Novartis Tafinlar® (dabrafenib) + Mekinist® (trametinib) demonstrates unprecedented efficacy in pediatric patients with BRAF V600 low-grade gliomas in Phase II/III study

• Treatment with targeted therapies Tafinlar + Mekinist resulted in 47% ORR versus chemotherapy (11%) and reduced risk of progression or death by 69%, showing significant efficacy improvement in patients ages 1 to 17 years old with BRAF V600 low-grade gliomas (LGG) requiring first systemic treatment¹ 
• If approved, Tafinlar + Mekinist may offer a potential new standard-of-care for pediatric patients with this brain cancer who are in need of a more efficacious and convenient option that can be administered orally and may also improve quality of life¹ 
• Results add to body of evidence demonstrating efficacy and safety of Tafinlar + Mekinist across multiple BRAF V600 solid tumors 
• Data highlighted as part of ASCO official press briefing and will form basis of upcoming regulatory submissions 

EAST HANOVER, N.J., June 6, 2022 /PRNewswire/ -- Novartis today announced Tafinlar^® (dabrafenib) + Mekinist^® (trametinib) significantly improved efficacy in patients ages 1 to 17 years old with BRAF V600 pediatric low-grade glioma (pLGG) requiring first systemic treatment compared to chemotherapy, the current standard-of-care for these patients¹. In this study, patients randomized to receive Tafinlar + Mekinist experienced a statistically significant overall response rate (ORR) of 47% (CI: 35-59%) compared to 11% (CI: 3-25%, p<0.001) for those randomized to receive chemotherapy. A new liquid formulation of Tafinlar + Mekinist that can be easier to administer than chemotherapy was used in this trial. The data will be highlighted today as part of an official press briefing and oral presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA2002). 

"These results show dabrafenib and trametinib demonstrate an improvement over chemotherapy for children and adolescents with BRAF V600 low-grade gliomas," said Eric Bouffet, MD, FRCPC, Senior Associate Scientist Emeritus at The Hospital for Sick Children (SickKids) in Toronto, Canada. "This work highlights the importance of testing for mutations like BRAF in patients with low-grade gliomas." 

LGG is the most common pediatric brain cancer and BRAF V600 mutations are present in 15-20% of pLGGs^2,5. Currently, standard chemotherapy is associated with poor outcomes and a high burden of care⁶. 

Additional results from the Phase II/III trial showed at a median follow-up of 18.9 months, median progression-free survival (PFS) was 20.1 months with Tafinlar + Mekinist (CI: 12.8 months-not estimable) compared to 7.4 months with chemotherapy (CI: 3.6-11.8 months, hazard ratio=0.31 [CI: 0.17-0.55] [p<0.001])¹. Additionally, tumors shrank or remained stable in 86% of patients in the Tafinlar + Mekinist arm (n=73; CI: 76-93%) compared to 46% of patients in the chemotherapy arm (n=37; CI: 30-63%). After one year of follow-up, nearly all patients on Tafinlar + Mekinist (89%) had a reduction in tumor size compared with baseline versus 70% of patients in the chemotherapy arm. Results from a quality-of-life analysis favored Tafinlar + Mekinist compared to chemotherapy at all time points¹. 

"These young patients and their families experience a heavy burden of care as BRAF V600 low-grade glioma poses a risk of neurological impairment and current standard-of-care treatment is intravenous and associated with frequent trips to the cancer clinic or hospital," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development at Novartis. "Tafinlar + Mekinist has shown unprecedented efficacy, and we will work with health authorities to bring these children the possibility of a more effective and easier to administer liquid oral treatment option as quickly as possible."  

The safety profile of Tafinlar + Mekinist was generally consistent with established safety observed in previous studies. Patients in the Tafinlar + Mekinist arm had fewer grade 3 or higher adverse events (AEs; 47% vs 94%) and fewer discontinuations due to AEs (4% vs 18%) than patients in the chemotherapy arm evaluated for safety (n=33)¹. The most frequent AEs in the Tafinlar + Mekinist arm were pyrexia, headache and vomiting¹.  

