“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.”
“Array BioPharma’s (NASDAQ: ARRY) wholly-owned MEK inhibitor, binimetinib, and BRAF inhibitor, encorafenib, were showcased at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO). At the meeting, preliminary data for the combination of binimetinib and encorafenib from a Phase 1b/2 dose escalation and expansion study in patients with BRAF-mutant melanoma who are BRAF inhibitor treatment naive were shared during an oral presentation. Results from the study indicate that binimetinib and encorafenib may be safely combined and show encouraging clinical activity consistent with MEK/BRAF inhibitor expectations in patients with BRAF-mutant melanoma who are BRAF inhibitor treatment naive. In addition, a differentiated safety profile relative to other MEK/BRAF inhibitor combinations is emerging in the dose range currently being used in the Phase 3 COLUMBUS trial. Array expects updated BRAF melanoma data from the ongoing Phase 2 combination trial (LOGIC-2) of binimetinib and encorafenib followed by the addition of a third targeted agent identified based on genetic testing at the time of progression will be submitted to a scientific conference later this year. LOGIC-2 utilizes the same dose of binimetinib and encorafenib currently being studied in the COLUMBUS trial.”
“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),.
“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.”
“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced follow-up data from two studies of the investigational MEK inhibitor cobimetinib in combination with Zelboraf® (vemurafenib). Updated data from the pivotal coBRIM Phase III study showed the combination helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of one year (12.3 months) without their disease worsening or death (progression-free survival; PFS) compared to 7.2 months with Zelboraf alone (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.46-0.72).1
“ ‘The combination of cobimetinib and Zelboraf extended the time people lived without their disease getting worse to a year,’ said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. ‘These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow.’ “
“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.”
Update: We are deeply saddened to report that Susan passed away on January 13, 2016. It is a privilege to continue to share her story and keep her memory alive.
When Susan Steel first noticed the mole that derailed her life ten years ago, she was busy raising two children and running two businesses. “I just wasn’t paying attention,” she says. It wasn’t until the mole grew and started to bleed that she finally saw a doctor—and then she was hit with the news that she had melanoma and that it had spread to her lymph nodes.
“My life changed very fast,” Susan recalls. “I was told that my chances were very slim and that I should get my affairs in order.” Continue reading…
“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.
The gist: Two new, similar melanoma treatments have been tested in clinical trials—research studies with volunteer patients. Both of the trials are focused on people with advanced melanoma whose tumors have mutations in the BRAF gene. Such patients are often treated with a targeted therapy called a BRAF inhibitor, but their tumors often become resistant and keep growing. In these two trials, the researchers hope that combining BRAF inhibitors with other targeted drugs known as MEK inhibitors might help patients avoid resistance. One of the trials tested a combination of the drugs vemurafenib and cobimetinib. The other trial combined dabrafenib and trametinib. In both trials, patients treated with the combination treatment fared better than patients treated with just a BRAF inhibitor alone.
“For patients with advanced melanoma that isBRAF-mutation positive, the combination of a BRAF and MEK inhibitor works better than a BRAF inhibitor alone. The data come from 2 phase 3 trials presented here at the presidential session of the European Society for Medical Oncology (ESMO) Congress 2014.
“Experts here say that such combinations should be the new standard of care in this patient population, which accounts for about 40% of all melanoma.
“At present, the first-line treatment for these patients is a BRAF inhibitor used alone, but while these drugs can elicit dramatic responses, they do not last, and after about 5 or 6 months, patients relapse. The tumor develops resistance to the drug via the MAPK pathway, and this is blocked by a MEK inhibitor. Adding a MEK inhibitor to the BRAF inhibitor from the beginning of treatment blocks this resistance pathway and improves outcomes.
“The 2 new trials are known as COMBI-v and coBRIM.
“Both studies used vemurafenib (Zelboraf, Roche/Plexxikon) as the single BRAF inhibitor, but each used a different combination of BRAF and MEK inhibitor.”
The gist: Drug company giant Roche is mixing drugs in new combinations to provide melanoma and breast cancer patients with potential new treatments. This article outlines the company’s endeavors.
“Mixing drugs in various combinations has given Roche Holding AG (ROG) effective new treatments for skin and breast cancer strains.
“Combining Zelboraf, a melanoma drug now on the market, with experimental cobimetinib showed significant improvement over Zelboraf alone, according to data presented today at the European Society for Medical Oncology’s annual meeting in Madrid.
“Roche said yesterday that a combination of two breast cancer drugs, plus chemotherapy, could add almost 16 months to the lives of a class of patients. Roche today also reported data from an early-stage study of its MPDL3280A immune therapy treatment in bladder cancer which showed a 52 percent response rate. If successfully developed, the drug will be the first new treatment for bladder cancer in 30 years, the Basel, Switzerland-based company said.
“ ‘This is a good meeting for Roche,’ said Asthika Goonewardene, an analyst with Bloomberg Intelligence. ‘They’re firing in three different areas.'”