Cobimetinib combined with vemurafenib shows added benefit for melanoma with BRAF V600 mutation

In continuation of my update on Cobimetinib   and Vemurafenib

Cobimetinib (trade name: Cotellic) has been approved since November 2015 in combination with vemurafenib for the treatment of adults with advanced, i.e. metastatic or unresectable, melanoma with a BRAF V600 mutation. In a dossier assessment from March 2016, the German Institute for Quality and Efficiency in Health Care (IQWiG) found both advantages and disadvantages of cobimetinib in combination with vemurafenib in comparison with the appropriate comparator therapy vemurafenib alone. This resulted in an indication of a minor added benefit.

 Cobimetinib 

In the subsequent commenting procedure, the drug manufacturer presented further data analyses, which were now included in the assessment in a so-called addendum. This increased the extent of the added benefit: There is now an indication of a considerable added benefit of cobimetinib plus vemurafenib in comparison with vemurafenib .

  vemurafenib 

Third data cut-off of the approval study decisive

The manufacturer dossier was based on the study coBRIM, which was decisive for the approval. In this study, cobimetinib in combination with vemurafenib was directly compared with vemurafenib. Besides advantages, particularly in overall survival, several disadvantages also resulted from the data.

In the commenting procedure conducted by the Federal Joint Committee (G-BA) after IQWiG's dossier assessment, the manufacturer now in particular presented more informative analyses on symptoms and health-related quality of life from the third data cut-off, as well as further results for the fourth and fifth data cut-off. The third data cut-off was decisive for the benefit assessment because the recording of symptoms and health-related quality of life was discontinued shortly afterwards. It was investigated whether the data from the later cut-off dates raised doubts about the overall conclusion on the added benefit - which was not the case.

Additional positive effects in symptoms and quality of life

Melanomas that develop resistance to vemurafenib also become addicted to the drug

Vemurafenib (marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,  Health Canada approval on February 15, 2012 and on February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer....

Mechanism : Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway if the B-Raf has the common V600E mutation.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. 

Melanomas that develop resistance to vemurafenib also become addicted to the drug

Cotellic (cobimetinib) approved to be used in combination with vemurafenib for melanoma treatment

The U.S. Food and Drug Administration today approved Cotellic (cobimetinib) to be used in combination with vemurafenib to treat advanced melanoma that has spread to other parts of the body or can't be removed by surgery, and that has a certain type of abnormal gene (BRAF V600E or V600K mutation).

Melanoma is the most aggressive and dangerous form of skin cancer in the United States. It forms in the skin cells that develop the skin's pigment and if not diagnosed early, the cancer is likely to spread to other parts of the body. The National Cancer Institute estimates that 73,870 Americans will be diagnosed with melanoma and 9,940 will die from the disease this year.

"As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Today's approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma."

Cotellic works by blocking the activity of an enzyme known as MEK, which is part of a larger signaling pathway. Abnormal activity of signaling pathways can lead to cancer. Cotellic prevents or slows cancer cell growth. Vemurafenib, marketed in the U.S. as Zelboraf, is a BRAF inhibitor that affects a different part of the same pathway and was approved in 2011 to treat patients with melanoma that has spread to other parts of the body or cannot be removed by surgery, whose tumors express a gene mutation called BRAF V600E, as detected by an FDA approved test. Health care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients' tumor specimens using one of the available FDA approved tests prior to starting treatment with Cotellic in combination with vemurafenib.

Cotellic (cobimetinib) approved to be used in combination with vemurafenib for melanoma treatment

Melanomas that develop resistance to vemurafenib also become addicted to the drug

In continuation of my update on vemurafenib

Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease. 

The team, based at the University of California, San Francisco (UCSF), the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, Calif., and University Hospital Zurich, found that one mechanism by which melanoma cells become resistant to vemurafenib also renders them "addicted" to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.

Ref : http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11814.html

Melanomas that develop resistance to vemurafenib also become addicted to the drug

2-year advanced melanoma survival benefit with dabrafenib, trametinib combination

Updated results from the COMBI-v trial show significantly improved overall and progression-free survival (OS, PFS) with first-line dabrafenib plus trametinib compared with vemurafenib in patients with advanced melanoma.

