Experimental Lung Cancer Drug Crizotinib Meets Some Resistance From Tumors

Pfizer (Nasdaq: PFE) Inc's xperimental Lung Cancer Drug Crizotinib ( PF-02341066) said to be helping as much as 5% of lung cancer patients, while seems to be promising, might meet some resistance from some mutations of lung cancer.
Lung cancer affects 1.61 million people world wide, every year and 1.2 million succumb tot he illness. So any drug that effective against lung cancer will help to save that many people.
Crizotinib said to have shrunk tumors in 57% of the patients introduced to the drug. Another 33% of patients had the the cancer stabilized according to a study published in the New England Journal of Medicine.

"While this is a Phase 1 study, the high response rates  observed in patients with ALK-positive (lung cancer) who received crizotinib suggest that we may be one step closer to the development of 'precision' or 'personalized' cancer treatments that target specific genetic factors that drive certain tumors," said Pfizer's Dr. Mace Rothenberg.

Doctors of the University of Tokyo found a patient who developed two mutations that were resistant to Crizotinib. But the doctors were positive about the drug and also about being able to isolate the resistive mutations. Because a new drug could be developed to target these tumors.
The Pfizer's drug, Crizotinib works against cells that have turned cancerous when two genes fuse to form a new gene called EML4-ALK. Although only about 3 percent to 5 percent of people with non-small-cell lung cancer fall into this category, that translates into nearly 10,000 cancer patients in the United States alone.
AstraZeneca's Iressa and Roche's Tarceva are already known to be effective against cancer in patients with a mutation activating the epidermal growth factor receptor (EGFR).
Pfizer plans to submit the drug for approval early next year.

Pfizer press release;

Oct 27, 2010
5:01pm

NEW YORK, Oct. 27-- Pfizer Inc. (NYSE: PFE) announced today the publication of data showing that 57 percent of ALK-positive advanced non-small cell lung cancer (NSCLC) patients treated with crizotinib (PF-02341066), an investigational oral anaplastic lymphoma kinase (ALK) inhibitor, had either a complete (one patient) or partial (46 patients) response to treatment.  Data from 82 patients in this Part 2 expansion cohort of the Phase 1 study were published in the October 28 issue of the New England Journal of Medicine.(1)

