For Advanced Anaplastic Lymphoma Kinase Positive Non- Small Cell Lung Cancer – First Line
Horizon Scanning Research June 2016 & Intelligence Centre
Ceritinib (Zykadia) for advanced anaplastic lymphoma kinase positive non- small cell lung cancer – first line
LAY SUMMARY
Lung cancer is one of the most common types of cancers. There are different types of lung cancer, the most common being non-small cell This briefing is based on lung cancer. The most common risk for developing lung cancer is information smoking. Lung cancer is usually symptomless in the early stages, and available at the time as a result, most cases of lung cancer are diagnosed at more of research and a advanced stages. The outcome for those diagnosed at later stages of limited literature lung cancer is very poor. search. It is not intended to be a Ceritinib is a new drug taken by mouth to treat non-small cell lung definitive statement cancer with a particular genetic mutation (anaplastic lymphoma kinase on the safety, or ALK positive). If licensed in the UK, ceritinib may be an option for efficacy or some patients with advanced non-small cell lung cancer. effectiveness of the health technology covered and should NIHR HSRIC ID: 10233 not be used for commercial purposes or commissioning without additional information.
This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre
TARGET GROUP
Non-small cell lung cancer: anaplastic lymphoma kinase (ALK) positive; locally advanced or metastatic - first line; previously untreated patients.
TECHNOLOGY
DESCRIPTION
Ceritinib (Zykadia; LDK-378; NVP-LDK 378; NVP-LDK378-NX) is a small molecule, ATP- competitive inhibitor of the tyrosine kinase ALK1. In preclinical studies, ceritinib showed anti- tumour activity against both crizotinib sensitive and crizotinib resistant tumours1. Ceritinib is administered orally at 750mg once daily until disease progression in previously untreated patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC).
Ceritinib is licensed in the EU for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib. Very common (>10%) adverse reactions reported include anaemia, decreased appetite, diarrhoea, nausea, vomiting, abdominal pain, constipation, oesophageal disorder, rash, fatigue, abnormal liver function tests and increase in blood creatinine2.
Ceritinib is also in phase II trials for gastrointestinal and thyroid cancers, haematological malignancies and other solid tumours.
INNOVATION and/or ADVANTAGES
If licensed, ceritinib will offer an additional oral first line treatment option for this patient group.
DEVELOPER
Novartis Oncology.
AVAILABILITY, LAUNCH OR MARKETING
Ceritinib is a designated orphan drug in the EU and USA.
PATIENT GROUP
BACKGROUND
There are two main histological types of lung cancer, small cell lung cancer and NSCLC. NSCLC is further divided into two common subtypes, namely squamous cell carcinoma and non-squamous cell carcinoma, which consists of adenocarcinoma and large cell carcinoma. Cigarette smoking is the single biggest risk factor for developing lung cancer, accounting for about 90% of cases3,4. Other risk factors include passive smoking, smoking cigars or cannabis, radon gas (associated with about 3% lung cancer deaths a year in England4), age (80% of cases are diagnosed in patients over the age of 60 years), asbestos, genetic determinants, previous cancer treatment and reduced immunity5. Horizon Scanning Research & Intelligence Centre
Due to the usually asymptomatic nature of lung cancer in the early stages, it is often diagnosed at an advanced stage resulting in a poor prognosis3. Common symptoms can include coughing, haemoptysis, dyspnoea, persistent chest infections and chest pain3,4. Other symptoms may include unilateral paralysis of the diaphragm, Pancoast’s syndrome and metastases, which most frequently spread to the liver, bone, brain and adrenal glands2.
The fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-ALK has been associated with the development of NSCLC in some patients2. Expert opinion suggests that these patients are generally younger than typically expected for lung cancer and are often of working age6. In addition, they have frequently never smoked and metastatic spread to the brain is more common at presentation6.
NHS or GOVERNMENT PRIORITY AREA
This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011). NHS England. 2013/14 NHS Standard Contract for Radiotherapy (All ages). B01/S/a. NHS England. 2013/14 NHS Standard Contract for Chemotherapy (All ages). B15/S/a. NHS England Clinical Commissioning Policy: Stereotactic Ablative Body Radiotherapy for Non- Small- Cell Lung cancer (Adults). B01/P/a April 2013.
CLINICAL NEED and BURDEN OF DISEASE
Lung cancer is the third most common cancer in the UK and accounts for 13% of all new cases7. In 2013, there were 39,036 new cases of lung cancer in England and Wales; 21,156 in men and 17,880 in women (approximately 68 cases per 100,000 in England)7. Twelve per cent of cases of lung cancer are classified as small cell lung cancer, 87% as NSCLC and 1% are carcinoid7. About half of patients with NSCLC have metastatic disease at diagnosis8. ALK mutations (EML4-ALK fusion events) are found in 1-7% of cases of NSCLC3.
Nine per cent of adult lung cancer patients (8.4% of men and 11.6% of women) in England survived cancer for five years or more in 2010-20117.
In 2014-15, there were 89,247 hospital admissions for malignant neoplasm of the bronchus and lung (ICD-10 C34) in England, resulting in 278,868 bed-days and 109,339 finished consultant episodes9. In 2014, there were 30,851 deaths in England and Wales from lung cancer; 16,948 men and 13,903 women10.
PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
NICE technology appraisal in development. Lung cancer (non-small-cell, anaplastic lymphoma kinase positive, previously treated) - ceritinib [ID729]. Expected date to be confirmed. NICE technology appraisal in development. Lung cancer (non-small-cell, untreated, ALK positive) - crizotinib [ID865]. Expected September 2016. Horizon Scanning Research & Intelligence Centre
NICE technology appraisal. Pemetrexed maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer (TA309). April 2014. NICE technology appraisal. Crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene (TA296). September 2013. NICE technology appraisal. Erlotinib monotherapy for maintenance treatment of non- small-cell lung cancer (TA227). June 2011. NICE technology appraisal. Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (TA192). July 2010.
NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small-cell lung cancer (TA190). June 2010. NICE technology appraisal. Pemetrexed for the first-line treatment of non-small-cell lung cancer (TA181). September 2009. NICE technology appraisal. Erlotinib for the treatment of non-small-cell lung cancer (TA162). November 2008. NICE technology appraisal. Pemetrexed for the treatment of non-small-cell lung cancer (TA124). August 2007.
NICE clinical guideline. Lung cancer: The diagnosis and treatment of lung cancer (CG121). April 2011.
Other Guidance
European Society for Medical Oncology. ESMO Consensus Guidelines: Locally- advanced stage III non-small-cell lung cancer (NSCLC). April 201511. American Society of Clinical Oncology. Molecular Testing for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the CAP/IASLC/AMP Guideline. October 201412. European Society for Medical Oncology. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. August 201413. Scottish Intercollegiate Guidelines Network. Management of Lung Cancer (SIGN 137). February 201414. London Cancer Alliance. LCA Lung Cancer Clinical Guidelines. December 201315. American Society of Clinical Oncology. The role of CT screening for Lung Cancer in clinical practice. The evidence based practice guideline of the American College of Chest Physicians and the American Society for Clinical Oncology. May 201216.
CURRENT TREATMENT OPTIONS
The aim of treatment for locally advanced or metastatic NSCLC is to prolong survival, improve quality of life and control disease-related symptoms17. Treatment strategies should take into account the tumour histology and molecular pathology, as well as the patient’s age, performance status, co-morbidities and preferences12. Patients who smoke should be encouraged to cease, as cessation improves treatment outcomes12.
Current guidelines recommend that chemotherapy should be offered to patients with stage IV NSCLC and good performance status (WHO 0 or 1 or a Karnofsky score of 80–100)16,18. Induction chemotherapy for advanced NSCLC should be a combination of a single third generation drug (docetaxel, gemcitabine, paclitaxel, or vinorelbine) plus a platinum drug (either carboplatin or cisplatin)18; if patients cannot tolerate a platinum combination (or are Horizon Scanning Research & Intelligence Centre
WHO performance status 2)6, a single agent chemotherapy with a third generation drug is recommended16.
Pemetrexed in combination with cisplatin is recommended if the tumour has been confirmed as adenocarcinoma or large-cell carcinoma18 on the basis of best survival figures and toxicity profile6. Pemetrexed is recommended as maintenance therapy after treatment with platinum- based chemotherapy in combination with gemcitabine, paclitaxel and docetaxel (switch maintenance) if the tumour is adenocarcinoma or large-cell carcinoma6,18. It is recommended that patients progressing after first-line chemotherapy be offered docetaxel or erlotinib monotherapy as a second-line treatment option18 or crizotinib for previously treated ALK- positive advanced NSCLC, though this is not currently recommended by NICE19.
