. Priority Review designation based on Phase III study showing 53% reduction in risk of recurrence or death with Tafinlar + Mekinist, as compared to placebo
?Improvements observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR)
?If approved, Tafinlar + Mekinist expected to be the first adjuvant targeted therapy combination to demonstrate a significant clinical benefit in patients with a BRAF V600 mutation
Basel, December 22, 2017 - Novartis announced today the US Food and Drug Administration (FDA) has accepted the Company's supplemental New Drug Application (sNDA) for filing, and granted Priority Review designation for Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with stage III melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, following complete resection. In October, the FDA also granted Breakthrough Therapy designation to Tafinlar in combination with Mekinist for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection.
"The FDA's decision to grant Tafinlar in combination with Mekinist Breakthrough Therapy designation and Priority Review designation validates the potential of the combination to have a significant impact on the lives of melanoma patients treated in the adjuvant setting," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "There remains a need to address the high risk of recurrence seen in these patients and improve the quality of care they receive."
Priority Review designation is based on results from COMBI-AD, a Phase III study evaluating Tafinlar + Mekinist in patients with stage III BRAF V600E/K mutation-positive melanoma after complete resection. The study met its primary endpoint by significantly reducing the risk of disease recurrence or death by 53% versus placebo (hazard ratio [HR]: 0.47 [95% confidence interval (CI): 0.39-0.58]). The combination treatment group also showed an improvement in the key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance). Other secondary endpoints where the combination demonstrated a clinically meaningful benefit include DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and FFR (HR: 0.47 [95% CI: 0.39-0.57]).
According to FDA guidelines, treatments that receive Priority Review designation are those that address a serious or life threatening disease or condition and, if approved, would provide a significant improvement in treatment safety or efficacy. If a treatment is granted Priority Review designation, the goal of the FDA is to issue a decision within six months of application submission, rather than ten months for standard review.
Tafinlar in combination with Mekinist is currently approved in the US for patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation as detected by an FDA-approved test and non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.
COMBI-AD was a randomized, double-blind, placebo-controlled, Phase III study and included a total of 870 patients with stage III, BRAF V600E/K-mutant melanoma who had undergone prior complete surgical resection, without prior anticancer therapy. Patients were treated with Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432) for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC).
The primary endpoint was relapse-free survival (RFS). Secondary endpoints included OS, DMFS, FFR and safety. Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported.
There are about 200,000 new diagnoses of melanoma (stages 0-IV) worldwide each year, approximately half of which have BRAF mutations. Biomarker tests can determine whether a tumor has a BRAF mutation,.
Melanoma is staged by how far it has metastasized. In stage III melanoma, tumors have spread to the regional lymph nodes, presenting a higher risk of recurrence or metastases. Patients who receive surgical treatment for stage III melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery; almost half (44%) of patients receiving placebo per the COMBI-AD study had a recurrence of disease within the first year,. Adjuvant therapy is additional treatment given after surgical resection, and may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning.
About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Japan, Australia, Canada and other countries.
The combination of Tafinlar + Mekinist is also approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation in the US and advanced NSCLC with a BRAF V600 mutation in the EU.
Tafinlar + Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.
The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.
Tafinlar + Mekinist are also indicated in more than 60 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Tafinlar + Mekinist Combination Important Safety Information
Tafinlar + Mekinist combination may cause serious side effects.
Tafinlar in combination with Mekinist should only be used to treat patients with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.
Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.
When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.
Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.
Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.
Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient's heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.
Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.
Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.
Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provide immediately.
Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.
Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.
Mekinist in combination with Tafinlar, or Mekinist alone, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognized risk of gastrointestinal perforation.
Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.
The most common side effects of Tafinlar + Mekinist combination include fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.
Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.
Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.
Please see full Prescribing Information for Tafinlar and Mekinist.
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking etc. etc.
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 Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf?. Accessed 2017.
 Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. British Journal of Cancer. 2013.
 Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/?. Accessed 2017.
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