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Zykadia) for Metastatic Non-Small Cell Lung Cancer pan-Canadian Oncology Drug Review Final Clinical Guidance Report Ceritinib (Zykadia) for Metastatic Non-Small Cell Lung Cancer December 3, 2015 DISCLAIMER Not a Substitute for Professional Advice This report is primarily intended to help Canadian health systems leaders and policymakers make well-informed decisions and thereby improve the quality of health care services. While patients and others may use this report, they are made available for informational and educational purposes only. This report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision making process, or as a substitute for professional medical advice. Liability pCODR does not assume any legal liability or responsibility for the accuracy, completeness or usefulness of any information, drugs, therapies, treatments, products, processes, or services disclosed. The information is provided "as is" and you are urged to verify it for yourself and consult with medical experts before you rely on it. You shall not hold pCODR responsible for how you use any information provided in this report. Reports generated by pCODR are composed of interpretation, analysis, and opinion on the basis of information provided by pharmaceutical manufacturers, tumour groups, and other sources. pCODR is not responsible for the use of such interpretation, analysis, and opinion. Pursuant to the foundational documents of pCODR, any findings provided by pCODR are not binding on any organizations, including funding bodies. pCODR hereby disclaims any and all liability for the use of any reports generated by pCODR (for greater certainty, "use" includes but is not limited to a decision by a funding body or other organization to follow or ignore any interpretation, analysis, or opinion provided in a pCODR report) FUNDING The pan-Canadian Oncology Drug Review is funded collectively by the provinces and territories, with the exception of Quebec, which does not participate in pCODR at this time. pCODR Final Clinical Guidance Report - Ceritinib (Zykadia) for Metastatic Non-Small Cell Lung Cancer pERC Meeting: September 17, 2015; pERC Reconsideration Meeting: November 19, 2015 © 2015 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW ii INQUIRIES Inquiries and correspondence about the pan-Canadian Oncology Drug Review (pCODR) should be directed to: pan-Canadian Oncology Drug Review 154 University Avenue, Suite 300 Toronto, ON M5H 3Y9 Telephone: 613-226-2553 Toll Free: 1-866-988-1444 Fax: 1-866-662-1778 Email: [email protected] Website: www.cadth.ca/pcodr pCODR Final Clinical Guidance Report - Ceritinib (Zykadia) for Metastatic Non-Small Cell Lung Cancer pERC Meeting: September 17, 2015; pERC Reconsideration Meeting: November 19, 2015 © 2015 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iii TABLE OF CONTENTS DISCLAIMER AND FUNDING .......................................................................................... ii INQUIRIES ............................................................................................................. iii TABLE OF CONTENTS ................................................................................................ iv 1 GUIDANCE IN BRIEF ............................................................................................. 1 1.1. Background ............................................................................................ 1 1.2. Key Results and Interpretation .................................................................... 1 1.3. Conclusions ............................................................................................ 3 2 CLINICAL GUIDANCE ............................................................................................ 4 2.1 Context for the Clinical Guidance ................................................................. 4 2.2 Interpretation and Guidance ...................................................................... 10 2.3 Conclusions ........................................................................................... 11 3 BACKGROUND CLINICAL INFORMATION .................................................................... 13 4 SUMMARY OF PATIENT ADVOCACY GROUP INPUT ....................................................... 16 5 SUMMARY OF PROVINCIAL ADVISORY GROUP (PAG) INPUT............................................. 22 6 SYSTEMATIC REVIEW .......................................................................................... 25 6.1 Objectives ............................................................................................. 25 6.2 Methods................................................................................................ 