In a separate single-arm cohort of this study evaluating pediatric patients with relapsed or refractory BRAF V600 high-grade gliomas (HGG), treatment with Tafinlar + Mekinist showed an independently assessed ORR of 56.1% [CI: 39.7%-71.5%] and generally consistent safety results⁴. These data were presented in a poster discussion at the 2022 ASCO Annual Meeting (Abstract #2009). 

Tafinlar + Mekinist was granted Breakthrough Therapy designation by the US Food and Drug Administration for the treatment of pediatric patients one year of age and older with LGG with a BRAF V600E mutation who require systemic therapy.  

This global Phase II/III, multicenter, open-label trial is evaluating patients aged 1 to 17 with BRAF V600 LGG (n=110) or relapsed or refractory HGG (n=41)¹. Tafinlar + Mekinist is administered orally either as new liquid formulations, or as capsules and tablets, respectively. The primary endpoint in both cohorts is overall response rate. Secondary outcome measures include duration of response, progression-free survival, overall survival and other endpoints¹. 

Gliomas are the most common pediatric central nervous system tumor type, representing about half of all pediatric brain cancers^5,7,8. Gliomas are classified as either low-grade (grades 1 and 2) or high-grade (grades 3 and 4)⁷.  

Pediatric low-grade gliomas positive for the BRAF V600E mutation have been associated with worse survival outcomes (OS/PFS) and are found in approximately 15-20% of pLGG^2,3. BRAF mutations are found in approximately 3% to 7% of people with HGG (all ages combined)^9,10.  

BRAF mutations have been identified as drivers of cancer growth across a wide range of solid tumors and often have limited treatment options^11,12. 

The combination of Tafinlar + Mekinist, the worldwide targeted therapy leader in BRAF/MEK-inhibition research and patients reached, may help to slow tumor growth by blocking signals associated with the BRAF and MEK kinases, which are implicated in the growth of various types of cancer^11-15. Tafinlar + Mekinist has been studied in more than 6,000 BRAF-positive patients in more than 20 ongoing and completed trials and has been prescribed to more than 200,000 patients worldwide¹⁵. 

Tafinlar + Mekinist is currently not approved for pediatric patients with LGG or HGG. These results will form the basis of regulatory discussions with global health authorities.  

TAFINLAR and MEKINIST are prescription medicines that can be used in combination to treat people with a type of skin cancer called melanoma: 

• that has spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable), and 
• that has a certain type of abnormal "BRAF" (V600E or V600K mutation-positive) gene 

TAFINLAR and MEKINIST are prescription medicines that can be used in combination to help prevent melanoma that has a certain type of abnormal "BRAF" gene from coming back after the cancer has been removed by surgery. 

TAFINLAR and MEKINIST are prescription medications that can be used in combination to treat a type of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic NSCLC), and that has a certain type of abnormal "BRAF V600E" gene. 

TAFINLAR and MEKINIST are prescription medications that can be used in combination to treat a type of thyroid cancer called anaplastic thyroid cancer (ATC): 

• that has spread to other parts of the body and you have no satisfactory treatment options and 
• that has a certain type of abnormal "BRAF" gene 

TAFINLAR, in combination with MEKINIST, should not be used to treat people with wild-type BRAF melanoma. MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma and it did not work or is no longer working. 

TAFINLAR, in combination with MEKINIST, should not be used to treat people with wild-type BRAF NSCLC. 

TAFINLAR should not be used to treat people with wild-type BRAF melanoma or NSCLC. MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma and it did not work or is no longer working. 

TAFINLAR should not be used to treat people with wild-type BRAF melanoma, NSCLC, or ATC. MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma and it did not work or is no longer working. 

Your health care provider will perform a test to make sure that TAFINLAR and MEKINIST, in combination, are right for you. 

It is not known if TAFINLAR and MEKINIST are safe and effective in children. 

TAFINLAR and MEKINIST, in combination, may cause serious side effects such as the risk of new cancers, including both skin cancer and nonskin cancer. Patients should be advised to contact their health care provider immediately for any skin changes, including a new wart, skin sore, or bump that bleeds or does not heal, or a change in the size or color of a mole. 