"It is gratifying to learn of responses like those seen in our study of crizotinib (PF-02341066), especially when you consider that most patients had already received two or more therapies by the time they entered the trial," said Dr. Eunice Kwak, MD, Ph.D., department of medicine, Harvard Medical School, assistant in medicine, hematology/oncology, Massachusetts General Hospital and lead author of the study.  "As we're discovering more about lung cancer, we have confirmed the fundamental need to test tumors for molecular changes, like the ALK fusion gene, so we can better identify the patients who may benefit from certain treatments."
Updated results from this study were also recently presented at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy, reporting on 113 patients and preliminary median progression-free survival (PFS) data of 9.2 months.(2)
Study A8081001 is a 2-part Phase 1 open-label, multi-center study evaluating crizotinib (PF-02341066), in patients with solid tumors.(3)  The Part 2 expansion cohort from study A8081001 is evaluating the safety and response of crizotinib (PF-02341066) in patients with ALK-positive advanced NSCLC treated with a dose of 250 mg twice daily.(1)
Crizotinib (PF-02341066) is a first-in-class compound that inhibits the anaplastic lymphoma kinase, or ALK.(4)  ALK is believed to be a tumor-exclusive target that is a key driver of oncogenesis, or tumor development.(5)  Approximately 3-5 percent of NSCLC tumors are ALK-positive.(4)
"The development of crizotinib is a testament to the benefits of collaboration and partnership, between industry and academia, with investigators from all over the world, including the United States, Japan, Korea and Australia, working together with the goal of discovering a more effective treatment for advanced NSCLC patients with few other options," said Dr. Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit.  "While this is a Phase 1 study, the high response rates observed in patients with ALK+ NSCLC who received crizotinib suggest that we may be one step closer to the development of "precision" or "personalized" cancer treatments that target specific genetic factors that drive certain tumors."
Pfizer is continuing to study crizotinib (PF-02341066) in an ongoing clinical development program,(6,7) and plans to submit crizotinib (PF-02341066) data in the first half of next year to the U.S. Food and Drug Administration (FDA) for regulatory review.
Additional trials of crizotinib (PF-02341066) include a randomized, Phase 3 open-label study, PROFILE 1007 (A8081007), evaluating the safety and anti-tumor activity of crizotinib (PF-02341066) versus standard of care chemotherapy in patients with previously treated ALK-positive advanced NSCLC.(5)  PROFILE 1005 (A8081005) is a Phase 2 open-label, single-arm study of efficacy and safety of crizotinib (PF-02341066) in patients with ALK-positive advanced NSCLC who have received more than one line of prior chemotherapy.(6)
For more information on these clinical trials, please contact the Pfizer Oncology Clinical Trial Information Service at 1-877-369-9753 (US/Canada) or 1-646-277-4066 (international), via email at PfizerHPTrials@emergingmed.com or visit www.pfizercancertrials.com.
Study Results Published in the New England Journal of Medicine
In the Part 2 expansion cohort study which included 82 patients with ALK-positive advanced NSCLC, 57 percent (n=47)(95% CI 46%, 68%) of patients treated with crizotinib (PF-02341066) at a dose of 250 mg twice daily had either a complete or partial response to treatment.  An additional 33 percent (n=27) met criteria for stable disease, including five unconfirmed partial responses.  At eight weeks, the disease control rate (complete response (n=1) + partial response (n=46) + stable disease (n=24)) was 87 percent (n=71).  Three patients with stable disease were not included in the disease control rate because their evaluation for response was outside a pre-specified timeframe.(1)
At the time of the analysis, 77 percent of patients (n=63) continued to receive treatment with crizotinib (PF-02341066).  The median duration of treatment was 6.4 months, and follow-up is ongoing.
The most commonly reported all-grade adverse events associated with crizotinib included nausea (n=44), diarrhea (n=39), vomiting (n=36), and mild visual disturbances (n=34).  Grade 3 ALT (alanine aminotransferase) and AST (aspartate aminotransferase) elevations occurred in four patients.  One patient experienced a Grade 4 elevation in ALT and one patient discontinued treatment due to Grade 3 ALT increases. Tumors in the analysis were primarily of adenocarcinoma histology, and patients tended to be young, and were never or former light smokers.  Ninety-three percent of patients (n=76) had received at least one prior therapy and five patients were treated in the first-line setting.(1)  This Part 2 expansion cohort study of patients with ALK-positive advanced NSCLC, independent of the number of previous chemotherapies, followed the completion of the dose-escalation study which enrolled 37 advanced cancer patients with various tumors, including NSCLC, colorectal, pancreatic and inflammatory myofibroblastic tumor (IMT) tumors.(8)
These data were previously presented at the 2010 American Society of Clinical Oncology Annual Meeting.(7)
About Crizotinib (PF-02341066)
Crizotinib (PF-02341066) is a first-in-class compound that inhibits the anaplastic lymphoma kinase, or ALK,(3) and is representative of Pfizer's personalized medicine approach to cancer treatment.  By inhibiting ALK, crizotinib (PF-02341066) blocks signaling in a number of cell pathways that may be critical for the growth and survival of tumor cells.(4)  Crizotinib (PF-02341066) is also an inhibitor of c-MET (mesenchymal endothelial transition factor).(3)
About Non-Small Cell Lung Cancer
Lung cancer is one of the most common cancers worldwide.(9)  NSCLC accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting. Approximately 75 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease, where the five-year survival rate is only 6 percent.(10,11)  In addition, the current standard of care for advanced NSCLC demonstrates a response rate of only about 15 percent.(12)  Approximately 3-5 percent of NSCLC tumors are ALK-positive.(4)