Novartis combination therapy Tafinlar® + Mekinist® demonstrates overall survival benefit at three-year follow-up in patients with advanced melanoma

EAST HANOVER, N.J., June 6, 2016 /PRNewswire/ -- Novartis today announced data from a Phase III study showing a significant survival benefit for patients with BRAF V600E/K mutation-positive advanced melanoma when treated with the first-line combination of Tafinlar^® (dabrafenib) + Mekinist^® (trametinib) compared to Tafinlar monotherapy¹. The results from the COMBI-d three-year follow-up analysis represent one of the longest survival follow-up studies to date with BRAF mutation-positive advanced melanoma patients. Results are being presented today at the 52^nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

"BRAF mutation remains the critical genetic feature in advanced melanoma that guides patients' treatment options," said Keith T. Flaherty, MD, Director of the Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "These results confirm that long-term survival can be achieved with this combination and it should be an important consideration for patients with BRAF mutation-positive advanced melanoma. It is particularly striking to note the excellent outcome for those with lower burden of disease at baseline."

Results from the COMBI-d study of 423 patients found the estimated three-year survival rate to be 44% for patients receiving the combination of Tafinlar + Mekinist (95% CI, 36.4%-50.5%) compared with 32% who received Tafinlar alone (95% CI, 25.4%-38.3%)¹. There were 26 patients who crossed over from the monotherapy arm to the combination arm after the combination demonstrated a significant overall survival (OS) benefit in a prior analysis¹. Additionally, the estimated three-year progression-free survival rate was 22% (95% CI, 16.2%-28.0%) for the combination arm and 12% (95% CI, 7.1%-18.0%) for the monotherapy arm¹. In an analysis of patients with normal lactate dehydrogenase (LDH) levels and fewer than three disease sites, the three-year survival rate for combination was 62% (95% CI, 49.3%-72.0%) compared with 45% who received Tafinlar alone (95% CI, 34.9%-55.1%)¹. In advanced melanoma, a patient's LDH level is often predictive of prognosis and may be a predictor of treatment response².

The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed¹. The most common adverse events (>20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, vomiting, joint pain (arthralgia), hypertension, cough and peripheral edema¹.

"Novartis is committed to improving outcomes for advanced melanoma patients, and we are gratified to see that these data show that we are extending the lives of many patients receiving therapy with Tafinlar + Mekinist," said Alessandro Riva, MD, Global Head, Oncology Development & Medical Affairs. "This data is also a strong example of the importance of rationally combining targeted therapies and identifying those patients who are likely to benefit from our medicines beyond three years. This type of treatment approach is not only helping to grow the practice of precision oncology, but has the potential to fundamentally change the way we treat cancer."

About the COMBI-d Study
COMBI-d is a pivotal Phase III randomized, double-blinded study (NCT01584648) comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo as first-line therapy in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients from investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety. There were 26 patients who crossed over from the monotherapy group to the combination group after the combination demonstrated a significant OS benefit in a prior analysis¹.

At three years of follow up, the combination of Tafinlar + Mekinist continued to demonstrate a benefit on the measures of DoR and ORR, in line with results seen at the two-year follow up analysis¹. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed¹.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates^3,4. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease³. 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 melanoma^3,6. Gene tests can determine whether a tumor has a BRAF mutation^3,7.

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.

Important Safety Information for Tafinlar + Mekinist Combination 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 "can," "committed," "helping to grow," "potential," "will," "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, quality or manufacturing 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, NJ 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 2015, the Group achieved net sales of USD 49.4 billion, while R&D throughout the Group amounted to approximately USD 8.9 billion (USD 8.7 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 118,000 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.     Flaherty, K.T. Genomic Analysis and 3-Year Efficacy and Safety Update of COMBI-d, a phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Abstract #9502. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.
2.     Palmer SR, Erickson LA, Ichetovkin I, et al. Circulating Serologic and Molecular Biomarkers in Malignant Melanoma. Mayo Clinic Proceedings. 2011; 86(10):981-990.
3.     Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed May 31, 2016.
4.     A Snapshot of Melanoma. National Cancer Institute. Available at: http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed May 31, 2016.
5.     GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed May 31, 2016.
6.     Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R metastatic melanoma. Eur J Cancer. 2013; 49(5):1073-1079.
7.     Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. British Journal of Cancer. 2013.

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