Novartis receives FDA regular approval for Tafinlar® + Mekinist® to treat aggressive form of melanoma based on long-term survival data

EAST HANOVER, N.J., Nov. 20, 2015 /PRNewswire/ -- Novartis today announced that the US Food and Drug Administration (FDA) has granted regular approval for the combination of Tafinlar^® (dabrafenib) + Mekinist^® (trametinib) for the treatment of patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. This is the first targeted therapy combination demonstrating more than two years overall survival in patients with the most aggressive form of skin cancer¹.

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"We're inspired by the difference Tafinlar + Mekinist can make for patients battling such a serious disease as metastatic melanoma," said Bruno Strigini, President, Novartis Oncology. "This approval of the combination in the US allows us to communicate more broadly with the melanoma community about the role of targeted therapies, our data, the possibility to improve clinical outcomes for patients, and our commitment to develop these medicines to their fullest potential."

More than 5,000 patients have had experience with the combination use of Tafinlar + Mekinist in clinical trials and since its initial approval in 2014, the combination of Tafinlar + Mekinist has extended the lives of many patients with BRAF mutation-positive metastatic melanoma. Today's regular approval is based on survival data from two Phase III studies: COMBI-d and COMBI-v. These studies showed that Tafinlar + Mekinist demonstrated statistically significant progression-free survival (PFS) and overall survival (OS) compared with dabrafenib or vemurafenib, in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma^2,3.

The FDA granted priority review in July 2015 for approval of the Tafinlar + Mekinist combination in BRAF V600E/K mutation-positive unresectable or metastatic melanoma. Since January 2014, the combination of Tafinlar + Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was initially approved based on Phase II data through the FDA's Accelerated Approval program and reviewed under a priority review designation. The approval was contingent on the results of the Phase III COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.

Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates^1,4. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease¹. There are about 200,000 new cases of melanoma diagnosed worldwide each year⁵, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma¹. Gene tests can determine whether a tumor has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment¹.

About the COMBI-d and COMBI-v Studies   

COMBI-d is a pivotal Phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK1/2 inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients at investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed progression-free survival. Secondary endpoints included overall survival, overall response rate (ORR), duration of response (DoR), and safety. There was no crossover between treatment arms². Updated results from the COMBI-d study showed that the combination of Tafinlar + Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95% CI, 0.55-0.92], p=0.01). The analysis for the combination also showed median PFS of 9.3 months compared to 8.8 months for those who received Tafinlar only; HR 0.75 [95% CI, 0.57-0.99, p=0.035].  ORR was 66% [95% CI, 60, 73] compared to 51% [95% CI, 44, 58] for those in the Tafinlar + Mekinist group and the Tafinlar only group, respectively. Median DoR was 9.2 months [95% CI, 7.4, not reached] compared to 10.2 months [95% CI, 7.5, not reached] for those receiving the combination of Tafinlar + Mekinist compared to those who received Tafinlar only, respectively.

COMBI-v is a two-arm, open-label, Phase III study comparing the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS³. The Independent Data Monitoring Committee (IDMC) stopped the trial early based on efficacy results observed in the Tafinlar + Mekinist study arm as part of a planned interim analysis. Results from the COMBI-v study showed that the combination of Tafinlar + Mekinist significantly improved OS compared to vemurafenib monotherapy. At the time the data were submitted to the FDA for approval, median OS had not yet been reached in the combination therapy arm and was 17.2 months in the vemurafenib arm. Median PFS was 11.4 months vs 7.3 months for the Tafinlar + Mekinist arm compared to the vemurafenib arm; HR 0.56 [95% CI, 0.46-0.69, p<0.001]. ORR was 64% [95% CI, 59, 69] in the Tafinlar + Mekinist arm and 51% in the vemurafenib arm [95% CI, 46, 56] and median DoR was 13.8 months for the Tafinlar + Mekinist combination [95% CI, 11.0 to not reached] and 7.5 months in the vemurafenib arm [95% CI, 7.3 to 9.3].

