“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.”
“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.’ ”
“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: 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.”
The gist: Certain metastatic melanoma patients who have not yet been treated may do better if they take the drugs dabrafenib and trametinib than if they take vemurafenib. This was true for patients who had BRAF V600E or V600K mutations in their tumors. The patients participated in a clinical trial to compare the two treatment approaches.
“Patients with previously untreated BRAF V600E or V600K metastatic melanoma had a significant improvement in overall survival when treated with a combination of a BRAF inhibitor and a MEK inhibitor compared with treatment with a BRAF inhibitor alone, according to the results of a study published in the January 1 issue of the New England Journal of Medicine.
“In fact, patients treated with dabrafenib and trametinib had a 31% relative risk reduction for death compared with patients assigned monotherapy with the BRAF inhibitor vemurafenib, with no significant increase in toxicity.
“ ‘Together with the previously reported phase II and phase III 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,’ wrote study author Caroline Robert, MD, PhD, Gustave Roussy and INSERM Unité 981, Villejuif-Paris Sud, and colleagues.”
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: Researchers tested a new melanoma treatment in a clinical trial—a research study with volunteer patients. The treatment combines the targeted drugs vemurafenib and cobimetinib. All of the patients who participated in the trial had melanoma tumors with mutations in the BRAF gene, as detected by molecular testing. The combination treatment proved more beneficial for these patients than vemurafenib alone.
“Combination therapy with both BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib achieves greater progression-free survival and response rates than vemurafenib plus placebo in BRAF-mutation positive melanoma, according to phase III data presented at the ESMO 2014 Congress in Madrid, Spain.
“ ‘Before the results of this study, we knew that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumour shrinkage; however until the performance of a scientifically rigorous randomised trial the potential magnitude of this benefit could not be measured,’ says lead author Dr Grant McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia.
“The ongoing CoBRIM study enrolled 495 treatment-naive patients with BRAFV600-mutation-positive unresectable locally advanced or metastatic melanoma. Patients were randomised to received a 28-day treatment cycle of vemurafenib (960 mg, twice daily), and either cobimetinib or placebo (60 mg daily from days 1-21), with a primary end-point of progression-free survival.
“Patients in the combination arm of the study showed a significantly improved median progression-free survival of 9.9 months, compared to 6.2 months in the placebo arm, and a 49% reduction in the risk of progression. Researchers observed a response rate of 68% in the combination arm and 45% in the control arm, including a complete response in 10% of patients treated with combination therapy compared to 4% of patients treated with vemurafenib alone.”
The gist: Researchers have conducted a clinical trial with volunteer patients to test a new melanoma treatment that combines the drugs cobimetinib and vemurafenib. The participants all had melanoma tumors with BRAFV600 mutations. People with BRAFV600 mutations often become resistant to treatment if they take a “BRAF inhibitor” like vemurafenib. The hope is that drugs like cobimetinib can be given alongside vemurafenib to circumvent resistance. The researchers found that the combination treatment was safe for these patients, and there was some promising evidence that the treatment was effective, but more follow-up will be needed.
“Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.
“Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.
“According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, ‘which frequently reactivates the MAPK pathway through MEK.’ Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.”
Editor’s note: Targeted therapies that fight tumors with specific genetic mutations opened up a new era in cancer treatment, but many patients become resistant to these treatments, and their cancer grows back. A new type of treatment called immunotherapy boosts a patient’s own immune system to fight cancer. Researchers are hopeful that combining targeted drugs with immunotherapy drugs could be highly effective. This article discusses the idea of combining immunotherapy with targeted drugs developed to treat melanomas with mutations in the GRAF gene. It is a scientific article, but may interest some patients and caregivers dealing with BRAF-mutant melanoma.
“Hu–Lieskovan S, et al. – In this review,the authors present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
“Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer.
“Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high.
“Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma.
“These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration.
“Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.
“However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.”