By Turna Ray
The recent approval of Pfizer's non-small cell lung cancer treatment Xalkori along with a companion test developed by Abbott Molecular serves as the latest example of how drug and diagnostic developers can use pharmacogenomic strategies to speed up drug development.
Xalkori's approval as an orphan drug also represents the successful use of available regulatory incentives to develop a drug that meets the unmet needs of a small, genomically defined patient subpopulation.
On Aug. 26, the US Food and Drug Administration approved Pfizer's Xalkori (crizotinib) for the treatment of locally advanced or metastatic NSCLC patients whose tumors harbor the EML4-ALK fusion gene. Simultaneously, the agency also approved Abbott Molecular's Vysis ALK Break Apart Fluorescence In Situ Hybridization Probe Kit. Under the terms of the drug/diagnostic codevelopment arrangement, Abbott is responsible for the commercialization and sale of the test. Pfizer is responsible for the commercialization and sale of Xalkori.
The approval came just weeks after the FDA approved Roche's melanoma drug Zelboraf alongside a companion test that detects the BRAF V600E mutation indicating which patients will respond to the drug — a step that Alberto Gutierrez, director of the FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, described as "a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner" (PGx Reporter 8/17/2011).
Pfizer highlighted the simultaneous approval of Xalkori and its companion test as the "first time a Pfizer oncology drug or any lung cancer medication was developed and approved in parallel with a diagnostic test." The company noted that Xalkori is also the first new NSCLC drug approved by the FDA in more than six years.
In addition to receiving orphan drug designation, the FDA granted Pfizer's new drug application for Xalkori priority review and fast-track status, providing a six-month window for approval of the drug, though the actual approval process for the combination product took around three months.
Upon approval of the combination product, Pfizer made the drug available immediately through a number of specialty pharmacies, including US Bioservices, CuraScript, and Walgreens. A website for the Vysis ALK Break Apart FISH Probe Kit allows visitors to find labs that offer the test. According to the site, the test is currently being performed by Abbott subsidiary and clinical lab Cynogen.
The drug costs $115,200 per year, and the test costs less than $250 per patient. Costly cancer drugs with limited efficacy and serious side effects have recently come under fire from critics who have flagged them as the types of expenditures that contribute to rising healthcare costs. However, a Pfizer spokesperson noted that "unnecessary costs for patients and payors may be avoided since [the drug] will be prescribed only to a select patient population more likely to respond to treatment."
The National Cancer Institute estimates that there were 222,520 newly diagnosed cases of NSCLC last year and 157,300 deaths from the disease. It is estimated that between 3 percent and 5 percent of NSCLC tumors harbor ALK gene fusions.
Pfizer will provide reimbursement support services for "eligible insured patients" through its First Resource Program. "For uninsured and underinsured patients, the program will provide eligible patients with free medicine," the company said in a statement, adding that through Pfizer's co-pay assistance program, privately insured patients who meet certain financial requirements will pay no more than $100 per month for their Xalkori prescription.
Xalkori was approved with orphan drug status, a mechanism that the FDA uses to incentivize the development of drugs for rare diseases. Industry observers have often urged FDA to apply the orphan drug designation more readily to genomically guided personalized drugs as a way to encourage pharmaceutical companies to invest in the development of such treatments for a small number of patients that harbor molecular changes that are often rare.
Based on the estimate that between 3 percent and 5 percent of NSCLC patients harbor the ALK rearrangements that Xalkori targets the drug would be indicated for between 6,500 and 11,000 NSCLC patients in the US annually.
Under a 1983 law, an orphan drug is defined as a treatment for a disease that affects fewer than 200,000 patients in the US. Companies who develop drugs that fall under this designation receive tax incentives for clinical research, are eligible for grant funding for early-phase studies, are exempt for application filing fees, and receive study design assistance from the FDA. Most importantly, orphan drugs have seven years of marketing exclusivity following FDA approval, instead of the five years given to new chemical entities and the three years granted for new indications of a previously approved drug.
Pharmacogenomically targeted drugs such as Xalkori qualify for orphan drug status since they treat a small, genetically differentiated subset of patients with a disease that otherwise wouldn't be considered a rare disease. "A sponsor may seek orphan drug designation for a rare subset of a non-rare disease or condition if there is some property of the product (mechanism of action, toxicity profile, etc.) such that the product would be considered promising for treating the rare subset of the disease or condition but would not be useful in treating the complement of the subset of the disease or condition," an FDA spokesperson explained to PGx Reporter in an e-mail. "This is defined as an 'Orphan Subset' or, in our regulations, a 'Medically Plausible Subset.'"
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Xalkori isn't the first example of a PGx-guided drug receiving orphan drug status. Well before Xalkori's approval, Novartis' Gleevec was approved in 2002 as an orphan drug for Philadelphia chromosome-positive chronic myeloid leukemia, a disease that affects 40,000 people in the US. The FDA spokesperson also noted that the agency had given orphan designation to ImClone's and Bristol-Myers Squibb's Erbitux as a treatment for squamous cell carcinoma of the head and neck in patients expressing epidermal growth factor receptor.
