Crizotinib Approval Personalizes Lung Cancer Therapy

The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represents another milestone in biomarker-driven, personalized medicine.

Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets. Pfizer is authorized to market crizotinib as Xalkori for use in patients who test positive for the abnormality.

The ALK fusion gene – comprising portions of the EML4 (echinoderm microtubule–associated proteinlike 4) gene and the ALK gene – is present in about 3%-5% of all patients with NSCLC. Although the percentage is small, it translates to approximately 6,000-11,000 new patients annually in the United States, which is more than the numbers being diagnosed with Hodgkin’s disease, cancer of the testis, or chronic myelogenous leukemia.

"Having this number of people we can affect is really an important development in oncology," commented Dr. Mark G. Kris, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York, during a press briefing sponsored by Pfizer.

The approval "is a delivery on the promise of personalized medicine and genomic medicine. Many folks have wondered how these concepts translate into reality. This is an example of exactly that," said Dr. Kris, a professor of medicine at Cornell University in New York.

Crizotinib is part of a paradigm shift in lung cancer management, observed Dr. Paul A. Bunn Jr., professor of medicine and the James Dudley Chair in Cancer Research at the University of Colorado at Denver. Increasingly, patients are tested for specific mutations and if they are positive, they can be treated with targeted therapies, usually pills that are safer and typically more effective than the conventional chemotherapy and radiation.

The American Society of Clinical Oncology and the National Comprehensive Cancer Network have each issued guidelines recommending that NSCLC patients be tested for mutation of the EGFR (epidermal growth factor receptor) to identify those who might benefit from tyrosine kinase inhibitors targeting EGFR. Gefitinib (Iressa) and erlotinib (Tarceva) have proved effective in clinical trials in this population, but only erlotinib is widely available in the United States.

The experimental BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trials program at the University of Texas M.D. Anderson Cancer Center in Houston has shown that it is feasible to biopsy late-stage NSCLC patients and base the choice of therapies on the results of molecular tests for abnormal KRAS, EGFR, and other genes.

Currently, the Lung Cancer Mutation Consortium is engaged in a collaborative project profiling 10 genes, including KRAS, ALK, and EGFR, in 1,000 patients at participating cancer centers. Investigators have reported that 280 (54%) of the first 516 patients were found to have at least one known driver mutation. Patients are being directed to approved targeted therapies where available, or to clinical trials of novel therapies targeting their specific mutations.

"The message is, lung cancers are not all the same. They have different molecular changes," Dr. Bunn said at the crizotinib briefing. "At the time of diagnosis, physicians need to be testing their patients for these molecular changes, and patients who have one of these changes are likely to have prolonged benefit from a pill that is more active than multiagent chemotherapy."

Indeed, Dr. Kris pointed out, in clinical trials crizotinib benefited nearly all patients with the ALK fusion gene, although the degree of benefit varied. On the other hand, withholding crizotinib from patients who test negative means they will be spared the side effects and the waste of time and resources associated with a treatment that won’t work for them. "Having a tablet makes the administration so much easier than intravenous chemotherapy," he added.

How Crizotinib Received FDA Approval

The FDA approval was based on two multicenter, single-arm studies that enrolled 255 late-stage NSCLC patients who tested positive for the ALK fusion gene before enrollment. In most cases, the patients had prior chemotherapy. Objective response rates were 50% (median duration, 42 weeks) in one study, and 61% (median duration, 48 weeks) in the other.

Among the most common side effects in the trials, the FDA listed vision disorders (visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects), nausea, diarrhea, vomiting, edema, and constipation. Pfizer noted that grade 3 or 4 adverse events occurring in 4% or more of patients included increased ALT and neutropenia; it said that QT prolongation has also been observed.

The FDA also warned that crizotinib has been associated with potentially life-threatening pneumonitis (4 of 255 patients; 1.6%); the drug should be stopped permanently in patients with treatment-related pneumonitis, the agency said. Pregnancy is also a contraindication.

Consideration of crizotinib was expedited under the FDA’s priority review program for drugs with the potential to provide major advances in diseases for which no effective therapy exists. No survival data were reported, and the agency granted accelerated approval based on the objective response rates being reasonably likely to predict clinical benefit. Confirmatory trials are required.

Pfizer is already conducting two randomized, open-label, postmarketing phase III studies: one comparing the safety and efficacy of crizotinib with standard of care chemotherapy (pemetrexed [Alimta] or docetaxel [Taxotere]) in patients with previously treated, advanced, ALK-positive NSCLC, and the other comparing efficacy and safety of the agent to pemetrexed/cisplatin or pemetrexed/carboplatin in previously untreated patients with advanced, ALK-positive, nonsquamous NSCLC, according to a Pfizer statement.

