Novartis AG Pivotal Data For Tafinlar + Mekinist Demonstrated A 63 Percent Overall Response Rate In Treating Rare Form Of Lung Cancer

EAST HANOVER, N.J., June 6, 2016 /PRNewswire/ -- Novartis today announced new data for multiple investigational and established non-small cell lung cancer (NSCLC) treatments, including results from a pivotal, Phase II study of Tafinlar^® (dabrafenib) in combination with Mekinist^® (trametinib) in patients with BRAF V600E-mutation positive (BRAF V600E+) NSCLC. In the study, patients treated with Tafinlar + Mekinist demonstrated an overall response rate (ORR) of 63% (95% CI, 49%-76%)¹. Data were presented during an oral session at the 52^nd Annual Meeting of the American Society of Clinical Oncology (ASCO) and also published simultaneously in TheLancet Oncology.

“This study confirms a fourth actionable biomarker in NSCLC BRAFV600E after EGFR, ALK and ROS-1,” said David Planchard, MD, PhD, Thoracic Oncology Specialist, Cancer Institute Gustave-Roussy, Villejuif, France and trial’s principal investigator. “The potential to treat this oncogene gives hope to a very small, underserved patient population.”

One-to-two percent (1-2%) of patients with NSCLC have a BRAF V600E mutation², which is associated with more aggressive tumors and a poorer prognosis, independent of smoking status³.

In this Phase II, multicenter, non-randomized, open-label study (NCT01336634), 57 patients with metastatic NSCLC who had the BRAF V600E mutation and failed at least one line of chemotherapy took 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily. The primary endpoint of the trial was investigator-assessed ORR, and key secondary endpoints were Duration of Response (DoR) and Progression-Free Survival (PFS). Independent review response rates were consistent with investigator-assessed response¹.

The investigator-assessed median DoR and PFS were 9.0 months (95% CI, 6.9 to 18.3) and 9.7 months (95% CI, 6.9 to 19.6), respectively. Thirty-six of 57 patients (63%) demonstrated a clinical response; of these patients, 50% (18 of 36) continued to respond to treatment at the time of analysis. The most common adverse events (incidence >20%) were pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, dry skin, chills, peripheral edema, cough and rash¹. Four patients (7%) died from fatal adverse events not related to study treatment as assessed by the investigator¹.

“Lung cancer is the number one cause of cancer death world-wide, and more than half of NSCLC patients’ tumors occur as a result of a genetic mutation,” said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. “Novartis is fully committed to bringing forth new, targeted options for NSCLC patients, many of whom remain underserved by today’s available therapies.”

Additional Novartis NSCLC Data at ASCO
Novartis presented several additional key pieces of data for INC280 (capmatinib) as well as one poster for Zykadia (ceritinib).

The INC280 (capmatinib) data, from a Phase I, single agent study (NCT01324479) in patients with advanced cMET+ NSCLC and a Phase Ib/II combination study (NCT01610336) with gefitinib in patients with EGFR-mutated, cMET+ NSCLC, demonstrated encouraging early signs of clinical activity^4,5. Based on these data, Novartis initiated ongoing Phase II studies to prospectively explore the predictive value of different mechanisms of cMET dysregulation (including cMET amplification and cMETex14 mutation) in advanced NSCLC. INC280 is a potent and selective, oral cMET inhibitor licensed by Novartis from Incyte Corporation.

Separately, a planned exploratory analysis from the Phase I, global, multicenter, open-label, single-arm ASCEND-1 trial (NCT01283516) reviewed genetic biomarkers of study participants to better understand determinants of response to Zykadia⁶.

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. Because of the uncertainty of clinical trials, there is no guarantee that the combination will become commercially available with additional indications.

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.

About Zykadia
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal “fusion protein” that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC). Zykadia was granted conditional approval in the EU for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib. In the US, Zykadia was granted accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Zykadia is currently approved in over 50 countries worldwide. Please visit www.NovartisOncology.com/news/product-portfolio/zykadia for additional information.

Zykadia Important Safety Information
Zykadia may cause serious side effects.

Zykadia may cause stomach upset and intestinal problems in most patients, including diarrhea, nausea, vomiting and stomach-area pain. These problems can be severe. Patients should follow their doctor’s instructions about taking medicines to help these symptoms, and should call their doctor for advice if symptoms are severe or do not go away.

Zykadia may cause severe liver injury. Patients should have blood tests prior to the start of treatment with Zykadia, every two weeks for the first month of treatment and monthly thereafter, and should talk to their doctor right away if they experience any of the following symptoms: tiredness (fatigue), itchy skin, yellowing of the skin or the whites of the eyes, nausea or vomiting, decreased appetite, pain on the right side of the abdomen, urine turns dark or brown, or bleeding or bruising more easily than normal.

Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Patients should tell their doctor right away about any new or worsening symptoms, including trouble breathing or shortness of breath, fever, cough, with or without mucous, or chest pain.

Zykadia may cause very slow, very fast, or abnormal heartbeats. Doctors should check their patient’s heart during treatment with Zykadia. Patients should tell their doctor right away if they feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats, blue discoloration of lips, shortness of breath, swelling of lower limbs or skin, or if they start to take or have any changes in heart or blood pressure medicines.

