Novartis drug Zykadia receives FDA Priority Review for first-line use in patients with ALK+ metastatic NSCLC

• Priority Review based on Phase III study results showing 16.6 month median progression-free survival in previously untreated ALK+ metastatic NSCLC patients on Zykadia vs. 8.1 months treated with chemotherapy[1]
   
• FDA also grants Breakthrough Therapy designation based on Phase III data in previously untreated ALK+ metastatic NSCLC patients with metastases to the brain
   
• If approved in the first-line setting, Zykadia will offer previously untreated ALK+ metastatic NSCLC patients a new treatment option

Basel, February 23, 2017 - Novartis today announced that the US Food and Drug Administration (FDA) accepted the Company's supplemental New Drug Application (sNDA) for filing, and granted Priority Review for the expanded use of Zykadia^® (ceritinib) as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The FDA also granted Breakthrough Therapy designation to Zykadia for the first-line treatment of patients with ALK+ metastatic NSCLC with metastases to the brain.

"We are committed to advancing our understanding of mutation-driven lung cancer, where there continues to be significant unmet need," said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. "Today's Priority Review of Zykadia for newly diagnosed patients with ALK+ metastatic NSCLC, including Breakthrough Therapy designation for those with brain metastases, brings us closer to delivering the right treatment to the right patient at the right time."

The sNDA submission for first-line use of Zykadia is based on the primary analysis of ASCEND-4, a global Phase III, randomized, open-label, multicenter clinical trial which evaluated safety and efficacy of Zykadia compared to platinum-based chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ NSCLC. The study was conducted at 134 clinical trial sites across 28 countries, and randomized across 376 patients. The study found:

• Patients treated with first-line Zykadia had a median progression-free survival (PFS) of 16.6 months (95% confidence interval [CI]: 12.6, 27.2), compared to 8.1 months (95% CI: 5.8, 11.1) for patients treated with standard first-line pemetrexed-platinum chemotherapy with pemetrexed maintenance. A 45% risk reduction in PFS was obtained in the Zykadia arm compared to the chemotherapy arm (hazard ratio [HR] = 0.55, [95% CI: 0.42, 0.73; one-sided p value <0.001])[1].
• In a pre-specified analysis of patients receiving Zykadia without brain metastases at screening, patients experienced a median PFS of 26.3 months (95% CI: 15.4, 27.7), compared with 8.3 months (95% CI: 6.0, 13.7) among patients treated with chemotherapy (HR = 0.48 [95% CI: 0.33, 0.69])[1].
• In a pre-specified analysis of patients receiving Zykadia with brain metastases at baseline, the median PFS was 10.7 months (95% CI: 8.1, 16.4) in the Zykadia group versus 6.7 months (95% CI: 4.1, 10.6) in the chemotherapy group (HR = 0.70 [95% CI: 0.44, 1.12])[1]. Intracranial overall response rate (ORR) (72.7%, [95% CI: 49.8, 89.3]) is consistent with whole body ORR (72.5% [95% CI: 65.5, 78.7]).

The most common adverse events (AEs) occurring in more than 25% of Zykadia patients were diarrhea (85% vs. 11% with chemotherapy), nausea (69% vs. 55% with chemotherapy), vomiting (66% vs. 36% with chemotherapy), ALT increase (60% vs. 22% with chemotherapy), AST increase (53% vs. 19% with chemotherapy), gamma-glutamyltransferase increase (37% vs. 10% in chemotherapy), decreased appetite (34% vs. 31% with chemotherapy), blood alkaline phosphate increase (29% vs. 5% with chemotherapy) and fatigue (29% vs. 30% with chemotherapy).

FDA grants Priority Review to applications for drugs that treat serious conditions and, if approved, would provide a significant improvement in treatment safety or efficacy[2]. For applications granted priority review, FDA is to take action within 6 months of submission instead of 10 months under standard review timelines.

Breakthrough Therapy designation is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement on at least one clinically significant endpoint over an available therapy[3]. Novartis has received 13 Breakthrough Therapy designations to date, underscoring the company's ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients. This latest designation is for the first-line treatment of patients with ALK+ NSCLC with brain metastases and is the second Breakthrough Therapy designation for Zykadia.

Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined[4], and an estimated 1.8 million new cases of lung cancer are diagnosed each year[5]. Among those patients with NSCLC, the most common type of lung cancer, 3-7% are ALK-positive[6].

Novartis' Commitment to Lung Cancer
Novartis Oncology's research into targeted therapies has helped transform treatment approaches for patients living with mutation-driven lung cancers. Patients with a mutation-driven NSCLC may be candidates for treatment with targeted therapies[7].

Zykadia was one of the first medicines to be approved following FDA Breakthrough Therapy designation. It is currently indicated for the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib. This indication was approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Zykadia was commercially available in the US less than three and a half years after the first patient entered a clinical trial.

Novartis continues its commitment to the global lung cancer community through ongoing studies of its marketed therapies as well as the exploration of investigational compounds that target genomic biomarkers in NSCLC.

About ASCEND-4
ASCEND-4 was a Phase III randomized, open-label, multicenter, global clinical trial to evaluate the safety and efficacy of Zykadia compared to standard chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ advanced NSCLC who received no prior therapy for their advanced disease. Patients received Zykadia orally at 750 mg/daily or standard pemetrexed-based platinum doublet chemotherapy per label (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for 4 cycles followed by pemetrexed maintenance.

Of 376 patients, 189 (59 with brain metastases) were randomized to Zykadia and 187 (62 with brain metastases) to chemotherapy. Approximately 60% of patients with baseline brain metastases treated with Zykadia did not have prior radiation therapy, the current standard of treatment for baseline brain metastases. Among patients randomized to the chemotherapy arm, 105 (72%) of 145 received an ALK inhibitor as their first treatment after discontinuation of chemotherapy.

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 is currently approved in over 64 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.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "Priority Review," "Breakthrough Therapy designation," "will," "committed," "brings us closer," "would," "intended," "commitment," "contingent," "ongoing," "investigational,"  or similar terms, or by express or implied discussions regarding potential new indications or labeling for Zykadia, or regarding potential future revenues from Zykadia. 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 Zykadia will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Zykadia will be commercially successful in the future. In particular, management's expectations regarding Zykadia 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; 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; 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 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 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 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] Soria JC, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomized, open-label Phase 3 study. The Lancet. 2017. 
[2] US Food and Drug Administration. Priority Review. Available at http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm. Accessed February 2, 2017.
[3] US Food and Drug Administration. Fact Sheet: Breakthrough Therapies. Available at http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed February 6, 2017.
[4] World Health Organization. Estimated number of deaths, both sexes, worldwide in 2012. World Health Organization. http://gco.iarc.fr/today/online-analysis-pie?mode=cancer&mode_populatio…
continents&population=900&sex=0&cancer=11&type=1&statistic=0&prevalence=
0&color_palette=default. Accessed on January 19, 2017.
[5] World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Lung Cancer. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung. Accessed February 2, 2017.
[6] Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome. Available at https://www.mycancergenome.org/content/disease/lung-cancer/. Accessed February 7, 2017.
[7] Riess JW, Wakelee, HA. Metastatic Non-Small Cell Lung Cancer Management: Novel Targets and Recent Clinical Advances. Clinical Advances in Hematology & Oncology. 2012; 10: 226-224.

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