“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.”
“More patients with advanced melanoma who had progressed on ipilimumab with or without a BRAF inhibitor were able to achieve an objective response when treated with the PD-1 immune checkpoint inhibitor nivolumab than with alternative chemotherapy options, according to the interim analysis results of the CheckMate 037 trial published recently in Lancet Oncology.
“In fact, the rate of objective response was about threefold greater with nivolumab compared with investigator’s choice of chemotherapy; however, no difference in progression-free survival in the intention-to-treat population was noted.
“These results were the basis of the December 2014 US Food and Drug Administration accelerated approval of nivolumab for this patient population.
“ ‘Findings from our study show that nivolumab leads to clinically meaningful improvements in the proportion of patients achieving an objective response and provide a manageable safety profile when compared with chemotherapy,’ wrote Jeffrey S. Weber, MD, of Moffitt Cancer Center, Tampa, Florida, and colleagues. ‘Nivolumab can now be considered as a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAF V600–mutated.’ ”
“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.
“Powerful drugs known as BRAF-inhibitors have been crucial for melanoma patients, saving lives through their ability to turn off the BRAF protein’s power to spur cancer cell growth.
“Yet they often work for only a year or less. Scientists know some of the DNA mutations that cause the drug resistance, but scientists have not been able to determine the underlying cause of the resistance in as many as a third of these patients. As a result, identifying genomic-based follow-up therapies for these patients has been a challenge.
“Researchers at The University of Texas MD Anderson Cancer Center may have found a way to more accurately predict which patients will likely respond to genomic-based follow-up therapies, by looking at unique ‘protein patterns’ in melanoma patients.
” ‘There are patients whose DNA does not reveal how their melanomas became resistant to BRAF inhibitors,’ said Lawrence Kwong, Ph.D., instructor in Genomic Medicine at MD Anderson. ‘So we looked at patterns of changes in 150 proteins which can give clues to the causes of resistance, even when DNA sequencing data is uninformative.’ “
The gist: An ongoing clinical trial has shown good results for certain metastatic melanoma patients treated with the drug dabrafenib (Tafinlar). Patients in the trial have tumors with “BRAF V600E” mutations. The researchers report that 45% of patients treated with Tafinlar are still alive at two years.
“GSK today announced updated results for Tafinlar® (dabrafenib) from a planned analysis of the phase III BREAK-3 study in 250 patients with BRAF V600E mutant metastatic melanoma. These results, which include new survival data, showed 45 per cent of patients treated with dabrafenib were still alive at two years.1 The data were presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.
“Analysis of the study’s primary endpoint, progression free survival (PFS), was reported in 2012.2 Today’s results relate to a secondary endpoint from this study, with a final analysis of the overall survival (OS) endpoint expected in 2016.
“45 per cent of patients treated with dabrafenib only, were alive at two years compared to 32 per cent of patients who began treatment with dacarbazine (DTIC). 59 per cent of patients on DTIC treatment whose disease progressed subsequently received dabrafenib treatment and are included in the DTIC control arm results. While allowing this treatment cross over means patients in the control arm get the potential benefit of an active experimental drug, this can impact the comparative study findings as patients who received both medicines are included in the DTIC arm results. At the planned two-year follow up, the study showed a median OS of 20.0 months for the dabrafenib arm (95% CI 16.8-24.4) compared to 15.6 months for the DTIC arm (95% CI 12.7-21.2) [hazard ratio (HR) 0.77 (95% CI 0.52-1.13) – not statistically significant].
“ ‘We are encouraged by the 45 per cent survival rate with dabrafenib at two years,’ said Dr. Paolo Paoletti, President of Oncology, GSK. ‘Treatments for melanoma have come a long way in recent years and we’re now seeing the benefits precision medicines can bring to the right patients.’ ”
The gist: People with advanced melanoma who have not yet been treated might benefit from the drug nivolumab (Opdivo). In December, the U.S. Food and Drug Administration (FDA) approved Opdivo for people who had tried other treatments unsuccessfully. Now, a new clinical trial shows that patients without prior treatment survive longer on Opdivo than chemotherapy.
“The PD-1 inhibitor nivolumab significantly increased overall survival compared with chemotherapy in patients with previously untreated metastatic melanoma without a BRAF mutation. In addition, the drug more than doubled the progression-free survival among these patients.
“ ‘The risk of death decreased by 58% with nivolumab, as compared with dacarbazine, among previously untreated patients with advanced melanoma,’ wrote study author Caroline Robert, MD, PhD, of INSERM Unité 981, Gustave Roussy, and colleagues. ‘The survival benefit was consistent across all the prespecified subgroups, including patients with poor prognostic factors.’
“The results of the phase III double-blind study were published in the January 22 issue of the New England Journal of Medicine.”
The gist: New research suggests that some melanoma patients might benefit from a treatment schedule that alternates BRAF inhibitor drugs with MEK inhibitor drugs. The scientists hypothesize that this schedule could help prevent drug resistance and metastasis. The researchers set out to figure out why patients who receive BRAF inhibitors develop more metastases than patients on standard chemotherapy. They found that unusually high activity of a protein called EphA2 on cancer cells may be the culprit. Taking away BRAF inhibitors seemed to lower the aggressiveness of these cells. So, periodically taking away BRAF inhibitors from patients might theoretically help stave off resistance and metastasis.
“Moffitt Cancer Center researchers have discovered a mechanism that leads to resistance to targeted therapy in melanoma patients and are investigating strategies to counteract it. Targeted biological therapy can reduce toxicity and improve outcomes for many cancer patients, when compared to the adverse effects of standard chemotherapeutic drugs. However, patients often develop resistance to these targeted therapies, resulting in more aggressive cells that can spread to other sites or cause regrowth of primary tumors.
“B-Raf is a protein that is frequently mutated in human cancers, leading to increased tumor cell growth, survival and migration. Drugs that target B-Raf or another protein in the same network called MEK have proved effective in clinical trials. Several B-Raf and MEK inhibitors have been approved with the combination of a B-Raf and a MEK inhibitor being the current standard of care for patients with B-Raf mutant melanoma. However over time many patients become resistant to B-Raf and B-Raf/MEK inhibitor therapy.
“Moffitt researchers found that patients who are on B-Raf inhibitor drugs develop more new metastases than patients who are on standard chemotherapy. The researchers wanted to determine how this acquired resistance develops in order to devise better treatment options for patients. They found that melanoma cells that are resistant to B-Raf inhibitors tend to be more aggressive and invasive, thereby allowing the tumor to spread to a new organ site. They used a large screening approach and discovered that this resistance and aggressive behavior was due to high activity of a cell surface protein called EphA2, which is also found on glioblastoma stem cells.”