“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.”
“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.”
“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: 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.’ ”
“UK drugs watchdog the National Institute for Health and Care Excellence (NICE) has issued final draft guidance recommending UK pharma giant GlaxoSmithKline’s (LSE: GSK) Tafinlar (dabrafenib) for the treatment of melanoma which has spread or can’t be completely removed by surgery and tests positive for the BRAF V600 mutation.
“NICE proposes recommending dabrafenib on the basis that GSK provides the drug to the National Health Service with a discount on the list price. The size of the discount is commercial in confidence.
“Carole Longson, Centre for Health Technology Evaluation director at NICE, said: ‘For a long time the treatments available for skin cancer which has spread have been very limited. However, in recent years a number of breakthrough treatments that can potentially significantly improve the prognosis for some people with malignant melanoma have become available. NICE has already recommended vemurafenib and ipilimumab and we hope to add dabrafenib to the list of options available. The information provided by GlaxoSmithKline, who markets the drug, suggested that dabrafenib works just as well as vemurafenib which also targets melanoma with the BRAF V600 mutation. Drugs like dabrafenib are also thought to have very rapid positive effect for patients, even in those who are very unwell or bed-ridden. In some cases, it has enabled people to resume everyday activities.’ ”
Editor’s note: Tafinlar is a targeted drug used to treat patients whose melanoma has spread (metastasized) or cannot be removed by surgery, and has a mutation called BRAF V600, as detected by molecular testing.
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.”
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…
“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.