September 1, 2011 — The US Food and Drug Administration (FDA) recently granted accelerated approval to crizotinib (Xalkori, Pfizer) for the treatment of patients with advanced-stage nonsmall-cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive.
A companion diagnostic test — the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc.) — was approved concurrently. It is designed to detect rearrangements of the ALK gene, which are found in about 4% to 5% of patients with NSCLC.
This is the first targeted agent to be developed with an accompanying diagnostic test, said Mace Rothenberg, MD, senior vice president of Pfizer's Oncology Business Unit.
The first target discovered was the epidermal growth-factor receptor (EGFR), but at the time the technology wasn't available to test which patients would benefit most from anti-EGRF therapies, he explained during an expert panel discussion sponsored by Pfizer.
Paul Bunn, MD, professor of medicine and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, in Aurora, who was on the panel, noted that the approval of crizotinib is part of a paradigm shift in the care and management of lung cancer.
"It used to be that everyone with lung cancer was treated the same, but then about 30 years ago, it was discovered that some patients with small-cell lung cancer could be cured with chemotherapy and radiation therapy," said Dr. Bunn. "So lung cancers were then divided into small cell and nonsmall cell."
"More recently, it has been appreciated that lung cancer is a group of heterogeneous diseases with different molecular origins," he explained. "It was then recognized the some lung cancers were driven by EGFR mutations — about 10% to 15% in Western countries. But then in 2007, it was recognized that some lung cancers are driven by the ALK oncogene, which is activated not by a mutation but by a breakage in chromosome 2 and a refusion of the 2 genes in the opposite direction."
The current paradigm is that the molecular features of a tumor have to be considered, not just histology, to select patients for the appropriate treatment, Dr. Bunn emphasized.
There are now 2 molecular subsets of lung cancer patients with specific therapies, namely those with EGFR and ALK mutations.
The question is, will we go 10 for 10?
Research coming out of the Lung Cancer Mutation Consortium has shown that almost 60% of patients with adenocarcinoma have 1 of 10 genomic abnormalities for which there is a drug. "We have 2 drugs approved now for 2 molecular abnormalities. The question is, will we go 10 for 10?" he asked.
There is also the question of being able to test patients for all 10 molecular abnormalities, but Dr. Bunn pointed out that technology is now moving as fast as drug development. "It is possible now to test for all 10 at a cost that is cheaper than it used to cost for testing for 1 in the past," he said.
Mark G. Kris, MD, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York City, noted that this is a "fantastic development."
I see this as a delivery on the promise of personalized medicine.
"I see this as a delivery on the promise of personalized medicine and genomic medicine," he said during the panel discussion. "Clinical trials have shown that virtually every patient with an ALK fusion who received crizotinib has had some benefit. It is very effective."
By testing for the ALK fusion gene, it is almost guaranteed that there will be some benefit, although the degree of benefit can vary, he noted. Conversely, if a patient lacks the ALK fusion gene, then crizotinib is not likely to demonstrate any efficacy. "This will be sparing individuals side effects, as well as not wasting time and resources for taking a drug that is not going to help them," he said.
Dr. Kris pointed out that there has been a lot of attention focused on the fact that only a small percentage of patients have the ALK fusion gene. "But in terms of lung cancer, even though the percentage is small, the numbers are quite large," Dr. Kris explained. "It is estimated that in United States alone, there are somewhere between 6,000 and 11,000 new patients each year who have an ALK fusion gene. To put that into perspective, that's more people than would have Hodgkin's disease, more patients than would have testicular cancer, and more patients than would have chronic myelogenous leukemia — all serious diseases where we have made important inroads."
Safety and Efficacy Established
The safety and efficacy of crizotinib were established in 2 multicenter, single-group studies that enrolled 255 patients with locally advanced or metastatic ALK-positive NSCLC: a phase 2 study (PROFILE 1005) and a part 2 expansion cohort of a phase 1 study (Study 1001).
In PROFILE 1005 (n = 136), the objective response rate (ORR) was 50%, and that included 1 complete response and 67 partial responses. The median duration of treatment was 22 weeks, and 79% of objective tumor responses were achieved during the first 8 weeks of treatment.
In Study 1001 (n = 119), the ORR was 61%, and that included 2 complete responses and 69 partial responses. The median duration of treatment was 32 weeks, and 55% of objective tumor responses were achieved during the first 8 weeks of treatment.
Like many targeted therapies, crizotinib comes with a hefty price tag. According to Geno Germano, president and general manager of specialty care and oncology at Pfizer, the drug will cost $9,600 per month, or $115,000 per year.
But Mr. Germano pointed out that with the approval of crizotinib, treatment will be improved. "We are going to be treating patients more effectively and avoiding treatments that don't work," he said.
He also noted that Pfizer has devised a number of programs to help with the cost. "We realize that we have to be attentive to the individual needs of each patient," he said.
Pfizer's initiatives would cut some patients' share of that cost significantly. The company is offering copay assistance of up to $24,000 per year with a program that would have privately insured patients pay only $100 per prescription. For example, if a patient has a 20% copay, that would cover a full year of treatment.
Pfizer has said it will also help patients who are uninsured or insured by Medicaid or Medicare figure out how to cover the cost of crizotinib. However, the assistance programs do not help payers cover their costs.
ALK Gene Test
The companion diagnostic test approved along with crizotinib uses Abbott's fluorescence in situ hybridization (FISH) technology to detect rearrangements of the ALK gene on the 2p23 chromosome.
It offers clinicians a standardized, clinically validated method of identifying the patients most likely to benefit from the therapy. Experts have predicted that the simultaneous FDA approvals will change clinical practice for the diagnosis and treatment of patients with NSCLC.
"The Abbott ALK FISH test was developed in conjunction with Pfizer and the clinical trials for crizotinib," said Kathryn B. Becker, PhD, director of Abbott Molecular Oncology. "It was configured to work specifically in NSCLC patients, and we have ensured that it is a very high-quality product that is reproducible."
The cost of the test is in line with other clinically validated assays of this type, and will be less than $250 per patient. "We believe that the test brings an extremely high value to this patient population and the outcome of the therapeutics," Dr. Becker said.
Dr. Becker also feels that this test will eventually be widely used. "In the clinic today, a number of biomarkers are commonly being tested for," she said. "We believe that the Abbott ALK FISH test will become a standard part of testing for nonsmall-cell lung cancer patients, along with EGFR mutations and KRAS status."
Both the diagnostic test and crizotinib were accelerated approvals. "The fact that Pfizer and Abbott were able to work together, in concert with the FDA, to bring both the therapeutic and the diagnostic to approval so early is a testament to the way that Pfizer and Abbott have communicated and collaborated throughout this whole process," she added. "It has been a great pleasure working with Pfizer. We had a really interactive collaboration; without that, we may not have been that successful."
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Cite this: Crizotinib Is 'Major Breakthrough for Genomic Medicine' - Medscape - Sep 01, 2011.