NICE does not recommend Xalkori (Crizotinib) - a new advance in 'personalised medicine' for lung cancer patients

Pfizer Ltd has expressed concern and disappointment that the final appraisal determination (FAD) from the National Institute of Health and Care Excellence (NICE) does not recommend Xalkori (crizotinib) for previously treated, ALK positive advanced non small cell lung cancer (NSCLC). [1] Whilst NICE has acknowledged that crizotinib may offer eligible patients better outcomes compared to standard chemotherapy, it has not been recommended for use within the NHS because NICE does not consider it to be cost- effective.[1]

Pfizer is concerned about the impact this decision will have on eligible patients with previously treated NSCLC, whose tumours have been identified as ALK positive. As a personalised medicine, crizotinib allows targeted treatment of a specific group of patients who are most likely to benefit. In reality, the UK's limited and slow-paced adoption of innovative medicines such as crizotinib poses a real threat to both the Government's goal to have UK cancer outcomes among the highest in Europe and its vision to make the UK a world leader in life sciences.

Dr Michael Peake, Clinical Lead, National Cancer Intelligence Network and Consultant Physician, University Hospitals of Leicester, commented: "As someone who cares for lung cancer patients on a regular basis, I am personally very saddened by this decision. Advanced lung cancer is an aggressive disease with very poor outcomes for many patients. Clinicians recognise the urgent need for personalised medicines which target the specific drivers of an individual patient's tumour. However, if patients are unable to routinely access such therapies, it leaves them at risk of potentially poorer outcomes than patients in other countries where they have access to personalised medicine."

Pfizer believes that the health technology assessment system makes it increasingly difficult for innovative medicines to be accepted for use within the NHS and available for the benefit of patients. During the appraisal process, NICE accepted that crizotinib offered patients a 'noteworthy' improvement in progression free survival and the number of patients responding to treatment was 'very high' for a second or later line therapy in this difficult-to-treat cancer. [4,1] Furthermore, NICE acknowledged that crizotinib was likely to extend patients' lives, but it was uncertain for how long.[4,1] This was due, in part, to uncertainty in estimating the magnitude of overall survival benefit attributed to crizotinib.[4,1]

Like many clinical trials for oncology medicines, the crizotinib trial was designed, for ethical reasons, to give patients allocated chemotherapy the opportunity to receive crizotinib once their cancer had progressed. This factor makes it difficult to compare the differences in overall survival between the two arms of the trial, because the majority of patients will have received crizotinib.

Following NICE's decision not to recommend crizotinib the only other route for patients with previously treated, ALK positive advanced NSCLC to access the treatment is through the National Cancer Drugs Fund (CDF).[5] However the CDF is only available to patients in England, treatments are not guaranteed to stay on it and the future of its existence remains unknown. As such, a NICE recommendation still remains the optimal way to ensure all eligible patients in England and Wales have routine access to a second line therapy. In addition, approval by NICE may improve the uptake of diagnostic testing, a necessary step in the treatment pathway for many targeted medicines. Dr David Montgomery, Medical Director, Pfizer Oncology UK commented: "The Government's strategy for personalised care in cancer includes treating people with medicines targeted at the specific characteristics of their cancer. Yet crizotinib has not been well served by the current assessment models employed by NICE. Today's decision is another example of NICE declining a medicine which we strongly believe is a clinically and cost effective treatment. If this trend of negative decisions continues, we could see the UK fall even further behind other European countries for cancer survival rates".

Dr Jesme Fox, medical director of Roy Castle Lung Cancer Foundation, said: "We are very disappointed that lung cancer patients in the UK will be denied a new therapy, which is routinely available in other parts of the world. [...] It is clear that clinically this is a good drug, which would benefit some lung cancer patients. I would urge the drug's manufacturer and NICE to urgently come together to discuss the price issue and ensure this is routinely available to all lung cancer patients who would benefit."

About Lung Cancer

Lung cancer is the most common cause of cancer death in the UK, accounting for more than a fifth of all cancer deaths.[6] Around 41,500 new cases of lung cancer are diagnosed in the UK every year.[7] NSCLC accounts for about 85 percent of lung cancer cases and remains difficult-to-treat, particularly in the metastatic (or advanced) disease setting.[8] Approximately 70 percent of NSCLC patients are diagnosed late with metastatic disease,[3] where the five year survival rate is only one to five percent.[9] Around 1 in 20 people (5 percent) with NSCLC have the genetic alteration that results in production of the ALK fusion protein.[3] Approximately 550 patients would be eligible for crizotinib treatment each year.[10]

About Crizotinib

Crizotinib is an oral therapy, and the first of a new class of treatments known as anaplastic lymphoma kinase (ALK) inhibitors. [11] The ALK fusion protein has been identified as a therapeutic target in lung cancer. It is a protein expressed by cancer cells and a direct and potent driver of the ALK-positive variant of this disease. By inhibiting the ALK fusion protein, crizotinib blocks signalling in a number of cell pathways that are believed to be critical for the growth and survival of cancer cells. This can lead to growth inhibition or regression of cancers.[12,13] Crizotinib is licensed for the treatment of patients with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC).[11]

Crizotinib's Licence[11]

Crizotinib was granted a conditional licence in December 2012 based on data from two multi-centre, single-arm studies, including a Phase 2 study and a Part 2 expansion cohort of a Phase I study. The primary endpoint in both studies was Objective Response Rate (ORR) (defined as complete response plus partial response), and ORRs of 53 percent and 60 percent were seen in the Phase 2 and Phase 1 studies respectively.

Pfizer is in the process of submitting the results of a confirmatory phase 3 trial to regulators with a view to gaining a normal licence for the medicine.

Crizotinib Adverse Reactions[11]

The most common adverse reactions observed in crizotinib Phase I and II studies were vision disorders (visual impairment, vision blurred, vitreous floaters and visual field defect) and gastrointestinal disorders (nausea, diarrhoea, vomiting and constipation). The most frequently reported Grade 3-4 adverse reactions included increased liver enzyme (ALT). Liver enzyme elevations were frequently reported and led to permanent discontinuation of the study drug. Additional cases of liver disorders have been reported from studies 1005 and 1007, including Hy's law cases and death. As expected with some tyrosine kinase targeting drugs, crizotinib has been associated with study-drug related pneumonitis/ILD (including pneumonitis with fatal outcome). Cardiac disorders including QT prolongation, bradycardia, syncope, dizziness, and sudden death have also been observed during the conducted studies. Most of the decrease in neutrophil count was mild in severity, however, grade 3 and grade 4 neutropenia were common.

ALK Molecular Testing

It is only possible to detect whether a tumour is ALK-positive by performing laboratory tests on a sample of a patient's tumour tissue. For a patient to be eligible for crizotinib, their tumour must have tested positive for an ALK re-arrangement using an accurate and validated test, undertaken by appropriately trained technicians with access to the required technology.

Current ALK testing methods in NSCLC include the following:

• Fluorescence In-Situ Hybridization (FISH) FISH provides researchers with a way to visualise and map the genetic material in individual cells, including specific genes or portions of genes. This is important for understanding a variety of chromosomal abnormalities and other genetic mutations.
• Immunohistochemistry (IHC) IHC uses antibodies that are specifically directed against particular protein structures. An enzyme coupled to the antibodies catalyzes a colour reaction which facilitates the detection of the particular protein under the light microscope.
• Polymerase Chain Reaction (PCR) PCR is a technique widely used in molecular biology. It derives its name from one of its key components, a DNA polymerase used to amplify a piece of DNA by in vitro enzymatic replication.