Novartis ALK+ metastatic NSCLC therapy Zykadia® extends progression-free survival beyond 18 months in Phase II study

• Progression-free survival (PFS) in ALKi-naïve patients is consistent with results previously reported from Phase I ASCEND-1 study
• Phase II study also showed overall response rate of 63.3% in ALKi-naïve patients with brain metastases at baseline, per blinded independent review committee
• Novartis' dedication to exploring Zykadia's efficacy in ALK+ NSCLC patients continues to grow, with first-line data from Phase III study expected in Q4 2016

Basel, October 9, 2016 - Novartis today announced updated results from a Phase II study (ASCEND-3), which demonstrated that anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients taking Zykadia^® (ceritinib) as their first ALK inhibitor (post-chemotherapy) had a median progression-free survival (PFS) of 18.4 months [95% CI: 10.9-26.3; median follow-up time of 25.9 months, as measured by blinded independent review committee (BIRC)][1]^.Results were presented during an oral session at the Annual European Society for Medical Oncology Congress (ESMO) in Copenhagen.

These results are consistent with findings from the Phase I ASCEND-1 study, which demonstrated a median PFS of 18.4 months (95% CI: 15.2-not reached) as per BIRC assessment with a median follow-up of 11.1 months[2]. The previous analysis by BIRC in ASCEND-3 indicated that the median PFS had not been reached after a median follow-up time of 8.3 months[3]. 

Further, in a sub-analysis of these data, patients who entered the study with brain metastases at baseline experienced an overall response rate (ORR) of 63.3% (95% CI: 48.3-76.6) and a disease control rate (DCR) of 83.7% (95% CI: 70.3-92.7), both as measured by BIRC. These results were similar to those in patients without brain metastases, who demonstrated an ORR of 64.0% (95% CI: 52.1-74.8) and DCR of 88.0% (95% CI: 78.4-94.4), based on BIRC assessment[1].

"The unfortunate reality of ALK+ NSCLC is that advancement is needed to delay disease progression in these patients," said lead investigator Dr. Enriqueta Felip, Head of the Thoracic Tumors Group, Vall d'Hebron University Hospital. "These data, coupled with a compelling response in the sub-analysis of patients with baseline brain metastases, provide greater evidence of Zykadia's potential efficacy in the ALKi-naïve population."

At the time of analysis, the estimated 18-month overall survival (OS) rate was 73.4% (95% CI: 64.6-80.4). This population also demonstrated an ORR of 63.7% (95% CI: 54.6-72.2) and median duration of response of 23.9 months (95% CI: 16.6-not estimable), according to BIRC assessment. A decrease in tumor burden from baseline was shown in 94.7% patients (investigator assessment only, no BIRC assessment available)[1].

"Novartis is committed to extending lives of patients with difficult-to-treat forms of cancer, and these data presented at ESMO affirm our desire to improve outcomes for those with metastatic NSCLC, specifically," said Alessandro Riva, MD, Global Head, Oncology Development and Medical Affairs, Novartis Oncology. "With our first-line Phase III results forthcoming as well as ongoing brain metastases studies, we look forward to sharing further evidence of Zykadia's full potential."

Results from the randomized Phase III ASCEND-5 study were also presented for the first time, and were included as part of a late-breaking oral session as well as in the ESMO press program. The ASCEND-5 study assessed median PFS in patients previously treated with crizotinib and one or two prior regimens of cytotoxic chemotherapy (including platinum doublet), who then received either Zykadia or standard chemotherapy. Results demonstrated a statistically significant and clinically meaningful improvement in median PFS by BIRC for patients taking Zykadia versus chemotherapy (HR 0.49, 95% CI 0.36-0.67; p<0.001 one sided). Median PFS by BIRC for Zykadia and chemotherapy were 5.4 months (95% CI: 4.1-6.9) vs. 1.6 months (95% CI: 1.4-2.8), respectively[4].

The ALK gene arrangement, one of the three most common biomarkers - or genetic drivers -of NSCLC, affects approximately 2-7% of cases each year[5],[6]. More than half of these patients are either former smokers or have never smoked[7],[8],[9]. These patients are candidates for treatment with a targeted ALK inhibitor[6].

About ASCEND-3
ASCEND-3 is a Phase II single-arm, open-label, multicenter study which included 124 patients with ALK+ NSCLC who had received up to three lines of chemotherapy and had no prior experience with an ALK inhibitor. Brain metastases at baseline were seen in 39.5% of patients. The most frequent adverse events were diarrhea [85.5% (3.2% grade 3/4)], nausea [77.4% (6.5% grade 3/4)] and vomiting [71.8% (6.5% grade 3/4)][1].

About ASCEND-5
ASCEND-5 is an open-label, randomized, active-controlled, multicenter Phase III study to compare the efficacy and safety of Zykadia to standard second-line chemotherapy (pemetrexed or docetaxel) in patients with advanced ALK+ NSCLC who progressed on prior crizotinib and one or two prior regimens of chemotherapy. Of 231 patients, 115 were randomized to ceritinib and 116 to chemotherapy. Of patients discontinuing chemotherapy due to disease progression, 75 crossed over to Zykadia. The most frequent adverse events were diarrhea [72.2% (4.3% grade 3/4)], nausea [66.1% (7.8% grade 3/4)] and vomiting [52.2% (7.8% grade 3/4)] with ceritinib; fatigue [28.3% (4.4% grade 3/4)], nausea [23.0% (1.8% grade 3/4)], alopecia [21.2% (0% grade 3/4)] and neutropenia [20.4% (15.0% grade 3/4)] with chemotherapy[4].

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 55 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 "dedication," "continues," "expected," "potential," "committed," "desire," "forthcoming," "ongoing," "look forward," "conditional approval," 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 receive additional regulatory approvals or 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 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 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] Felip, E. et al. Phase 2 study of ceritinib in previously treated ALKi-naïve patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC): whole body efficacy in all pts and in pts with baseline brain metastases (BM). Abstract #1208O. European Society for Medical Oncology. Annual Meeting, Copenhagen, 9 October 2016.
[2] Kim, DW. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicenter, open-label, phase 1 trial. Lancet Oncol 2016; 17: 452-463.
[3] Felip, E. et al. ASCEND-3: A single-arm, open-label, multicenter Phase 2 study of ceritinib in ALKi-naïve adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC). Abstract #8060. American Society of Clinical Oncology Annual Meeting, Chicago, 1 June 2015.
[4] Scagliotti, G. et al. Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study. Abstract #LBA42_PR. European Society for Medical Oncology. Annual Meeting, Copenhagen, 9 October 2016.
[5] International Cancer Control: Global Cancer Statistics. Centers for Disease Control and Prevention Website. http://www.cdc.gov/cancer/international/statistics.htm. Last updated February 2015.
[6] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. NCCN 2014 3:1-148.
[7] Thun MJ, et al. Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies. PLOS Medicine, 2008. 5(9): e185.
[8] Park E, Japuntich S, Rigotti N, et al. A Snapshot of Smokers After Lung and Colorectal Cancer Diagnosis. Cancer, June 2012. http://onlinelibrary.wiley.com/doi/10.1002/cncr.26545/abstract.
[9] Lovly C, Horn L, Pao W. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome. https://www.mycancergenome.org/content/disease/lung-cancer/. Updated March 2016.

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