Dr. Kris predicted that the addition of the required ALK fusion diagnostic test – at a cost of $250 – won’t be a large burden. "I think it will be very quick to add ALK testing as part of that," he said, noting the ASCO and NCCN recommendations for EGFR testing.

Because the fusion gene has been seen in patients with lung tumors other than adenocarcinomas, testing should ideally be done in all lung cancer patients, Dr. Kris added. "Based on broader experience with EGFR mutations, I think we’ve learned that there is no clinical profile that comes anywhere near the accuracy of the testing. ... I would caution against any particular kind of profile that would make one select who to test and who not to test," he said.

Recommended dosing is 250 mg taken orally twice daily with or without food. In some patients, a dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required; if further reduction is necessary, the label recommends 250 mg taken orally once daily.

Monthly treatment with crizotinib will cost $9,600. And because the tumor is driven by the mutation, the treatment is indefinite. Several patients from the trials have now been taking the drug for more than a year. "There is no stop time as long as they’re benefiting," said Dr. Mace Rothenberg, Pfizer senior vice president of clinical development and medical affairs in the oncology business unit.

Pfizer has two financial assistance programs for patients. The Pfizer First Resource Program connects eligible insured patients to specialty pharmacies to get reimbursement-support services and to obtain the medications. For uninsured and underinsured patients, the program will provide eligible patients with free medication. There is also a copay assistance program for eligible privately insured patients. Information about eligibility can be obtained by calling First Resource (1-877-744-5675), or by visiting XALKORI.com.

Dr. Kris is a consultant for Pfizer. Dr. Bunn has served as a consultant or on an advisory board for several companies in the past 2 years, but noted that he received no funding for any press discussions or research on crizotinib and has no Pfizer stock.

The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represents another milestone in biomarker-driven, personalized medicine.

Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets. Pfizer is authorized to market crizotinib as Xalkori for use in patients who test positive for the abnormality.

The ALK fusion gene – comprising portions of the EML4 (echinoderm microtubule–associated proteinlike 4) gene and the ALK gene – is present in about 3%-5% of all patients with NSCLC. Although the percentage is small, it translates to approximately 6,000-11,000 new patients annually in the United States, which is more than the numbers being diagnosed with Hodgkin’s disease, cancer of the testis, or chronic myelogenous leukemia.

"Having this number of people we can affect is really an important development in oncology," commented Dr. Mark G. Kris, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York, during a press briefing sponsored by Pfizer.

The approval "is a delivery on the promise of personalized medicine and genomic medicine. Many folks have wondered how these concepts translate into reality. This is an example of exactly that," said Dr. Kris, a professor of medicine at Cornell University in New York.

Crizotinib is part of a paradigm shift in lung cancer management, observed Dr. Paul A. Bunn Jr., professor of medicine and the James Dudley Chair in Cancer Research at the University of Colorado at Denver. Increasingly, patients are tested for specific mutations and if they are positive, they can be treated with targeted therapies, usually pills that are safer and typically more effective than the conventional chemotherapy and radiation.

The American Society of Clinical Oncology and the National Comprehensive Cancer Network have each issued guidelines recommending that NSCLC patients be tested for mutation of the EGFR (epidermal growth factor receptor) to identify those who might benefit from tyrosine kinase inhibitors targeting EGFR. Gefitinib (Iressa) and erlotinib (Tarceva) have proved effective in clinical trials in this population, but only erlotinib is widely available in the United States.

The experimental BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trials program at the University of Texas M.D. Anderson Cancer Center in Houston has shown that it is feasible to biopsy late-stage NSCLC patients and base the choice of therapies on the results of molecular tests for abnormal KRAS, EGFR, and other genes.

Currently, the Lung Cancer Mutation Consortium is engaged in a collaborative project profiling 10 genes, including KRAS, ALK, and EGFR, in 1,000 patients at participating cancer centers. Investigators have reported that 280 (54%) of the first 516 patients were found to have at least one known driver mutation. Patients are being directed to approved targeted therapies where available, or to clinical trials of novel therapies targeting their specific mutations.

"The message is, lung cancers are not all the same. They have different molecular changes," Dr. Bunn said at the crizotinib briefing. "At the time of diagnosis, physicians need to be testing their patients for these molecular changes, and patients who have one of these changes are likely to have prolonged benefit from a pill that is more active than multiagent chemotherapy."

Indeed, Dr. Kris pointed out, in clinical trials crizotinib benefited nearly all patients with the ALK fusion gene, although the degree of benefit varied. On the other hand, withholding crizotinib from patients who test negative means they will be spared the side effects and the waste of time and resources associated with a treatment that won’t work for them. "Having a tablet makes the administration so much easier than intravenous chemotherapy," he added.

How Crizotinib Received FDA Approval

The FDA approval was based on two multicenter, single-arm studies that enrolled 255 late-stage NSCLC patients who tested positive for the ALK fusion gene before enrollment. In most cases, the patients had prior chemotherapy. Objective response rates were 50% (median duration, 42 weeks) in one study, and 61% (median duration, 48 weeks) in the other.