The findings of the phase III trial comprising patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma were presented at the European Cancer Congress in Vienna, Austria, by Caroline Robert, from the Institut Gustave Roussy in Paris, France.

A previous interim analysis with a median follow-up of 11 months showed a significant improvement in OS with dabrafenib and trametinib, explained Robert in her presentation, so much so that the trial was terminated early and patients in the vemurafenib group were allowed to crossover.

In this most recent analysis, the 352 patients randomly assigned to receive the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib had a median OS of 25.6 months. This was not only significantly longer than the 18.0 months observed for the 352 participants given the BRAF inhibitor vemurafenib, but also the “longest ever reached” in a randomised phase III trial in this patient population, said Robert.

And after a median follow-up of 19 months, the 2-year survival rate was significantly higher for the dabrafenib plus trametinib group than for the vemurafenib group, at 51% versus 38%.

Median PFS was also significantly longer, with corresponding times of 12.6 and 7.3 months, and overall response rate and duration of response were similarly improved in the dual therapy compared with the monotherapy arm, at 66% versus 53% and 13.8 versus 8.5 months, respectively.

The incidence of all-grade adverse events continued to be high during the additional follow-up period, with pyrexia (55%) most common in the combination group and arthralgia (52%) in the vemurafenib group, but Robert said this was not surprising.

2-year advanced melanoma survival benefit with dabrafenib, trametinib combination

FDA Approves Zelboraf (vemurafenib) for Erdheim-Chester Disease with BRAF V600 Mutation

In continuation of my update on Vemurafenib

The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD.

“Today’s approval of Zelboraf for patients with ECD demonstrates how we can apply knowledge of the underlying genetic characteristics of certain malignancies to other cancers,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This product was first approved in 2011 to treat certain patients with melanoma that harbor the BRAF V600E mutation, and we are now bringing the therapy to patients with a rare cancer with no approved therapies.”

ECD is a slow-growing blood cancer that originates in the bone marrow. ECD causes an increased production of histiocytes, a type of white blood cell. Excess histiocytes can result in tumors infiltrating many organs and tissues throughout the body, including the heart, lungs, brain and others. ECD is estimated to affect 600 to 700 patients worldwide. Approximately 54 percent of patients with ECD have the BRAF V600 mutation. Patients with ECD have very limited life expectancies.

Zelboraf is a kinase inhibitor that works by blocking certain enzymes that promote cell growth.

The efficacy of Zelboraf for the treatment of ECD was studied in 22 patients with BRAF-V600-mutation positive ECD. The trial measured the percent of patients who experienced a complete or partial reduction in tumor size (overall response rate). In the trial, 11 patients (50 percent) experienced a partial response and 1 patient (4.5 percent) experienced a complete response.

Common side effects of Zelboraf in patients with ECD include joint pain (arthralgia); small, raised bumps (maculo-papular rash); hair loss (alopecia); fatigue; change in the heart’s electrical activity (prolonged QT interval) and skin growths (papilloma).

FDA Approves Zelboraf - Potent New Melanoma Drug

Plexxikon Inc., a member of the Daiichi Sankyo Group, today announced that applications for market approval for vemurafenib ( PLX4032/RG7204, see below structure) for the treatment of metastatic melanoma have been submitted to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The company had 

Phase 2 and 3 trials (BRIM2 and BRIM3) that evaluated vemurafenib in patients with BRAF ^V600 mutation-positive melanoma, as determined by the cobas 4800 BRAF ^V600 Mutation Test.

 Earlier this year, the company reported positive data from an interim analysis of BRIM3 which showed that the study met the pre-specified criteria for co-primary endpoints for BRIM3 for progression-free survival and overall survival, and that the safety profile was generally consistent with the previous vemurafenib studies. Based on these results, the data safety monitoring board for the trial recommended early termination of the trial and allowed dacarbazine-treated patients to immediately cross over to vemurafenib treatment. BRIM2 results reported earlier showed a 52 percent confirmed response rate, with tumor shrinkage in the majority of patients, consistent with results from earlier studies. 

More....

Skin cancer drug, vemurafenib may prolong survival in advanced cases: Study

In continuation of my update on vemurafenib...