But not every drug that relies on a companion test to identify a subpopulation of responders or nonresponders qualifies for orphan status. For example, the FDA has updated the labels of Erbitux and Amgen's Vectibix in metastatic colorectal cancer to recommend that patients with certain KRAS mutations should not receive the drugs. However, these PGx indications were not deemed to be an orphan subset for several reasons.
First, the sponsors did not request such a designation. "It should be noted that the fact that a drug might be more effective in treating a rare subset of a disease or condition in which the patient is deficient in the KRAS mutation … would not automatically qualify that product for orphan drug designation if the product could still be effective in patients that had the KRAS mutation," the agency spokesperson said.
Another factor barring Erbitux and Vectibix from receiving orphan drug status is that these treatments had their labels updated with PGx data in the post-market setting. "The Orphan Drug Act was meant to provide incentives for a sponsor to develop new or improved products for the treatment, diagnosis, or prevention of rare diseases or conditions," the FDA spokesperson noted. "A request for orphan drug designation must be submitted prior to the submission of a marketing application by the sponsor for use of the product for the rare disease or condition."
Similarly, companion tests for drugs or biologics that meet the orphan drug criteria could also receive a rare test designation. However, "when talking of a diagnostic in terms of drugs or devices, it is not the prevalence or incidence of the disease or condition that has the particular gene mutation that must be under the threshold for designation," the FDA spokesperson explained. Rather, the "total number of patients that will be subjected to the device or receive the drug per year in order to diagnose the mutation in the disease or condition must be under the threshold in order to meet the criteria for designation."
Toward Validating a Hypothesis
The time span between the discovery of the role of the EML4-ALK fusion gene in NSCLC and FDA approval of Xalkori and its companion genetic test was around four years. This represents a "remarkable feat in the oncology world" and "reinforces the importance of collaboration among academic research, pharmaceutical, diagnostic and regulatory organizations," according to Mace Rothenberg, senior VP of clinical development and medical affairs for Pfizer's Oncology Business Unit.
In a 2007 publication in Nature, researchers from Japanese institutions led by Hiroyuki Mano reported their finding that a small proportion of NSCLC patients harbor an EML4-ALK fusion gene in their lung cancer cells. "Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC," Mano et al. wrote.
Meanwhile, Pfizer's development program for PF-02341066, which would later be named crizotinib and then Xalkori, was already been underway. Pfizer researchers in La Jolla, Calif., had discovered the molecule in 2005, and began looking at it as a potential C-Met inhibitor and ALK inhibitor. After Mano and colleagues published their paper showing the EML4-ALK fusion gene's role in NSCLC, Pfizer decided to focus initially on patients with ALK-positive NSCLC.
After completing the necessary studies, Pfizer initiated a rolling submission for the drug in January of this year, and completed the last of its data submissions at the end of March. Following acceptance of the NDA and Abbott's premarket approval application for the FISH test it took the agency just over three months to issue a positive decision on the combination product.
"The scientific discoveries of the ALK fusion gene in NSCLC and the Xalkori molecule rapidly converged into one scientific path, which led to the development of a targeted … compound along with a companion diagnostic for a patient population with significant unmet need," the Pfizer spokesperson said.
Supporters of personalized medicine have long predicted that pharmacogenomic strategies would help drug developers run more efficient clinical trials by giving early indications of potentially successful products and lowering late-stage attrition rates. The speedy development and approval of Xalkori — as well as that of Roche/Plexxikon's melanoma drug Zelboraf — have tested and confirmed that hypothesis.
A few weeks before Xalkori's approval, the FDA simultaneously green-lighted Zelboraf and a companion test that picks out patients with BRAF mutations who are most likely to respond to the treatment. The agency had also granted Zelboraf priority review, which places the agency under a six-month clock to come to a decision, but approved the drug/test combination ahead of schedule in three months. The development program for Zelboraf — from the first published report linking BRAF mutations to melanoma in 2002 to receiving regulatory approval of the combination product — took nine years.
Given that the development of a drug from discovery to market launch is generally estimated to take between 15 to 20 years, the time frames for Xalkori and Zelboraf were still significantly faster than for drugs developed without the aid of companion tests. In both cases, the development of the drug was spurred by the knowledge of well-established pharmacogenomic biomarker leads.
The fact that Abbott already had a FISH-based ALK reagent in its portfolio certainly helped Abbott decrease the test development time and allowed Pfizer to run an efficient trial for Xalkori. Abbott originally launched its ALK FISH probe test in 1998. "Two years ago, Pfizer came to us to let us know that some of their collaborators had been using the Abbott FISH reagent for early studies and research and it was looking promising," Kathryn Becker, director of Abbott Molecular oncology, told PGx Reporter. "So that was how we started our conversations and eventually entered into an agreement to co-develop a companion product."