Among the most common side effects in the trials, the FDA listed vision disorders (visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects), nausea, diarrhea, vomiting, edema, and constipation. Pfizer noted that grade 3 or 4 adverse events occurring in 4% or more of patients included increased ALT and neutropenia; it said that QT prolongation has also been observed.

The FDA also warned that crizotinib has been associated with potentially life-threatening pneumonitis (4 of 255 patients; 1.6%); the drug should be stopped permanently in patients with treatment-related pneumonitis, the agency said. Pregnancy is also a contraindication.

Consideration of crizotinib was expedited under the FDA’s priority review program for drugs with the potential to provide major advances in diseases for which no effective therapy exists. No survival data were reported, and the agency granted accelerated approval based on the objective response rates being reasonably likely to predict clinical benefit. Confirmatory trials are required.

Pfizer is already conducting two randomized, open-label, postmarketing phase III studies: one comparing the safety and efficacy of crizotinib with standard of care chemotherapy (pemetrexed [Alimta] or docetaxel [Taxotere]) in patients with previously treated, advanced, ALK-positive NSCLC, and the other comparing efficacy and safety of the agent to pemetrexed/cisplatin or pemetrexed/carboplatin in previously untreated patients with advanced, ALK-positive, nonsquamous NSCLC, according to a Pfizer statement.

Dr. Kris predicted that the addition of the required ALK fusion diagnostic test – at a cost of $250 – won’t be a large burden. "I think it will be very quick to add ALK testing as part of that," he said, noting the ASCO and NCCN recommendations for EGFR testing.

Because the fusion gene has been seen in patients with lung tumors other than adenocarcinomas, testing should ideally be done in all lung cancer patients, Dr. Kris added. "Based on broader experience with EGFR mutations, I think we’ve learned that there is no clinical profile that comes anywhere near the accuracy of the testing. ... I would caution against any particular kind of profile that would make one select who to test and who not to test," he said.

Recommended dosing is 250 mg taken orally twice daily with or without food. In some patients, a dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required; if further reduction is necessary, the label recommends 250 mg taken orally once daily.

Monthly treatment with crizotinib will cost $9,600. And because the tumor is driven by the mutation, the treatment is indefinite. Several patients from the trials have now been taking the drug for more than a year. "There is no stop time as long as they’re benefiting," said Dr. Mace Rothenberg, Pfizer senior vice president of clinical development and medical affairs in the oncology business unit.

Pfizer has two financial assistance programs for patients. The Pfizer First Resource Program connects eligible insured patients to specialty pharmacies to get reimbursement-support services and to obtain the medications. For uninsured and underinsured patients, the program will provide eligible patients with free medication. There is also a copay assistance program for eligible privately insured patients. Information about eligibility can be obtained by calling First Resource (1-877-744-5675), or by visiting XALKORI.com.

Dr. Kris is a consultant for Pfizer. Dr. Bunn has served as a consultant or on an advisory board for several companies in the past 2 years, but noted that he received no funding for any press discussions or research on crizotinib and has no Pfizer stock.

The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represents another milestone in biomarker-driven, personalized medicine.

Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets. Pfizer is authorized to market crizotinib as Xalkori for use in patients who test positive for the abnormality.

The ALK fusion gene – comprising portions of the EML4 (echinoderm microtubule–associated proteinlike 4) gene and the ALK gene – is present in about 3%-5% of all patients with NSCLC. Although the percentage is small, it translates to approximately 6,000-11,000 new patients annually in the United States, which is more than the numbers being diagnosed with Hodgkin’s disease, cancer of the testis, or chronic myelogenous leukemia.

"Having this number of people we can affect is really an important development in oncology," commented Dr. Mark G. Kris, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York, during a press briefing sponsored by Pfizer.

The approval "is a delivery on the promise of personalized medicine and genomic medicine. Many folks have wondered how these concepts translate into reality. This is an example of exactly that," said Dr. Kris, a professor of medicine at Cornell University in New York.

Crizotinib is part of a paradigm shift in lung cancer management, observed Dr. Paul A. Bunn Jr., professor of medicine and the James Dudley Chair in Cancer Research at the University of Colorado at Denver. Increasingly, patients are tested for specific mutations and if they are positive, they can be treated with targeted therapies, usually pills that are safer and typically more effective than the conventional chemotherapy and radiation.

The American Society of Clinical Oncology and the National Comprehensive Cancer Network have each issued guidelines recommending that NSCLC patients be tested for mutation of the EGFR (epidermal growth factor receptor) to identify those who might benefit from tyrosine kinase inhibitors targeting EGFR. Gefitinib (Iressa) and erlotinib (Tarceva) have proved effective in clinical trials in this population, but only erlotinib is widely available in the United States.

