Pfizer Limited has announced that Xalkori (crizotinib), the first of a new class of therapy for a type of lung cancer is now available in the UK. Crizotinib, an oral treatment, has been granted a conditional licence for patients with previously treated advanced non-small cell lung cancer (NSCLC), whose tumours test! positively for a specific protein known as ALK.1 It is the only approved therapy for this subset of NSCLC patients and signals the most recent advance in personalised therapy* in lung cancer.
Professor Dean Fennell, University of Leicester commented, “The launch of crizotinib heralds one of the most exciting breakthroughs that we have seen in cancer treatment in recent years. Up until now, patients with NSCLC have had few treatment options available to them. Crizotinib is the first treatment to target the ALK fusion protein specifically and as a result, patients expressing this fusion protein have a good chance of response. In other words, we know that we will be giving the right treatment to the right patient. Personalised medicines such as crizotinib represent the future of cancer treatment.”
The conditional licence for crizotinib is 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.1 The primary endpoint in both studies was Objective Response Rate (ORR) (defined as complete response plus partial response), and ORRs of 50 percent and 61 percent were seen in the Phase 2 and Phase 1 studies respectively.1
“Today’s news is a significant milestone for people with ALK-positive advanced NSCLC in the UK,” said Dr David Montgomery, Medical Director, Pfizer Oncology UK. “Crizotinib is a new personalized treatment which offers the hope of better outcomes for people with this kind of lung cancer. It demonstrates Pfizer’s commitment to advancing the unde! rstanding of the underlying genetic drivers of diseases to help us to better identify people who are most likely to benefit from our treatments.”
Pfizer will submit the results of a confirmatory phase 3 trial to regulators with a view to gaining a normal licence for the medicine. The phase 3 study, presented recently at the European Society for Medical Oncology (ESMO) 2012 annual congress, showed that in patients whose lung cancer is ALK-positive and whose cancer has progressed after first line chemotherapy, crizotinib provides superior tumour response, progression-free survival and quality of life compared to standard practice of second line single agent chemotherapy.2
The global randomised phase 3 study of 347 patients with ALK-positive lung cancer showed that crizotinib more than doubled progression-free survival to a median of 7.7 months compared to 3.0 months among those patients who received the chemotherapy (HR 0.49; 95% CI 0.37-0.64 ; P<0.0001). The overall response rate was also significantly higher in those treated with crizotinib (65% vs 20%; P<0.0001). These findings establish crizotinib as the standard of care for patients with previously treated advanced ALK positive NSCLC.2
ALK is a newly identified therapeutic target in lung cancer. It is a protein expressed by cancer cells and is 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.8,9
It is only possible to detect whether a tumour is ALK positive by performing laboratory tests on sample of a patient’s tumour tissue. For a patient to be eligible for crizotinib, their tumour must have tested positive for ALK using an accurate and validated test, undertaken by appropriately trained technicians with access to the required technology.
Lung cancer is the most common cause of cancer death in the UK, accounting for more than a fifth of all cancer deaths.3 Around 41,500 new cases of lung cancer are diagnosed in the UK every yea! r.4 NSCLC accounts for about 85 percent of lung canc er cases and remains difficult-to-treat, particularly in the metastatic (or advanced) disease setting.5 Approximately 75 percent of NSCLC patients are diagnosed late with metastatic disease, where the five year survival rate is only one to five percent.5,6 Preliminary epidemiology suggests that approximately three to five percent of NSCLC tumours are ALK-positive.7
Crizotinib will undergo review by the National Institute for Health and Clinical Excellence (NICE), and the Scottish Medicines Consortium (SMC) in 2013.
*A personalised therapy uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease. Knowledge of a patient’s genetic profile can help doctors select the proper medication or therapy and administer it using the proper dose or regimen.
Crizotinib is an oral therapy, and the first of a new class of treatments known as anaplas! tic lymphoma kinase (ALK) inhibitors. Crizotinib is licenced for the treatment of patients with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC).
Crizotinib works by inhibiting the ALK fusion protein, which blocks signalling in a number of cell pathways that are believed to be critical for the growth and survival of tumour cells, which may lead to growth inhibition or regression of tumours.8,9 Crizotinib is licensed for patients with previously treated ALK-positive advanced non-small cell lung cancer (NSCLC).1
Crizotinib Adverse Reactions
The most common adverse reactions observed in crizotinib Phase I and II studies were vision disorders (visual impairment, vision blurred, vitreous f! loaters and visual field defect) and GI 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.1
ALK Molecular Testing
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) – Immunohistochemistry 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) – The polymerase chain reaction (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.
1 Crizotinib UK Summary of Product Characteristics
2 Phase III study of crizotinib versus peme! trexed or docetaxel chemotherapy in patients with advanced ALK-positiv e non-small cell lung cancer (NSCLC) (PROFILE 1007). Study presented at the European Society of Medical Oncology (ESMO), 30th September, 2012.
3 Taken from: cancerresearchuk.org: uk-lung-cancer-mortality-statistics (accessed on 14.11.12)
4 Taken from roycastle.org: Lung-Cancer-Facts-and-Figures (accessed 14.11.12)
5 Reade CA, Ganti AK. EGFR targeted therapy in non-small cell lung cancer: potential role of cetuximab. Biologics. 2009; 3:215-224
6 American Cancer Society. Detailed guide: lung cancer – non-small cell. Non-small cell lung cancer survival rates by stage. cancer.org (accessed May 1, 2012)
7 Garber K. ALK, lung cancer and personalized therapy: portent of the future? J Natl Cancer Inst. 2010;102:672-675
8 Chiarle R, Voena C, Ambrogio C et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8(1):11-23
9 Zou HY, Li Q, Lee JH et al. An orally available small-molecule inhibitor of cMET, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007;67:4408-4417