According to an international study a new treatment for advanced skin cancer almost doubles survival times. Researchers say 132 patients in the U.S. and Australia who were given the drug vemurafenib gained several extra months of life. The treatment is one of two drugs for late-stage melanoma, approved on fast-track in the US last year, which offer hope for patients with advanced melanoma. Vemurafenib is suitable for about half of patients with advanced melanoma as it targets tumors that express a certain gene mutation. Before that, there had been no new drugs for the cancer for more than a decade...

More...

Vemurafenib: Result unchanged despite new data

In continuation of my update on Vemurafenib

Longer survival, but also major side effects

The drug approved since February 2012 can be an option for adults whose melanoma cannot be removed by surgery or has formed secondaries (metastases) and in whose cancer a change (mutation) has occurred in a certain gene (BRAF-V600). G-BA had specified the drug dacarbazine as the appropriate comparator therapy.

In its first AMNOG assessment in June 2012, the Institute concluded that vemurafenib had major advantages in overall survival, but also major disadvantages in the form of side effects. Overall, this resulted in an indication of a considerable added benefit.

Vemurafenib: Result unchanged despite new data

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells ..

The primary method used to test compounds for anti-cancer activity in cells is flawed, Vanderbilt University researchers report May 2 in Nature Methods. The findings cast doubt on methods used by the entire scientific enterprise and pharmaceutical industry to discover new cancer drugs.

"More than 90 percent of candidate cancer drugs fail in late stage clinical trials, costing hundreds of millions of dollars," said Vito Quaranta, M.D., director of the Quantitative Systems Biology Center at Vanderbilt. "The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact."

Quaranta and his colleagues have developed a new metric to evaluate a compound's effect on cell proliferation -- called the DIP (drug-induced proliferation) rate -- that overcomes the flawed bias in the traditional method.

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound to cells and counting how many cells are alive after 72 hours. But these "proliferation assays" that measure cell number at a single time point don't take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said Darren Tyson, Ph.D., co-author and research assistant professor of Cancer Biology.

"Cells are not uniform; they all proliferate exponentially, but at different rates," said Quaranta, professor of Cancer Biology. "At 72 hours, some cells will have doubled three times and others will not have doubled at all."

In addition, he noted, drugs don't all behave the same way on every cell line -- for example, a drug might have an immediate effect on one cell line and a delayed effect on another.

In a close collaboration with computational biologist Carlos Lopez, assistant professor of Cancer Biology, Quaranta's team used a systems biology approach -- a mixture of experimentation and mathematical modeling -- to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

"Systems biology is what really makes the difference here," Quaranta said. "It's about understanding cells -- and life -- as dynamic systems."

Tyson, an experimentalist, conceived the method with Leonard Harris, Ph.D., a systems biology postdoctoral fellow and co-first author Peter Frick, Ph.D., a recent Vanderbilt graduate.

The findings have particular importance in light of recent international efforts to generate data sets that include the responses of "thousands of cell lines to hundreds of compounds," Quaranta said. The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line's molecular makeup.

"The idea is to look for statistical correlations -- these particular cell lines with this particular makeup are sensitive to these types of compounds -- to use these large databases as discovery tools for new therapeutic targets in cancer," Quaranta said. "If the metric by which you've evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good." The researchers evaluated the responses of four different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric -- used for the CCLE and GDSC databases -- and with the DIP rate. In one cell line, they found a stark disagreement between the two metrics.

"The static metric says that the cell line is very sensitive to vemurafenib. However, our analysis shows this is not the case," Harris said. "A brief period of drug sensitivity, quickly followed by rebound, fools the static metric, but not the DIP rate."

The findings "suggest we should expect melanoma tumors treated with this drug to come back, and that's what has happened, puzzling investigators," Quaranta said. "DIP rate analyses may help solve this conundrum, leading to better treatment strategies."

The DIP rate metric offers another advantage -- it can reveal which drugs are truly cytotoxic (cell-killing), rather than merely cytostatic (cell growth-inhibiting). Although cytostatic drugs may initially have promising therapeutic effects, they may leave tumor cells alive that then have the potential to cause the cancer to recur.