EFFICACY and SAFETY
Trial ASCEND 4, NCT01828099, NCT01685138, CLDK378A2203 2012- CLDK378A2301, 2013-000319-26; 003474-36; ceritinib; phase II. ceritinib vs chemotherapy; phase III. Sponsor Novartis Pharmaceuticals. Novartis Pharmaceuticals. Status Ongoing. Ongoing. Source of Trial registry20, manufacturer. Trial registry21. information Location EU (incl UK) and other countries. EU (incl UK), USA, Canada and other countries. Design Randomised, active-controlled. Non-randomised, single arm. Participants n=348 (planned); aged ≥18 yrs; non- n=348 (planned); aged ≥18 yrs; ALK- squamous, ALK-positive NSCLC; newly positive NSCLC; stage IIIB or IV; diagnosed stage IIIB (who are not a chemotherapy naïve or progressed candidate for definitive multimodality despite 1-3 lines of cytotoxic therapy), stage IV or relapsed locally chemotherapy to treat locally advanced advanced or metastatic disease not or metastatic disease; no prior treatment previously treated with systemic anti- with crizotinib or other ALK inhibitor. cancer therapy (with exception of neo- adjuvant or adjuvant therapy). Schedule Randomised to ceritinib 750mg oral once Participants received ceritinib 750mg oral daily; or pemetrexed via intravenous (IV) once daily. infusion at 500mg/m2 with cisplatin 75mg/m2 IV every 21 days for 4 cycles, followed by pemetrexed 500mg/m2 IV every 21 days; or pemetrexed 500mg/m2 IV plus carboplatin AUC 5-6 IV every 21 days for 4 cycles, followed by pemetrexed 500mg/m2 IV every 21 days. Follow-up Active treatment until disease Active treatment 6 cycles of 28 days up to progression, follow every 6 wks until mth 24 weeks, follow up until disease 33 then every 9 wks. progression. Primary Progression-free survival (PFS). ORR. outcome/s Secondary Overall survival (OS); overall response OS; PFS; DOR; DCR; TTR; ORR by outcome/s rate (ORR); duration of response (DOR); Blinded Independent Review Committee disease control rate (DCR); time to (BIRC) assessment; safety profile; overall response (TTR); patient reported intracranial response rate. outcomes. Expected Study completion date reported as June Study completion date reported as Nov reporting 2018. 2016. date
Horizon Scanning Research & Intelligence Centre
ESTIMATED COST and IMPACT
COST
The cost of ceritinib is not yet known. The table below shows the cost of selected comparators:
Drug Dose Cost (£)22,a Pemetrexed 500mg/m2 every 21 days for 4 cycles 5,600 Cisplatin 75mg/m2 every 21 days for 4 cycles 313.20 Crizotinib 1 pack of 60×200mg capsules (30-day supply) 4,689
IMPACT - SPECULATIVE
Impact on Patients and Carers
Reduced mortality/increased length of survival Reduced symptoms or disability
Other: No impact identified
Impact on Health and Social Care Services
Increased use of existing services Decreased use of existing services: oral treatment option.
Re-organisation of existing services Need for new services
Other: None identified
Impact on Costs and Other Resource Use
Increased drug treatment costs Reduced drug treatment costs
Other increase in costs: Other reduction in costs:
Other: uncertain unit cost compared to current None identified comparators.
Other Issues
Clinical uncertainty or other research question None identified identified:
REFERENCES
1 Shaw AT, Kim DW, Mehra R et al. Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine 2014;370:1189-97. 2 Electrical Medicines Compendium. Zykadia 150mg hard capsules. http://www.medicines.org.uk/emc/medicine/30882 Accessed 20 April 2016. 3 Semlitsch MT and Jeitler K. Crizotinib (Xalkori) for the treatment of anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC). Horizon Scanning in Oncology 2013: Nr. 35: ISSN online 2076-5940. 4 NHS Choices. Lung cancer causes. http://www.nhs.uk/Conditions/Cancer-of-the- lung/Pages/Causes.aspx Accessed 25 April 2016.
a Based on an average surface area of 1/88m2. Assumes wastage. Horizon Scanning Research & Intelligence Centre
5 Macmillian. Risk factors and causes of lung cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lung/Aboutlungcancer/Riskfactorsc auses.aspx Accessed 25 April 2016. 6 Horizon Scanning Research & Intelligence Centre. Crizotinib (Xalkori) for ALK-positive, locally advanced or metastatic, non-small cell lung cancer – first line. University of Birmingham; February 2015. 7 Cancer Research UK. Lung cancer incidence statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/incidence/ Accessed 25 April 2016. 8 Chen A, Cronin A, Weeks J et al. Palliative radiation therapy practice in patients with metastatic non–small-cell lung cancer: A Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study. Journal of Clinical Oncology 2013;31(5):558-564. 9 Health & Social Care Information Centre, Hospital Episode Statistics for England. Admitted Patient Care, 2014-15. http://www.hscic.gov.uk/ 10 Office for National Statistics. Deaths registered in England and Wales (series DR), 2014. www.ons.gov.uk 11 Eberhardt WEE, De Ruysscher D, Weder W et al. ESMO Consensus Guidelines: Locally- advanced stage III non-small-cell lung cancer (NSCLC). Annals of Oncology (2015);26(8):1573- 1588. 12 Leighl NB, Rekhtman N, Bierman WA et al. Molecular testing for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the CAP/IASLC/AMP Guideline. Journal of Clinical Oncology 2014;57:3055. 13 Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25(suppl3):iii27-iii39. 14 Scottish Intercollegiate Guidelines Network. Management of Lung Cancer SIGN 137.Scotland. February 2014. 15 London Cancer Alliance. LCA Lung Cancer Clinical Guidelines. London. December 2013. 16 Bach PB, Mirkin JN, Oliver TK et al. The role of CT screening for Lung Cancer in clinical practice. The Journal of the American Medical Association 2012;307(22):2418-2429. 17 National Cancer Institute. Stage IV NSCLC Treatment. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page11 Accessed 25 April 2016. 18 National Institute of Health and Clinical Excellence. Lung cancer: diagnosis and treatment. Clinical guidelines CG121. London: NICE; April 2011. 19 National Institute of Health and Clinical Excellence. Clinical guidelines. Crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Technology appraisal TA296. London: NICE; September 2013. 20 ClinicalTrials.gov. LDK378 versus chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT01828099 Accessed 25 April 2016. 21 ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT01685138 Accessed 25 April 2016. 22 Joint Formulary Committee. British National Formulary. BNF April 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com