National Institute for Health and Care Excellence (NICE) UK published on 22 June 2016 evidence-based recommendations on ceritinib. Ceritinib is recommended, within its marketing authorisation, as an option for treating anaplastic lymphoma kinase (ALK)-positive non‑small cell lung cancer (NSCLC) in adult patients previously treated with crizotinib.
Ceritinib is recommended only if the company provides it with the discount agreed in the patient access scheme. Crizotinib is available through the Cancer Drugs Fund. The guidance on this technology will be considered for review when the results of the ongoing studies are reported. A review should also be considered if crizotinib is no longer available through the Cancer Drugs Fund.
The summary of product characteristics lists the following grade 3 and 4 adverse reactions that occur in at least 5% of patients treated with ceritinib: liver laboratory test abnormalities, fatigue, diarrhoea, nausea and hyperglycaemia. The ALK inhibitor, ceritinib is taken orally, once daily. The recommended dose is 750 mg (5 × 150‑mg capsules). The company submission stated that the NHS list price is £4,923.45 for a 30‑day supply. The summary of product characteristics states that treatment should be continued as long as clinical benefit is seen. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ceritinib at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.
The appraisal committee considered evidence submitted by Novartis and a review of this submission by the evidence review group. The company presented efficacy data from 2 phase I or II single-arm studies identified by a systematic review: ASCEND‑1 and ASCEND‑2. These were multicentre, open-label studies of patients with ALK-positive locally advanced or metastatic NSCLC, whose disease had progressed after chemotherapy.
The phase I ASCEND‑1 study (n=304) enrolled patients with a range of treatment histories and explored several different doses of ceritinib. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less and a life expectancy of at least 12 weeks. The company's analysis included only the subgroup of 163 adults who had previously been treated with crizotinib and who had the licensed dose of ceritinib (750 mg). This subgroup had ALK‑positive, locally advanced or metastatic NSCLC that had progressed despite standard therapy and a mean age of 51.5 years. Patients continued treatment with ceritinib until unacceptable toxicity or disease progression, or at the discretion of the investigator, or by patient request.
The 2 primary outcomes were overall response rate (defined as complete or partial response using the Response Evaluation Criteria in Solid Tumours [RECIST]) and duration of response, both assessed by the investigator. The secondary outcomes included overall-response rate assessed by a blinded independent review committee rather than by the investigator, overall survival, progression-free survival (defined as the time from starting treatment to the time of disease progression or death), and adverse events.
The phase II ASCEND‑2 study enrolled 140 patients previously treated with crizotinib. The mean age of patients was 51.2 years. It included adults:
- with ALK‑positive stage IIIB or IV NSCLC
- with World Health Organization performance status of 0 to 2
- with a life expectancy of at least 12 weeks
- who had previously had chemotherapy
- whose disease had progressed after treatment with crizotinib.
The primary outcome was overall response rate measured by the investigator. Secondary outcomes included overall response rate assessed by a blinded independent review committee, progression-free survival, overall survival, and safety.
The PFS in ASCEND‑1 was 6.9 month and 5.7 month in ASCEND‑2. The OS was 16.7 month in ASCEND-1 and 14.9 month in ASCEND-2. The company also presented a pooled analysis using individual patient data assessed by the blinded independent review committee in ASCEND‑1 and ASCEND‑2. The pooled median progression-free survival was 7.0 months and the pooled median overall survival was 15.6 months.
Health-related quality of life was not measured in ASCEND‑1. In ASCEND‑2 it was measured using the European Organisation for Research and Treatment of Cancer's core quality-of-life questionnaire (EORTC-QLQ-C30). In total, 125 patients completed the EORTC-QLQ-C30, of whom 69 (55.2%) showed improved global health status and 26 (20.8%) showed poorer global health status.
The ASCEND‑1 and ASCEND‑2 studies did not include control groups, so the company could not directly compare ceritinib with best supportive care (BSC). The company searched the literature to find evidence of outcomes for patients who had BSC. It then did a naive indirect comparison of ceritinib with BSC, meaning the comparison was not adjusted for differences in patient or study characteristics between the studies.
The whole text of this guidance, you can find here.