FDA Approves Tafinlar + Mekinist for the Treatment of BRAF-Positive Anaplastic Thyroid Cancer

In continuation of my update on Tafinlar (dabrafenib) and Mekinist (trametinib)

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

  dabrafenib      trametinib

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” 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 approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.

Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.

Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

FDA grants approval for two drugs administered together to treat aggressive form of thyroid cancer

 In continuation of my update on dabrafenib & trametinib

     dabrafenib                 trametinib

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

"This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat," 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 approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients."

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.

Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.

Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

Novartis Receives FDA Approval of Tafinlar + Mekinist for Adjuvant Treatment of BRAF V600-Mutant Melanoma

Novartis announced that the US Food and Drug Administration (FDA) has approved Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. The FDA granted the combination Breakthrough Therapy Designation for this indication in October 2017 and Priority Review in December 2017.

"Since the initial approval of Tafinlar and Mekinist in metastatic melanoma in 2013, the combination has become an important therapy for many patients carrying a BRAF mutation in both melanoma and lung cancers," said Liz Barrett, CEO, Novartis Oncology. "Today's FDA approval is an important milestone for patients who previously had limited treatment options in the adjuvant setting, and reflects our commitment to the ongoing development of this breakthrough treatment."

The melanoma approval is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection[1]. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% as compared to placebo (HR: 0.47 [95% CI: 0.39-0.58]; p<0.0001; median not reached with combination therapy vs. 16.6 months with placebo)[1]. The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage[1]. Improvements were also observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR)[1]. These results were published in the New England Journal of Medicine, October 2017[1].

"The purpose of adjuvant therapy is to improve recurrence-free and overall survival in our patients with melanoma. Adjuvant therapy options are crucial today because more than half of patients have a recurrence after surgery," said John M. Kirkwood, M.D., Usher Professor of Medicine, Director of Melanoma and Skin Cancer, University of Pittsburgh. "We developed the first adjuvant therapy approved by the FDA 22 years ago, and now we have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes."

"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," said Sancy Leachman, M.D., Ph.D., Chair of the Department of Dermatology at OHSU School of Medicine. "With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options - a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status is crucial to our patients' care plans."

Novartis Receives FDA Approval of Tafinlar + Mekinist for Adjuvant Treatment of BRAF V600-Mutant Melanoma

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

A subset of lung tumours is exquisitely sensitive to a class of recently approved anti-cancer drugs. Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Ludwig Institute for Cancer Research in Oxford published this finding in the journal Nature Communications. It opens the way for new clinical trials in a type of cancer considered to be "undruggable" and may lead to a therapy for up to 10% of lung cancer patients.

(Vienna, 6th of December 2016) Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations - this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10% of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer.

With cutting edge high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman, CeMM Adjunct PI and Group Leader at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery: Cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications (DOI: 10.1038/NCOMMS13701)

MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to keep proliferating and leads to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer.

"Normally lung cancer cells are resistant to MEK inhibition as they activate compensatory signals," Ferran Fece, one of the two first authors on the study and former PhD student at CeMM, explains. "In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality".

  Trametinib

Michal Smida, the other shared first author on the article and former PostDoc at CeMM, adds: "We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky."

The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10% of lung adenocarcinomas - given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. 


More : http://www.nature.com/articles/ncomms13701

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

CU Cancer Center study reports 'robust antitumor activity' of TAK-733 drug in mouse models of colorectal cancer

In continuation of my update on TAK-733

A University of Colorado Cancer Center study recently published online ahead of print in the journal Oncotarget reports "robust antitumor activity" of the drug TAK-733 in cells and mouse models of colorectal cancer. In all, 42 of 54 tested cell lines were sensitive to the drug, as were 15 of 20 tumors grown on mice from patient samples. Nine of these patient-derived tumors showed regression, meaning that tumor tumors shrank in response to the drug.

"This was a large preclinical study that showed good activity for the drug and gave preliminary evidence for a potential biomarker that could predict which tumors would respond best to the drug," says Christopher Lieu, MD, investigator at the CU Cancer Center and assistant professor of medical oncology at the University of Colorado School of Medicine.

