This article has been updated to clarify that the companion test being developed by Abbott is part of the development program for Pfizer's crizotinib, and is intended to be used to gauge best responders for that specific drug.
By Turna Ray
Pfizer and Abbott are simultaneously filing submissions to the US Food and Drug Administration for a drug/diagnostic combination product for the treatment of non-small cell lung cancer.
The drug firm received fast-track designation in December for crizotinib (PF-02341066), an investigational NSCLC treatment in patients with a fusion gene joining portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. Crizotinib is an inhibitor of ALK2 alternation in the ALK gene.
Pfizer is pursuing a personalized strategy for crizotinib, by administering the drug only to NSCLC patients carrying the EML4-ALK-fusion oncogene. The drug is being advanced in clinical trials with the help of a FISH test by Abbott Molecular (PGx Reporter 06/09/10). Pfizer is also exploring RT-PCR diagnostics for gauging ALK alterations.
Pfizer expects to complete its rolling submission in the first half of this year. A spokesperson for Abbott told PGx Reporter that the company is also in the process of filing a pre-market approval application simultaneously with Pfizer's NDA for crizotinib.
"We submitted information to the FDA to demonstrate that ALK-positive NSCLC is a serious and life-threatening condition with no adequate treatment available," a Pfizer spokesperson told PGx Reporter via e-mail. "Additionally, we provided information from clinical studies to indicate that crizotinib (PF-02341066) has the potential to address the unmet medical need for patients with ALK-positive NSCLC." FDA's fast-track regulatory filing facilitates the speedy approval and availability of treatments for life-threatening conditions and that fill an unmet medical need.
The Abbott spokesperson added that the development program for the FISH test will validate its use to gauge ALK rearrangements. The clinical trial that Pfizer and Abbott will conduct using the test will validate its use as a diagnostic to gauge best responders for crizotinib.
"The clinical development study report is the link between the diagnostic and the drug compound," the Abbott spokesperson said. "There is one study/report for the combination product. The clinical section of the PMA for the diagnostic includes the data from this study."
According to Clinicaltrials.gov, Pfizer is currently recruiting patients for the ongoing study, A8081007, a Phase III trial comparing the safety and anti-tumor activity of crizotinib versus pemetrexed or docetaxel in advanced NSCLC patients who are EML4-ALK positive. The primary endpoint is progression-free survival in crizotinib-treated patients compared to those receiving pemetrexed or docetaxel. Secondary measures include objective response at 23 months, duration of response at 23 months, disease control rate at 30 months, overall survival at 30 months, quality of life, adverse events related to the drug and lab test abnormalities, as well as EML4-ALK fusion variants and ALK gene expression at 30 months.
Another study currently recruiting patients is a Phase II trial evaluating the safety and efficacy of crizotinib in NSCLC patients who are EML4-ALK positive. This trial will enroll patients who received standard of care in A8081007. The primary endpoint in this study, A8081005, is objective response rate at 30 months, as well as drug-related adverse events and lab test abnormalities.
Unfortunately, early studies suggest that some patients who initially have good response to crizotinib become resistant to the drug's effects after several months. In a study published in the New England Journal of Medicine in October, researchers from Jichi Medical University, Tokyo University, and elsewhere reported on the identification of two mutations in EML4-ALK that appear to confer resistance to the drug.
In the NEJM study, Young Lim Choi and colleagues reported on the experience of a 28-year-old man who, upon failing chemotherapy treatment for his lung cancer, was tested for the presence of the EML4-ALK-fusion oncogene and found to be positive. He was enrolled in a clinical trial studying crizotinib and given the drug. The patient experienced marked improvement in his symptoms but lung tumors began to grow again after five months of treatment. At this point the patient was withdrawn from the trial.
In order to gauge resistance mutations, researchers performed molecular analysis on a sample from the patient's right lung. Deep sequencing using Illumina's Genome Analyzer and subsequent confirmation by Sanger Sequencing revealed "two new alterations, G→A and C→A changes at positions corresponding to nucleotides 4374 and 4493 of wild-type ALK cDNA." According to the study authors, these alterations were detected at high frequencies in the patient’s pleural effusion cDNA.
