Moffitt Researchers Discover Mechanism Leading to Drug Resistance, Metastasis in Melanoma Patients

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.”


Drug Combo Cuts Death by One-Third in Metastatic Melanoma with BRAF V600E or V600K Mutations

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.”


New Standard in Melanoma: Combo of BRAF and MEK Inhibitors

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.”


ESMO 2014 Press Release: New Data on Combination Treatments for Melanoma

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.”


Combined MEK, BRAF Inhibitors Promising in Melanoma

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.”


New Targeted Drugs May Offer Treatment for KRAS-Mutant Lung Cancer

Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules “downstream” in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.


NRAS Mutation in Melanoma: A Challenging Target


Among melanomas, BRAF-mutated disease gets the vast majority of attention. Fifty percent of melanomas harbor BRAF mutations, which can be targeted with BRAF inhibitors. However, despite its notoriety, BRAF is not the only important melanoma mutation.

Another melanoma-linked mutation can be found in the NRAS gene. Like BRAF mutations, NRAS mutations are ‘driver mutations’—a tumor with an NRAS mutation is dependent on the mutation for its growth and survival. Continue reading…


New Combination Treatment May Target Melanomas with BRAF Mutations Safely

While melanomas with BRAF mutations can be targeted with a combination of BRAF inhibitors and MEK inhibitors, the treatment can have side effects such as fever, light sensitivity, and rashes. But early results of a phase I clinical trial suggest that BRAF-mutant melanomas could be treated safely and effectively with a new combination: LGX818, a BRAF inhibitor developed by Novartis and MEK162, a MEK inhibitor developed by Array BioPharma. Moreover, using these drugs together may decrease common side effects of targeted BRAF treatments, including skin toxicities and muscle and joint pain. A phase III trial of this new combination treatment is expected to begin later in 2013.


Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment

A recently completed clinical trial examining the use of genetic testing to direct cancer treatment was able to exceed its enrollment goal of 600 participants in less than 2 years instead of the expected 5 years. Patients were willing to participate even though they had to undergo an additional biopsy, revealing considerable interest in personalized treatment based on genetic tests. The trial confirmed that erlotinib (Tarceva) is highly effective in non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. It also found that NSCLC patients with mutations in the KRAS gene did not benefit from the novel cancer drug selumetinib. In contrast, not enough small cell lung cancer (SCLC) patients had any of the investigated mutations to properly test how they responded to treatments. Such mutations will require trials involving thousands of patients to draw reliable conclusions.