When TAFINLAR is used in combination with MEKINIST, it can cause serious bleeding problems, especially in the brain or stomach, that can lead to death. Patients should be advised to call their health care provider and get medical help right away if they have any signs of bleeding, including headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," or red or black stools that look like tar. 

MEKINIST, alone or in combination with TAFINLAR, can cause inflammation of the intestines or tears in the stomach or intestines that can lead to death. Patients should report to their health care provider immediately if they have any of the following symptoms: bleeding, diarrhea (loose stools) or more bowel movements than usual, stomach-area (abdomen) pain or tenderness, fever, or nausea. 

TAFINLAR, in combination with MEKINIST, 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. 

The combination of TAFINLAR and MEKINIST can cause heart problems, including heart failure. A patient's heart function should be checked before and during treatment. Patients should be advised to call their health care 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, can cause severe eye problems that can lead to blindness. Patients should be advised to call their health care provider right away if they get: 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, can cause lung or breathing problems. Patients should be advised to tell their health care provider if they have new or worsening symptoms of lung or breathing problems, including shortness of breath or cough. 

Fever is common during treatment with TAFINLAR in combination with MEKINIST, but may also be serious. 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 health care provider right away if they get a fever.  

Rash and other skin reactions are common side effects of TAFINLAR in combination with MEKINIST. In some cases, these rashes and other skin reactions can be severe or serious, may need to be treated in a hospital, or lead to death. Patients should be advised to call their health care provider if they get any of the following symptoms: blisters or peeling of skin, mouth sores, blisters on the lips or around the mouth or eyes, high fever or flu-like symptoms, and/or enlarged lymph nodes.  

Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR in combination with MEKINIST. For patients who are diabetic, their health care provider should check their blood sugar levels closely during treatment. Their diabetes medicine may need to be changed. Patients should be advised to tell their health care provider if they have increased thirst, urinate more often than normal, or produce an increased amount of urine. 

TAFINLAR may cause healthy red blood cells to break down too early in people with glucose-6-phosphate dehydrogenase deficiency. This may lead to a type of anemia called hemolytic anemia, where the body does not have enough healthy red blood cells. Patients should be advised to tell their health care provider if they have yellow skin (jaundice), weakness or dizziness, or shortness of breath. 

TAFINLAR, in combination with MEKINIST, can cause new or worsening high blood pressure (hypertension). A patient's blood pressure should be checked during treatment. Patients should be advised to tell their health care provider if they develop high blood pressure, their blood pressure worsens, or if they have severe headache, lightheadedness, blurry vision, or dizziness. 

Men (including those who have had a vasectomy) should use condoms during sexual intercourse during treatment with TAFINLAR and MEKINIST and for at least 4 months after the last dose of TAFINLAR and MEKINIST. For women of reproductive potential, TAFINLAR and MEKINIST, in combination, may harm your unborn baby. Use effective birth control (contraception) during treatment with TAFINLAR and MEKINIST in combination, and for 4 months after stopping treatment with TAFINLAR and MEKINIST. The most common side effects for patients with metastatic melanoma are: pyrexia, nausea, rash, chills, diarrhea, headache, vomiting, hypertension, arthralgia, peripheral edema, and cough. The most common side effects for patients with stage III melanoma receiving the combination as adjuvant therapy are: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. The most common side effects for patients with NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. 

Please see full Prescribing Information for TAFINLAR at https://www.novartis.us/sites/www.novartis.us/files/tafinlar.pdf
and MEKINIST at https://www.novartis.us/sites/www.novartis.us/files/mekinist.pdf.

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Located in East Hanover, NJ Novartis Pharmaceuticals Corporation – an affiliate of Novartis – is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis employs nearly 15,000 people in the United States. For more information, please visit https://www.novartis.us.

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5. Ostrom QT, et al. Neuro Oncol. 2021;23(12 suppl 2):iii1-iii105 
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13. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 
14. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 
15. Data on file. 

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