Pooled safety data from the COMBI-d and COMBI-v trials show the most common adverse events reported with Tafinlar + Mekinist (greater than or equal to 20%) were pyrexia, nausea, rash, chills, diarrhea, headache, vomiting, hypertension, joint pain (arthralgia), peripheral edema, and cough. The most common Grade 3/4 adverse reactions (greater than or equal to 2%) were hypertension, pyrexia, and hemorrhage. In COMBI-d, 11% of patients receiving the combination discontinued the combination due to an adverse reaction.

About Tafinlar + Mekinist Combination 

Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600E/K mutation is approved in the US. In addition, combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the EU, Australia, Canada and additional countries.

Tafinlar and 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.

In 2015, as part of its purchase of oncology products from GlaxoSmithKline, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco Inc. (JT) to develop, manufacture, and commercialize trametinib. JT retains co-promotion rights in Japan.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside the approved indication.

Tafinlar and Mekinist are also indicated in more than 35 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 for Metastatic Melanoma

Tafinlar + Mekinist combination may cause serious side effects, such as the risk of new cancers including both skin cancer and non-skin cancer. Patients should be advised to contact their doctor 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, and 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," or have red or black stools that look like tar.

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 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 can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare 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 healthcare 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 more 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 healthcare provider right away if they get a fever.

Rash is a common side effect of Tafinlar in combination with Mekinist. Tafinlar in combination with Mekinist can also cause other skin reactions. In some cases these rashes and other skin reactions 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.

Some people may develop high blood sugar or worsening diabetes during treatment with Tafinlar in combination with Mekinist. For patients who are diabetic, their healthcare 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 healthcare provider if they have increased thirst, urinating more often than normal, or urinating an increased amount of urine.

Tafinlar in combination with Mekinist may cause healthy red blood cells to break down too early in people with G6PD 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 healthcare 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 healthcare provider if they develop high blood pressure, their blood pressure worsens, or if they have severe headache, lightheadedness, or dizziness.

The most common side effects of Tafinlar in combination with Mekinist include nausea, chills, diarrhea, vomiting, high blood pressure (hypertension), swelling of the face, arms, or legs, thickening of the outer layers of skin, headache, joint aches, cough, warts, hair loss, or redness, swelling, peeling, or tenderness of hands or feet.

Please see full prescribing information for Tafinlar and Mekinist at http://www.pharma.us.novartis.com/product/pi/pdf/tafinlar.pdf and http://www.pharma.us.novartis.com/product/pi/pdf/mekinist.pdf.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by words such as "inspired," "can," "possibility," "commitment," "potential," "contingent," "will," "priority review," "being investigated," "ongoing," "yet," or similar terms, or by express or implied discussions regarding potential marketing approvals or new indications or labeling for Tafinlar and Mekinist, either in combination or as single agents, or regarding potential future revenues from Tafinlar and Mekinist, either in combination or as single agents. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management 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 Tafinlar and Mekinist, either in combination or as single agents, will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Tafinlar and Mekinist, either in combination or as single agents, will be submitted or approved for sale in any additional markets, or at any particular time. Nor can there be any guarantee that Tafinlar and Mekinist, either in combination or as single agents, will be commercially successful in the future. In particular, management's expectations regarding Tafinlar and Mekinist, in combination and as single agents, could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected safety issues; unexpected manufacturing or quality issues, 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

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets innovative medicines aimed at improving patients' lives. We offer a broad range of medicines for cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, neurological disease, organ transplantation, psychiatric disease, respiratory disease and skin conditions. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, 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, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 120,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed November 2, 2015.
2. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial [published online May 30, 2015]. Lancet. 2015.
3. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
4. A Snapshot of Melanoma. National Cancer Institute. Available at: http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed November 2, 2015.
5. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. Available at: http://globocan.iarc.fr/. Accessed November 2, 2015.

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