Novartis receives FDA approval of Tafinlar® + Mekinist® for adjuvant treatment of BRAF V600-mutant melanoma

EAST HANOVER, N.J., April 30, 2018 /PRNewswire/ -- Novartis announced today 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 mutation, 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 resection¹. 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-stage¹. 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 2017¹.

"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."

Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported¹. Of patients treated with the combination, 97% experienced an AE, 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo)¹.

About COMBI-AD
The COMBI-AD study is 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 for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC, based on American Joint Committee on Cancer Melanoma of the Skin staging, 7^th edition).

The primary endpoint was RFS. Secondary endpoints included OS, DMFS, FFR and safety.

AEs were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported¹.

About Melanoma
There are nearly 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^2,3.

Some patients who receive surgical treatment for 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^1,4. 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 returning⁴.

About Tafinlar and Mekinist
In the EU, Tafinlar in combination with Mekinist is approved for the treatment of patients with a BRAF V600 mutation in metastatic melanoma and non-small cell lung cancer (NSCLC).

In the US, Tafinlar in combination with Mekinist is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as detected by an FDA-approved test, and for the adjuvant treatment of melanoma with BRAF V600E or K mutations and involvement of lymph node(s) following complete resection. Tafinlar + Mekinist is also approved for BRAF V600E mutation-positive NSCLC.

Tafinlar and 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.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of Tafinlar and Mekinist have not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that Tafinlar and Mekinist will become commercially available for additional indications anywhere else in the world.

Tafinlar + Mekinist Combination Important Safety Information
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 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, and may need to be treated in a hospital. Patients should be advised to call their health care 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, or skin redness.

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, in combination with MEKINIST, 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.

The most common side effects of TAFINLAR, in combination with MEKINIST, include fever, rash, nausea, fatigue, headache, chills, diarrhea, vomiting, high blood pressure (hypertension), joint aches, muscle aches, swelling of the face, arms, or legs, and cough.

Please see full Prescribing Information for TAFINLAR and MEKINIST at https://www.hcp.novartis.com/products/tafinlar-mekinist/.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Located in East Hanover, NJ Novartis Pharmaceuticals Corporation is an affiliate of Novartis which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 124,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib Plus Trametinib for Stage III BRAF V600E/K–Mutant Melanoma. New England Journal of Medicine. 2017; 377:1813-182. DOI: 10.1056/NEJMoa1708539.
2. Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed April 2018.
3. Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. British Journal of Cancer. 2013; 108 (10): 2164–2171. DOI:  10.1038/bjc.2013.143.
4. Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/. Accessed April 2018.

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