Quaranta noted that using the DIP rate is possible because of advances in automation, robotics, microscopy and image processing.

His team has developed a software package that will be available to other researchers through a hyperlink in the Nature Methods paper. Quaranta is working with the Vanderbilt Center for Technology Transfer and 

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells  

Positive results from Plexxikon's vemurafenib Phase 2 and 3 trial against metastatic melanoma

We know that, PLX-4032(RG7204, Vemurafenib) is a highly selective inhibitor of BRAF kinase activity, with an IC50 of 44 nmol/L against V600E-mutant BRAF. BRAFV600E cancer-causing mutation occurs in most melanomas and about eight percent of all solid tumors....

More....

Novel drug prevents memory impairment in mice exposed to simulated deep space radiation

NASA and private space companies like SpaceX plan to send humans to the red planet within the next 15 years--but among the major challenges facing future crewed space missions is how to protect astronauts from the dangerous cosmic radiation of deep space.

Now the lab of UCSF neuroscientist Susanna Rosi, PhD, has identified the first potential treatment for the brain damage caused by exposure to cosmic rays--a drug that prevents memory impairment in mice exposed to simulated space radiation. The study was published May 18, 2018 in

Humans venturing beyond the Earth's protective magnetic fields will be exposed to levels of cosmic radiation estimated to be 1000 times higher than what we experience on Earth or even in the International Space Station's low-earth orbit. Protecting astronauts from this harmful radiation will be key to making deep space exploration--and perhaps one day colonization--possible.

Rosi, who is Director of Neurocognitive Research in the

Rosi's team has previously found that exposing mice to simulated space radiation causes problems with memory, social interactions, and anxiety, and has linked these symptoms of radiation exposure to activation of cells called microglia--part of the brain's immune system. Activated microglia drive brain inflammation similar to what is seen in neurodegenerative disorders such as Alzheimer's disease, and also seek out and consume synapses, the information-bearing connections between brain cells.

"We are starting to have evidence that exposure to deep space radiation might affect brain function over the long term, but as far as I know, no one had explored any possible countermeasures that might protect astronauts' brains against this level of radiation exposure," said Rosi, who is a member of the

In the new study, the researchers collaborated with co-authors at Loma Linda University in Southern California to expose mice for a day to a dose of radiation comparable to what they might experience in deep space. The experiments were conducted at the NASA Space Radiation Laboratory at Brookhaven National Laboratory in New York, the only facility in the country where such experiments are possible. A week later, after being shipped back to UCSF, some of the mice were treated for 15 days with PLX5622, a drug produced by Berkeley-based pharmaceutical company Plexxikon, Inc, and which the Rosi lab had previously shown to prevent cognitive deficits in a mouse model of cancer radiation therapy when administered prior to irradiation of the brain.

In the present study, the irradiated animals initially displayed no cognitive deficits, but after three months they began showing signs of memory impairment. Normally, when researchers place mice in a room with a familiar and an unfamiliar object, the animals spend more time exploring the new object. But mice that had been exposed to space radiation three months earlier explored the two objects equally--presumably because they didn't remember having seen one of the objects just the day before.

Remarkably, animals that had been treated with PLX5622 soon after being exposed to radiation performed just like healthy mice on the memory task. The researchers examined the animals' brains and showed that while the brains of untreated mice were full of activated microglia and had lost significant numbers of synapses, the brains of treated mice looked just like normal. The authors hypothesize that by forcing the brain to replace irritable, radiation-exposed microglia with new, healthy microglia, the drug had allowed the animals avoid the cognitive consequences of radiation.

"This is really neat evidence, first that rebooting the brain's microglia can protect cognitive function following radiation exposure, and second that we don't necessarily need to treat immediately following the radiation exposure for the drug to be effective," Rosi said.

Similar compounds to PLX5622 produced by Plexxikon (inhibitors of a cellular receptor molecule called CSF1R) are already in clinical trials for multiple forms of human cancer, which suggests that the new findings could soon be translated to human use, the researchers say. Beyond spaceflight, these compounds could potentially be used to prevent cognitive impairments following cancer radiation therapy, or in age-related cognitive impairment--which has also been linked to microglia-driven brain inflammation.

