“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.’ ”
The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors have mutations called BRAF V600E or BRAF V600K. This treatment combines the drugs dabrafenib and trametinib. In the trial, some patients were treated with the combination, and some were treated with only the drug vemurafenib (aka Zelboraf). People who took dabrafenib and trametinib lived several months longer than people who took vemurafenib. None of the patients had taken any previous treatments for their melanoma.
“The combination of dabrafenib and trametinib significantly extended OS compared with vemurafenib monotherapy in patients with treatment-naive metastatic melanoma who harbored BRAF V600E or V600K mutations, according to results of a randomized, open-label phase 3 study.
“The regimens demonstrated comparable toxicity profiles, researchers wrote.
“ ‘Together with the previously reported phase 2 and 3 trials of dabrafenib plus trametinib as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,’ Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave-Roussy in Paris, and colleagues wrote.”
Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack. How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…
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: Two new targeted treatment approaches are showing promise for some lung cancer patients. Researchers are testing the targeted drug dabrafenib in a clinical trial—a research study with volunteer patients. Dabrafenib is meant to treat certain people who have already been treated for advanced non-small cell lung cancer (NSCLC) but who need additional treatment. The patients who participated in the trial had a tumor mutation called BRAF V600E. The study results supported dabrafenib as an effective treatment for these patients. In another clinical trial, researchers found that a combination of the drugs temsirolimus and neratinib had beneficial effects for people with advanced non-small cell lung cancer (NSCLC) whose tumors had mutations in the HER2 gene.
“The BRAF inhibitor dabrafenib has significant anti-tumour activity in patients with advanced BRAF V600E mutant non-small cell lung cancer whose disease has progressed after chemotherapy, according to phase II data presented at the ESMO 2014 Congress in Madrid, Spain.
” ‘Reports of lung cancers bearing mutations in BRAF have generated considerable interest because these mutations may be associated with increased sensitivity to BRAF tyrosine-kinase inhibiting agents,’ says lead author Dr David Planchard, pulmonary oncologist at the Gustav-Roussy Cancer Campus, Paris, France.
“Planchard says studies suggest that activating BRAF mutations are present in around 2% of lung carcinomas — approximately 80% of which are V600E mutations. The BRAF V600E mutations are frequently associated with shorter disease-free, overall survival, and lower response rates to platinum-based chemotherapy.
“This open-label phase II study involves patients with BRAF V600E mutant non-small cell lung cancer, treated with dabrafenib alone (150 mg, twice daily). The primary endpoint is investigator-assessed overall response rate, with secondary endpoints of progression-free survival, duration of response, overall survival, safety and tolerability, and population pharmacokinetics.”
The gist: Researchers tested a new melanoma treatment in a clinical trial—a research study with volunteer patients. The treatment combines the targeted drugs dabrafenib and trametinib. All of the patients who participated in the trial had inoperable stage IIIC or stage IV melanoma. Also, each patient’s tumors had one of two particular mutations in the BRAF gene, known as V600E and V600K. In the trial, patients who were treated with the combination therapy had significantly lower chances of their cancer worsening and lower chances of death.
“A world-first study in today’s New England Journal of Medicine heralds the efficacy of a targeted combination drug therapy after reporting major declines in the risk of disease progression and death in people with metastatic melanoma.
“The multi-centre, double-blind, randomised, phase 3 trial compared oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) combination therapy with oral dabrafenib (150 mg twice daily) and placebo.
“All trial patients had inoperable stage 3C or 4 metastatic melanoma that had a BRAF gene mutation V600E or V600K. Among cancer patients with metastatic melanoma, about 40 per cent have a BRAF gene mutation – an abnormality that assists some melanoma tumours to grow and spread.
“Led by Associate Professor Georgina Long of Melanoma Institute Australia at the University of Sydney, the finding affirms accumulating evidence of the efficacy of targeted combination therapies in extending life and halting disease progression in patients with cancers that carry genetic mutations that resist monotherapies.”
“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.