Gautschi, a medical oncologist from Lucern Cantonal Hospital in Switzerland, presented the results of the retrospective EURAF cohort study, which included lung cancer patients whose tumours carried specific mutations in the BRAF gene. The study was conducted by a network of European oncologists, without company involvement.

“BRAF mutations are commonly seen in melanoma patients, and are found in about 2% of lung adenocarcinomas, Gautschi explains. Several inhibitors of the B-Raf protein, including vemurafenib and dabrafenib, have been developed for use in melanoma patients, however there is currently no approved drug for BRAF-mutant lung cancer.

“As a result, experience with B-Raf inhibitors in lung cancer remains limited. ‘In the current study, we wanted to find out how many patients in Europe received B-Raf inhibitors outside of a clinical trial, and what their outcomes were,’ Gautschi says.

“The EURAF study gathered information on 35 lung cancer patients who had been identified as carrying BRAF mutations, who were treated with B-Raf inhibitors between 2012 and 2014.”

Triple Combo: Two Targeted Drugs Plus Immunotherapy Show Promise in BRAF-Mutant Melanoma

“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.”

Advanced Melanoma Therapy Should Continue beyond Disease Progression

“Continued use of vemurafenib, even after disease progression, can improve survival outcomes for patients with BRAF V600-mutated advanced melanoma.

“More than half of diagnosed melanomas harbor BRAF V600 mutations, and the introduction of targeted agents such as vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib (Tafinlar, GlaxoSmithKline) triggered a paradigm shift in the treatment of BRAF-mutated melanoma.

“However, standard treatment practice is to discontinue use of these targeted agents upon disease progression, not unlike classic regimens such as cytotoxic chemotherapy.

“Because BRAF-mutated melanoma progresses rapidly after treatment, John Haanen, PhD, of the division of immunology at Netherlands Cancer Institute, and colleagues conducted a single-institution retrospective study to determine whether continued use of vemurafenib after disease progression could extend OS in patients with BRAF V600-mutated advanced melanoma.