Pfizer’s crizotinib, an oral, selective, small-molecule inhibitor for non-small cell lung cancer (NSCLC) has gone remarkably fast from lab bench to late-stage trials and now to the FDA for review.
Pfizer’s crizotinib, an oral, selective, small-molecule inhibitor for non-small cell lung cancer (NSCLC) has gone remarkably fast from lab bench to late-stage trials and now to the FDA for review. Pfizer announced on January 12 that it has begun a rolling submission of a new drug application (NDA) to the FDA for the treatment of NSCLC in patients who harbor a mutation in anaplastic lymphoma kinase (ALK). Completion of the submission is expected in the first half of 2011. Crizotinib was granted fast-track status in December 2010 allowing the FDA to review submitted data on a rolling basis.
In the lab; image courtesy of stock.xchng
The fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells was discovered in 2007. Approximately 5% of newly diagnosed NSCLC patients, or 45,000 people worldwide, harbor this mutation. Lung cancer patients with the ELM4-ALK mutation are typically non-smokers who do not have mutations in epidermal growth factor receptor (EGFR) or the KRAS gene.
Lung cancer is still the leading cause of cancer-related mortality in the United States and the leading cause of cancer death in men worldwide. The disease is particularly difficult to treat and remains largely undiagnosed with 75% of patients diagnosed with metastatic and late-stage cancer where the survival rate is under 6% because of poor response to current standards of care. Treatment for NSCLC is therefore a critically unmet need, which is why both researchers and clinicians are excited about the promising results of crizotinib in this patient population.
Crizotinib was being studied as a c-MET-inhibitor for cancer when, it was discovered that it is also a potent inhibitor of the ELM4-ALK mutation, which results in unregulated ALK kinase activity that facilitates tumor growth. Crizotinib works by binding to the active portion of the ALK protein, inhibiting its activity.
The drug was very well tolerated and produced dramatic antitumor activity in early-stage trials which facilitated a faster than normal move into late-stage trials. The data was so promising that the phase I/II data was featured in the plenary session at the 2010 American Society for Clinical Oncology annual meeting. The final data from 82 patients, most of whom were previously treated, was published in the New England Journal of Medicine, showed a 57% response rate with one patient having a complete response and 46 patients showing a partial response to crizotinib treatment.
Crizotinib is currently in phase III compared to standard of care chemotherapy for ALK-positive NSCLC patients who have previously failed a chemotherapy treatment as well as in a phase II single-arm study for patients who have failed at least one chemotherapy regimen or have progressed on the chemotherapy arm of the phase III trial. Pfizer has said that the results of the phase III trial will be disclosed at a scientific meeting sometime this year. Pfizer is currently developing a phase III NSCLC trial for treatment-nave patients.
Pfizer has partnered with Abbott to develop a diagnostic genetic test to screen patients for the ELM4-ALK mutation. This is a step towards better cancer treatment based on gene expression profiling that is becoming increasingly more prevalent. Such diagnostics will allow physicians to personalize treatments, resulting in a higher probability of response to treatment as patients receive the right drug for their specific type of cancer.