The experimental BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trials program at the University of Texas M.D. Anderson Cancer Center in Houston has shown that it is feasible to biopsy late-stage NSCLC patients and base the choice of therapies on the results of molecular tests for abnormal KRAS, EGFR, and other genes.

Currently, the Lung Cancer Mutation Consortium is engaged in a collaborative project profiling 10 genes, including KRAS, ALK, and EGFR, in 1,000 patients at participating cancer centers. Investigators have reported that 280 (54%) of the first 516 patients were found to have at least one known driver mutation. Patients are being directed to approved targeted therapies where available, or to clinical trials of novel therapies targeting their specific mutations.

"The message is, lung cancers are not all the same. They have different molecular changes," Dr. Bunn said at the crizotinib briefing. "At the time of diagnosis, physicians need to be testing their patients for these molecular changes, and patients who have one of these changes are likely to have prolonged benefit from a pill that is more active than multiagent chemotherapy."

Indeed, Dr. Kris pointed out, in clinical trials crizotinib benefited nearly all patients with the ALK fusion gene, although the degree of benefit varied. On the other hand, withholding crizotinib from patients who test negative means they will be spared the side effects and the waste of time and resources associated with a treatment that won’t work for them. "Having a tablet makes the administration so much easier than intravenous chemotherapy," he added.

How Crizotinib Received FDA Approval

The FDA approval was based on two multicenter, single-arm studies that enrolled 255 late-stage NSCLC patients who tested positive for the ALK fusion gene before enrollment. In most cases, the patients had prior chemotherapy. Objective response rates were 50% (median duration, 42 weeks) in one study, and 61% (median duration, 48 weeks) in the other.

Among the most common side effects in the trials, the FDA listed vision disorders (visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects), nausea, diarrhea, vomiting, edema, and constipation. Pfizer noted that grade 3 or 4 adverse events occurring in 4% or more of patients included increased ALT and neutropenia; it said that QT prolongation has also been observed.

The FDA also warned that crizotinib has been associated with potentially life-threatening pneumonitis (4 of 255 patients; 1.6%); the drug should be stopped permanently in patients with treatment-related pneumonitis, the agency said. Pregnancy is also a contraindication.

Consideration of crizotinib was expedited under the FDA’s priority review program for drugs with the potential to provide major advances in diseases for which no effective therapy exists. No survival data were reported, and the agency granted accelerated approval based on the objective response rates being reasonably likely to predict clinical benefit. Confirmatory trials are required.

Pfizer is already conducting two randomized, open-label, postmarketing phase III studies: one comparing the safety and efficacy of crizotinib with standard of care chemotherapy (pemetrexed [Alimta] or docetaxel [Taxotere]) in patients with previously treated, advanced, ALK-positive NSCLC, and the other comparing efficacy and safety of the agent to pemetrexed/cisplatin or pemetrexed/carboplatin in previously untreated patients with advanced, ALK-positive, nonsquamous NSCLC, according to a Pfizer statement.

Dr. Kris predicted that the addition of the required ALK fusion diagnostic test – at a cost of $250 – won’t be a large burden. "I think it will be very quick to add ALK testing as part of that," he said, noting the ASCO and NCCN recommendations for EGFR testing.

Because the fusion gene has been seen in patients with lung tumors other than adenocarcinomas, testing should ideally be done in all lung cancer patients, Dr. Kris added. "Based on broader experience with EGFR mutations, I think we’ve learned that there is no clinical profile that comes anywhere near the accuracy of the testing. ... I would caution against any particular kind of profile that would make one select who to test and who not to test," he said.

Recommended dosing is 250 mg taken orally twice daily with or without food. In some patients, a dosing interruption and/or dose reduction to 200 mg taken orally twice daily may be required; if further reduction is necessary, the label recommends 250 mg taken orally once daily.

Monthly treatment with crizotinib will cost $9,600. And because the tumor is driven by the mutation, the treatment is indefinite. Several patients from the trials have now been taking the drug for more than a year. "There is no stop time as long as they’re benefiting," said Dr. Mace Rothenberg, Pfizer senior vice president of clinical development and medical affairs in the oncology business unit.

Pfizer has two financial assistance programs for patients. The Pfizer First Resource Program connects eligible insured patients to specialty pharmacies to get reimbursement-support services and to obtain the medications. For uninsured and underinsured patients, the program will provide eligible patients with free medication. There is also a copay assistance program for eligible privately insured patients. Information about eligibility can be obtained by calling First Resource (1-877-744-5675), or by visiting XALKORI.com.

Dr. Kris is a consultant for Pfizer. Dr. Bunn has served as a consultant or on an advisory board for several companies in the past 2 years, but noted that he received no funding for any press discussions or research on crizotinib and has no Pfizer stock.