"NASA is very interested in finding ways of ensuring both astronaut safety and mission success during deep space travel," said study co-lead author Karen Krukowski, PhD, a postdoctoral researcher in Rosi's lab. "But astronauts are a small population--it's exciting that these findings could potentially help prevent many other forms of cognitive impairment.

Melanoma Drug Nearly Doubles Survival « VICC News & Publications

In continuation of my update on Zelboraf (vemurafenib)

Melanoma Drug Nearly Doubles Survival « VICC News & Publications

Diabetes drug points the way to overcoming drug resistance in melanoma

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. Researchers  identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B^high subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

Ref: http://www.cell.com/cancer-cell/retrieve/pii/S1535610813001967 

Diabetes drug points the way to overcoming drug resistance in melanoma

Combinatory therapy may be effective in suppressing drug resistance in treatment of melanoma

"About 50 percent of melanomas are driven by mutations in the BRAF gene, and about 60-80 percent of these melanomas initially respond to BRAF inhibitors such as vemurafenib and dabrafenib, but most develop resistance within seven to eight months," said Dr. Lo. "Our goal is to study comprehensively how this cancer escapes from BRAF inhibitors, so we can design new treatment approaches to overcome this resistance.

"It is very exciting to see work funded under a Stand Up To Cancer Innovative Research Grant (IRG) yield these important results," stated Sherry Lansing, co-founder & member of the SU2C Council of Founders and Advisors. "We created the IRG program to enable some of the best and brightest young researchers across disciplines to think out of the box and attempt to make major breakthroughs in their field with bold research projects." The SU2C IRG program is one of two initial funding models created by SU2C to focus on groundbreaking translational research aimed at getting new therapies to patients quickly. IRG grants support work that incorporates new ideas and new approaches to solve critical problems in cancer research. Dr. Lo's grant was one of the initial 13 IRG grants awarded in December 2009. Thirteen additional IRG grants were awarded in April 2011. To date, SU2C has funded $19.42 million for IRG research.

"There are several types of resistance, and one of these studies focused on early resistance, because most melanomas respond to BRAF inhibitors partially, leaving behind tumors subject to further evolutionary selection and development of late resistance," said Lo. "We found that suppressing the BRAF-regulated MAPK signaling quickly led to an increase in PI3K-AKT pathway signaling [causing early resistance] in many but not all melanomas. In those that do not display this early adaptive response, certain tumor subclones with the 'right' genetic variants in the PI3K-PTEN-AKT pathway would then have selective growth advantage during BRAF inhibitor therapy and eventually contribute to acquired [late] resistance," he explained.

Lo and colleagues studied melanoma tumors from patients collected before and early during treatment with BRAF inhibitors, and found that there was an increase in the amount of the activated form of a protein called AKT, early on after the start of treatment. They further confirmed these findings using melanoma cells cultured in the laboratory. This increase in activated AKT was associated with various inhibitors that block MAPK signaling at different points along the pathway, such as BRAF and MEK inhibitors.

Combinatory therapy may be effective in suppressing drug resistance in treatment of melanoma

Drug combinations show promise against metastatic melanoma

In continuation of my update on Vemurafenib..

A Phase I study in 44 patients shows that the combination of the MEK inhibitor GDC-0973  (see structure) and vemurafenib can be delivered safely, Dr Rene Gonzalez of the University of Colorado Cancer Center, Denver, and colleagues report.

"BRAF inhibition has resulted in high response rates and improved survival in patients with BRAF mutated melanoma," Dr Gonzalez said. "One of several mechanisms of resistance has been reactivation of the MAPK pathway. Preclinical models show that combined inhibition of BRAF and MEK can delay the acqusition of resistance compared to BRAF inhibitor monotherapy. Inhibition of the pathway downstream from BRAF with the MEK inhibitor GDC-0973 could theoretically overcome or delay this resistance mechanism and improve outcomes."

The study was not designed to evalate efficacy. "While early data in a small number of patients did show tumor reduction, it would be premature to comment on efficacy based on these preliminary results and further research is warranted," Dr Gonzalez said.

Drug combinations show promise against metastatic melanoma