On 4 July 2018, the NICE published evidence-based recommendations on crizotinib (Xalkori, Pfizer) for treating ROS1-positive advanced non-small cell lung cancer (NSCLC) in adults. Crizotinib is recommended for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced NSCLC in adults, only if the conditions in the managed access agreement are followed. More evidence on crizotinib is being collected, until April 2023 (at the latest). After this NICE will decide whether or not to recommend it for use on the NHS and update the guidance. It will be available through the Cancer Drugs Fund until then.
This recommendation is not intended to affect treatment with crizotinib that was started in the NHS before this guidance was published. Patients having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Less than 2% of patients have ROS1‑positive advanced NSCLC. ROS1 oncogene was only recently discovered; so limited information is available on the natural history, patient characteristics and the clinical effectiveness of chemotherapy for tumours that are ROS1‑positive. From the limited information available, there appear to be similarities between ROS1‑positive advanced NSCLC and ALK‑positive NSCLC: for example, both are most often seen in younger patients who do not smoke. In the absence of any targeted therapy until now, ROS1‑positive advanced NSCLC is treated with cytotoxic chemotherapy. The clinical experts considered crizotinib a step-change in treatment because it is taken orally and offers a marked improvement in quality of life. The appraisal committee concluded that crizotinib has a better safety profile than standard care (cytotoxic chemotherapy) and would be valued by both patients and clinicians.
The clinical-effectiveness evidence for crizotinib in ROS1‑positive advanced NSCLC is from a small (n=53), single-arm study that included mostly patients with previously treated disease (PROFILE 1001). Although the study showed crizotinib to be effective at shrinking tumours and slowing disease progression, the lack of data comparing it with other treatments makes the size of the benefit uncertain.
Because of the limited evidence in ROS1‑positive NSCLC, the company presented data from 2 randomised controlled trials for crizotinib in ALK‑positive NSCLC instead (comparing crizotinib with chemotherapy) as proxy data for ROS1‑positive advanced NSCLC. However, using data from a proxy population is far from ideal, and makes the assessment of clinical and cost effectiveness highly uncertain.
Crizotinib meets NICE's criteria to be considered a life-extending end-of-life treatment, but there are uncertainties in the clinical- and cost-effectiveness estimates. For previously treated disease, the range of cost-effectiveness estimates was broader than for untreated disease and all estimates are higher than what NICE normally considers acceptable for end-of-life treatments. Crizotinib therefore cannot be recommended for routine use in the NHS to treat ROS1‑positive advanced NSCLC.
Crizotinib is innovative but there were no relevant additional benefits that had not been captured in the quality-adjusted life-year calculations. Collecting further data on its use in the Cancer Drugs Fund would help address uncertainties in crizotinib's survival benefit, and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC. Using crizotinib in a managed approach would also encourage standardisation of ROS1 status testing in non-squamous NSCLC.
In clinical practice, crizotinib is most likely to be used for non-squamous NSCLC; the comparators chosen by the company were for non-squamous NSCLC; the trial results from PROFILE 1001 and the ALK‑positive proxy data from PROFILE 1014 and 1007 were almost exclusively in patients with non-squamous histology and predominately in adenocarcinoma; and the testing costs included in the cost-effectiveness analysis were based on a non-squamous lung cancer population.
The appraisal committee was aware that the incidence of ROS1 in squamous NSCLC is around 1.7% to 1.8%, but recognised that testing of ROS1 status in all patients with NSCLC would be very costly for the Cancer Drugs Fund. It accepted that ROS1 testing and the use of crizotinib in the Cancer Drugs Fund would be in patients with non-squamous NSCLC only.
ROS1 status should be tested upfront
The marketing authorisation for crizotinib states that it is indicated as monotherapy for the treatment of adults with ROS1‑positive advanced NSCLC. It also states that it is necessary to have an accurate and validated assay for ROS1 before treatment with crizotinib is started. The company proposed initial testing with immunohistochemistry, and follow-up confirmation testing for positive cases with the highly accurate fluorescence in situ hybridisation test.
The clinical experts explained that only a few centres test for ROS1, and that assay methods vary. The NICE stated in its recommendation that an accurate and validated assessment for ROS1 should be done by laboratories with demonstrated proficiency in the specific test being used before starting crizotinib therapy. It is important that a well-validated and robust methodology is chosen to avoid false-negative or false-positive results.
The appraisal committee understood that although the marketing authorisation for crizotinib did not specify non-squamous disease, ROS1‑positive NSCLC is almost exclusively seen in non-squamous tumours and therefore the testing would most likely be in patients with non-squamous tumours only.
The appraisal committee discussed when ROS1 testing should be done: it could be done at diagnosis, along with testing for other mutations (such as EGFR and ALK), or later, once patients have tested negatively for other mutations (because the different mutations are mutually exclusive). The clinical experts highlighted practical difficulties in testing different mutations at different stages, because more biopsy samples might be needed and the risk of delayed or missed diagnoses with sequential testing. The appraisal committee also noted that any delay in diagnosing ROS1‑positive advanced NSCLC would delay access to therapy. It agreed that testing for ROS1 status in all newly diagnosed non-squamous NSCLC would be the best strategy, in line with testing for other types of tumour expression in NSCLC.
The summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma.
Dosage in the marketing authorization is 250 mg twice daily (500 mg daily) taken orally. Dosing interruption and/or dose reduction may be needed based on individual safety and tolerability. If necessary, dose may be reduced to 200 mg twice daily and then 250 mg once daily.
The list price of crizotinib is 4,689 GBP for 60 capsules (excluding VAT; British national formulary [BNF] online, accessed December 2017).
The company has a commercial agreement. This makes crizotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.