Specifically, the drug intercedes in the MAPK signaling pathway, a cascade of cellular communication that controls cell growth and survival and is frequently altered in many cancers (especially including melanoma, non-small cell lung cancer, and colorectal cancer). The drug does this by silencing an essential link in this signaling chain, namely the molecule MEK. Without activity of the MEK kinase, MAPK signaling cannot occur and instead of surviving and proliferating, cancer cells dependent on this pathway die.

A handful of successful MEK kinase inhibitors exist, including trametinib and selumetinib.

"The preclinical results for TAK-733 were fairly impressive. We had high hopes that TAK-733 could be a next-generation MEK inhibitor that might support or replace the use of current drugs," Lieu says.

The study seemed a perfect precursor to a human clinical trial of TAK-733 in colorectal cancer.

CU Cancer Center study reports 'robust antitumor activity' of TAK-733 drug in mouse models of colorectal cancer

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

New triple combination therapy shows promise in controlling advanced melanoma

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) (trametinib)  (dabrafenib)

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.

New triple combination therapy shows promise in controlling advanced melanoma

Mekinist Plus Tafinlar Approved for Late-Stage Melanoma

The U.S. Food and Drug Administration on Friday approved Mekinist for use with another drug, Tafinlar, to treat advanced melanoma that is spreading or cannot be removed by surgery.

Melanoma is the most deadly form of skin cancer, accounting for an estimated 9,480 American deaths last year, the FDA said Friday in a news release. Mekinist (trametinib) is newly approved to be used in combination with Tafinlar (dabrafenib). Both drugs were first sanctioned in May 2013 to be used by themselves to battle advanced melanoma, the agency said.

The combination therapy is newly approved for people who have certain mutations in the BRAF V600E and V600K genes, the FDA said. About half of melanoma cases have the mutated genes.

The combination therapy was clinically evaluated in 162 people. Of those treated, 78 percent had their cancer shrink or disappear for an average of 10.5 months, the agency said.

Mekinist Plus Tafinlar Approved for Late-Stage Melanoma - Drugs.com MedNews

FDA Approves Mekinist (trametinib) for Advanced Melanoma

In continuation of my update on Trametinib

 

GlaxoSmithKline plc announced today that the U.S. Food and Drug Administration (FDA) has approved Mekinist (trametinib) as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy. The mutation must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux S.A., THxID™-BRAF.

FDA Approves Mekinist (trametinib) for Advanced Melanoma

Combination of targeted treatment drugs delays resistance in melanoma patients

In continuation of my update on dabrafenib and trametinib.....

Combination of targeted treatment drugs delays resistance in melanoma patients

Kinase Inhibitor Trials Show Melanoma Benefits | News | Drug Discovery and Development Magazine

Findings from GlaxoSmithKline (GSK) plc’s Phase 3 clinical study program evaluating single agent therapy with the targeted anti-cancer agents, dabrafenib (below left structure) and trametinib (below right structure), in patients with BRAF V600 mutation positive metastatic melanoma have been released. 

Both the BREAK3 study of dabrafenib (BRAF inhibitor) and the METRIC study of trametinib (MEK inhibitor) demonstrated a statistically significant benefit in the length of time patients with BRAF V600 mutation positive advanced or metastatic melanoma lived without progression of their disease or death (Progression Free Survival or PFS) compared to those receiving chemotherapy. Additionally, patients in the METRIC study who received trametinib lived significantly longer (overall survival or OS) than those who received chemotherapy with dacarbazine. OS data are not yet mature in the BREAK3 trial.

“The results from the clinical studies of dabrafenib and trametinib presented at this meeting represent important progress towards understanding how these investigational agents could benefit patients with advanced and metastatic melanoma. Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial.” said Dr. Rafael Amado, Head of Oncology R&D for GlaxoSmithKline. “We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a Phase 3 program to further investigate the effect of the combination in this disease.”