Zykadia may cause high levels of glucose in the blood. People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Patients should have glucose blood tests prior to the start of treatment with Zykadia and during treatment. Patients should follow their doctor’s instructions about blood sugar monitoring and call their doctor right away with any symptoms of high blood sugar, including increased thirst and/or urinating often.

Zykadia may cause high levels of pancreatic enzymes in the blood and may cause pancreatitis. Patients should have blood tests prior to the start of treatment with Zykadia and as needed during their treatment with Zykadia. Patients should talk to their doctor if they experience signs and symptoms of pancreatitis which including upper abdominal pain that may spread to the back and get worse with eating.

Before patients take Zykadia, they should tell their doctor about all medical conditions, including liver problems; diabetes or high blood sugar; heart problems, including a condition called long QT syndrome; if they are pregnant, if they think they may be pregnant, or if they plan to become pregnant; are breastfeeding or plan to breastfeed.

Zykadia may harm unborn babies. Women who are able to become pregnant must use a highly effective method of birth control (contraception) during treatment with Zykadia and up to 3 months after stopping Zykadia. It is not known if Zykadia passes into breast milk. Patients and their doctor should decide whether to take Zykadia or breastfeed, but should not do both.

Patients should tell their doctor about medicines they take, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements. If they take Zykadia while using oral contraceptives, the oral contraceptives may become ineffective.

The most common adverse reactions with an incidence of 10% were diarrhea, nausea, vomiting, tiredness (fatigue), liver laboratory test abnormalities (requires blood test monitoring), abdominal pain, decreased appetite, constipation, rash, kidney laboratory test abnormalities (requires blood test monitoring), heartburn and anemia. Grade 3-4 adverse reactions with an incidence of 5% were liver laboratory test abnormalities, tiredness (fatigue), diarrhea, nausea and hyperglycemia (requires blood test monitoring).

Patients should stop taking Zykadia and seek medical help immediately if they experience any of the following, which may be signs of an allergic reaction:

• Difficulty in breathing or swallowing
• Swelling of the face, lips, tongue or throat
• Severe itching of the skin, with a red rash or raised bumps

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 Zykadia. For more information, patients should ask their doctor or pharmacist.

Patients should take Zykadia exactly as their health care provider tells them. Patients should not change their dose or stop taking Zykadia unless their health care provider advises them to. Zykadia should be taken once a day on an empty stomach. Patients should not eat for at least 2 hours before and 2 hours after taking Zykadia. If a dose of Zykadia is missed, they should take it as soon as they remember. If their next dose is due within the next 12 hours, they should skip the missed dose and take the next dose at their regular time. They should not take a double dose to make up for a forgotten dose. Patients should not drink grapefruit juice or eat grapefruit during treatment with Zykadia, as it may make the amount of Zykadia in their blood increase to a harmful level. If patients have to vomit after swallowing Zykadia capsules, they should not take more capsules until their next scheduled dose.

Please see full Prescribing Information for Zykadia.

About INC280
INC280 (capmatinib) is an investigational, highly selective cMET inhibitor currently in Phase II clinical development. Efficacy and safety have not been established. There is no guarantee that INC280 will become commercially available. INC280 is licensed by Novartis from Incyte Corporation.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as “growing,” “commitment,” “investigational,” “actionable,” “potential,” “hope,” “committed,” “encouraging,” “initiated,” “ongoing,” “prospectively,” “planned,” “exploratory,” “being investigated,” “yet,” “may,” “can,” “currently,” “will,” 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 for Zykadia, regarding potential marketing approvals for INC280, or regarding potential future revenues from Tafinlar and Mekinist, either in combination or as single agents, Zykadia and INC280. 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, or Zykadia, 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, or Zykadia, will be submitted or approved for sale in any additional markets, or at any particular time. Nor can there be any guarantee that INC280 will be submitted or approved for sale in any market, or at any particular time. Neither can there be any guarantee that any of Tafinlar and Mekinist, either in combination or as single agents, Zykadia and INC280 will be commercially successful in the future. In particular, management’s expectations regarding such products and the investigational compound INC280 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, 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 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. Planchard, D. et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600Emutant advanced non-small cell lung cancer. Abstract #107. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.
2. Chen D. et al. BRAF Mutations in Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. PLOS One 2014; 9:6, 1-7.
3. Marchetti A. et al. Clinical Features and Outcome of Patients with NonSmall-Cell Lung Cancer Harboring BRAF Mutations. Journal of Clinical Oncology 2011; 29:26, 3574-3579.
4. Schuler, M. et al. Phase I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET+ non-small cell lung cancer (NSCLC). Abstract #9067. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.
5. Wu, Y. et al. Phase II safety and efficacy results of a single-arm Ph Ib/II study of capmatinib (INC280) + gefitinib in patients with EGFR-mutated (mut), cMET-positive (cMET+) non-small cell lung cancer (NSCLC). Abstract #9020. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.
6. Tan, D. et al. Genetic landscape of ALK+ non-small cell lung cancer (NSCLC) patients and response to ceritinib in ASCEND-1. Abstract #9064. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.

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