25 6.3 Results ................................................................................................. 28 6.4 Ongoing Trials ........................................................................................ 46 7 SUPPLEMENTAL QUESTIONS ................................................................................. 49 8 ABOUT THIS DOCUMENT ..................................................................................... 50 APPENDIX A: LITERATURE SEARCH STRATEGY ................................................................. 51 REFERENCES ......................................................................................................... 51 pCODR Final Clinical Guidance Report - Ceritinib (Zykadia) for Metastatic Non-Small Cell Lung Cancer pERC Meeting: September 17, 2015; pERC Reconsideration Meeting: November 19, 2015 © 2015 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW iv 1 GUIDANCE IN BRIEF 1.1 Background The purpose of this review is to evaluate the safety and efficacy of ceritinib (Zykadia) monotherapy, as compared to an appropriate comparator in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have disease progression on or with intolerance to crizotinib. Ceritinib is an oral, small-molecule, ATP-competitive, tyrosine kinase of ALK. Ceritinib has a Health Canada indication with conditions which is the same as the indication under pCODR review. Ceritinib is available in a 150 mg capsule, it has Health Canada approval with conditions for 750 mg taken orally once daily until disease progression. 1.2 Key Results and Interpretation 1.2.1 Systematic Review Evidence Two non-randomized phase one/two multi-centre, open-label, single-arm trials, ASCEND-1 and ASCEND-2 evaluating the efficacy and safety of ceritinib 750 mg orally daily in ALK- positive NSCLC were included in the pCODR systematic review. The single-arm, non- randomized designs make interpreting the efficacy and safety results difficult, especially when assessing outcomes such as response rate and progression-free survival which are more open to subjective bias. ASCEND-1 included a dose-escalation phase followed by an expansion phase while ASCEND-2 included only one phase where all patients received the recommended dose of 750 mg per day and had been pretreated with crizotinib as their last prior therapy. The primary endpoint for both studies was objective response rate (ORR) as evaluated by the investigator, with confirmatory assessment conducted by an independent review committee. Secondary outcomes included progression-free survival (PFS), overall survival (OS), intracranial response rate, safety and tolerability. Of the 246 patients in ASCEND-1, 163 (66%) patients were treated with a prior ALK inhibitor (ALKi) and 83 (34%) patients were ALKi naïve. In ASCEND-2, all patients’ (n=140) last prior therapy was crizotinib and had at least one line of platinum-based therapy. Efficacy In ASCEND-1, the ORR was 56.4% (95%CI: 48.5-64.2) patients with prior ALKi treatment. In ASCEND-2, the ORR was 38.6% (95%CI: 30.5-47.2). The median duration of response was 8.3 months in ASCEND-1 for patients with prior ALKi treatment and 9.7 months ASCEND-2. The median PFS was 6.9 (95%CI: 5.6-8.7) and 5.7 months (95%CI: 5.4-7.6) in ASCEND-1 for patients with prior ALKi treatment and ASCEND-2, respectively. Data on patient-reported outcomes was assessed in ASCEND-2 using the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC-QLQC30) and lung cancer specific questionnaire (QLQ-LC13) and the Lung Cancer Symptom Scale (LCSS). Throughout the treatment period, the change from baseline in global health status remained close to zero which suggested quality of life was maintained and did not worsen during ceritinib treatment. Patients reported consistent but not pCODR Final Clinical Guidance Report - Ceritinib (Zykadia) for Metastatic Non-Small Cell Lung Cancer pERC Meeting: September 17, 2015; pERC Reconsideration Meeting: November 19, 2015 © 2015 pCODR | PAN-CANADIAN ONCOLOGY DRUG REVIEW 1 clinically important improvements in lung-related symptoms (i.e. cough, pain in chest and dyspnea) and no worsening of cancer symptoms while on treatment. Harms The most frequent grade 3 or 4 adverse event was increased alanine aminotransferase levels which is associated with liver damage, this occurred in 29.8% and 13.6% of patients in ASCEND-1 and ASCEND-2, respectively. Other commonly reported grade 3 or 4 adverse events included but were not limited to nausea, diarrhea, and fatigue. Seventeen (10.4%) and 10 (7.1%) of patients discontinued treatment due to adverse events in ASCEND-1 and ASCEND-2, respectively. 1.2.2 Additional Evidence pCODR received
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