Although these findings require further confirmation in larger cohorts, the investigators posited that its "likely that [these] gatekeeper alterations constitute a universal mechanism for the acquisition of tyrosine kinase–inhibitor resistance in oncogenic tyrosine kinases."
Pfizer estimates that between 3 percent and 5 percent of NSCLC tumors are ALK-positive. "By inhibiting ALK, crizotinib … blocks signaling in a number of cell pathways that are critical for the growth and survival of tumor cells," Pfizer said in a statement, adding that drug is also an inhibitor of c-mesenchymal endothelial transition factor, or C-MET.
Metastatic NSCLC cancer patients account for around 85 percent of lung cancer cases, and 15 percent of patients with an advanced form of the disease respond to standard care.
Bosutinib Filing Plans
Pfizer also plans regulatory submissions to the FDA and the European Medicines Agency for two other investigational oncology compounds in 2011 — axitinib, an oral and selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, for the treatment of patients with metastatic renal cell carcinoma; and bosutinib, an oral dual SRC and ABL kinase inhibitor, for the treatment of newly diagnosed and previously Gleevec-treated patients with Philadelphia chromosome-positive chromic myeloid leukemia.
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Ph+ CML is caused by a mutation that results in the translocation between the proto-oncogene ABL and the BCR gene, which in turn drives the growth and spread of CML cells in the body. Ph+ CML mutations can be detected via FISH, reverse transcriptase PCR, or real-time PCR.
Pfizer is hoping that bosutinib, as an inhibitor of both SRC and ABL kinases, will block cell signaling in CML. However, it is unclear how far Pfizer has gone in validating the role of certain BCR-ABL mutations that might improve bosutinib response in patients who harbor them.
At the American Society of Clinical Oncology's annual meeting last year, researchers from Pfizer, MD Anderson, and institutes in Korea, Russia, and Italy reported results from a Phase I/II study investigating the efficacy and safety of bosutinib in patients with chronic phase chronic myeloid leukemia who failed treatment with Gleevec (imatinib). Resistance to Gleevec has been attributed to a number of reasons, including over-expression of the BCR-ABL transcript, BCR-ABL gene amplification, as well as point mutations in the ATP-binding site of BCR-ABL.
In the Phase I/II study involving nearly 300 chronic phase CML patients, of 132 evaluable for hematological response, 78 percent had a complete response and 58 percent achieved a major cytogenetic response, 46 percent of which were complete responses. Additionally, 156 patients were analyzed for molecular responses, and 30 percent had a complete molecular response.
In this study, researchers identified 20 different mutations at baseline in 45 out of 99 patients tested. Complete response occurred in 78 percent of patients with mutations and in 89 percent of patients with no mutations. Major cytogenetic response occurred in 60 percent of patients with mutations and 54 percent of patients with no mutations.
Based on these results, researchers concluded that “bosutinib is an active agent for patients with CP CML who failed prior imatinib, including patients with a wide variety of BCR-ABL mutations.” Additionally, researchers noted that the drug “demonstrated a favorable toxicity profile with minimal hematologic toxicity.”
Currently, the submission plans for bosutinib to the FDA and EMA do not discuss analysis of BCR-ABL response mutations.
According to Pfizer, the submission to the EMA will be based on results from an ongoing, Phase III, randomized trial comparing bosutinib and imatinib in newly diagnosed patients with chronic phase Ph+ CML, called the Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia, or BELA, study.
Pfizer's submission for bosutinib to the FDA would be based on 24-month efficacy and safety data in Study 200, a single-arm study of bosutinib in more than 500 patients with previously treated Ph+ CML, including patients resistant to or intolerant to Gleevec as well as patients who have become refractory to dasatinib or nilotinib. If approved for this indication, it would cater to an unmet need in Ph+ CML, since currently there are no approved therapies for patients who have failed treatment with dasatinib or nilotinib in the second line.
At the annual meeting of the American Society of Hematology last year, Pfizer presented preliminary data from BELA in which bosutinib failed to show superior complete cytogenetic response to Gleevec in Ph+ CML patients, the primary endpoint. However, the drug did meet a secondary endpoint for superior major molecular response compared to Gleevec in newly diagnosed Ph+ CML patients.
Additionally, according to initial data from BELA, more patients on bosutinib experienced serious adverse events and discontinued participation in the trial than did patients on Gleevec.
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