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Becker said that collaborating with Pfizer to develop the companion test likely shortened the time frame in which the treatment was approved and commercialized. Abbott and Pfizer not only submitted their respective applications for the test and treatment to the FDA around the same time, but they also took joint meetings with the agency's drug and device divisions.
"Doing that absolutely helped speed up the process," said Becker. "It's brought out the value of using a quality-controlled, clinically validated test that selects the right patient population who are more likely to respond favorably to Xalkori," she said. "So, it's a combination of working together, having the right test and technology in FISH, and being able to select that patient population to show the greatest response."
Abbott and Pfizer will simultaneously launch the combination product globally on a country-by-country basis, including in the US, Europe, Japan, and in Latin American countries. Abbott is also working with Pfizer on other clinical trials around the ALK marker.
The companion diagnostic deal between Pfizer and Abbott is non-exclusive, leaving open the possibility for Pfizer to work with other test makers to launch new diagnostics in line with technology advancements or if additional response markers are added to Xalkori's label in the future. For now, however, the Abbott test is the only one approved for use with the drug.
"The Xalkori label states that an FDA-approved test be used to identify ALK-positive tumors for treatment with [the drug]," the Pfizer spokesperson said. "Although other assays are currently available to detect ALK, the Abbott ALK FISH test is the only FDA-approved test. Research is underway to determine other methodologies to determine ALK status."
According to a researcher reviewing data on Xalkori that was presented at the American Society of Clinical oncology's annual meeting in June, while FISH tests detect ALK rearrangements, PCR-based tests can hone in the specific ALK fusion partner, and immunohistochemistry tests can gauge the expression of the ALK protein. FISH testing for the time being can remain the standard, according to this reviewer, as more research is done to establish how ALK rearrangements and other fusion variants impact the drug's response (PGx Reporter 6/8/2011).
The FDA approved Xalkori based on Xalkori's effect on objective response in two single-arm studies, one involving 136 patients and another enrolling 119 patients. In these studies, the drug was administered to these 255 patients with locally advanced or metastatic ALK-positive NSCLC. The majority of the patients in the studies consisted of non-smokers who had metastatic disease and had received prior treatment for NSCLC.
In the study with 136 patients, 50 percent of patients experienced an objective response rate, with a median response duration of 42 weeks. In the second study, 61 percent of patients saw an ORR and the median response duration was 48 weeks. One percent of patients experienced a complete response when treated with Xalkori.
The most common adverse reactions associated with Xalkori treatment included vision disorders, such as visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia. Other common adverse events experienced by patients were nausea, diarrhea, vomiting, edema, and constipation.
Xalkori-related grade 3/4 adverse reactions, such as ALT and neutropenia, were seen in at least 4 percent of patients. Around 1.6 percent of patients in clinical trials had severe, life-threatening, or fatal treatment-related pneumonitis, which occurred within two months after the start of Xalkori treatment.
In its approval letter to Pfizer, the FDA indicates that since Xalkori received expedited approval based on single-arm studies, the company must complete more rigorous post-market studies confirming the safety and efficacy of the drug in order to keep it on the market.
"If post-marketing trials fail to verify that clinical benefit is conferred by Xalkori … or are not conducted with due diligence, we may … withdraw or modify approval," the FDA states in its letter.
Among the post-marketing studies listed in the letter, Pfizer must investigate Xalkori in a Phase III, randomized trial against pemetrexed or docetaxel in advanced NSCLC patients with ALK-positive tumors. The final report on this trial is to be completed by June 2014. Additionally, the FDA has asked Pfizer to conduct a Phase III study comparing Xalkori to pemetrexed/cisplatin or pemetrexed/carboplatin in untreated ALK-positive patients with non-squamous carcinoma. The outcomes from this trial are slated to be reported to the FDA in June 2016.
Pfizer will also have to conduct clinical trials to further study the risk of visual disorders, long QT prolongation, as well as drug-drug interactions with CYP3A inhibitors and inducers and gastric pH-elevating drugs. The drug's label instructs doctors to avoid giving Xalkori to patients with congenital long QT syndrome. Using CYP3A inhibitors concomitantly may increase plasma concentrations of Xalkori and should be avoided, the label instructs.
The FDA also instructs Pfizer to "conduct a clinical trial to explore response to [Xalkori] in ALK-negative patients based on current assay cut-off," and compare their response to the response seen in ALK-positive patients. "Additional biomarkers should be assessed in ALK-negative patients," the FDA notes.
Following the approval of Xalkori in ALK-positive NSCLC, Pfizer is continuing to investigate the drug's safety and efficacy in other disease settings, study it in combination with other drugs, and explore its impact on other biomarkers to tackle cancer resistance.
In a Phase Ib trial, Pfizer is evaluating the drug in patients with ALK-positive tumors, except non-small cell lung cancer. In the Phase I/II ADVL0912 trial, led by the Children's Oncology Group, researchers are investigating the tolerated dose and are beginning to study the efficacy of Xalkori in children with relapsed or refractory solid tumors, such as tumors affecting the central nervous system and anaplastic large cell lymphomas. In February, a study published in the New England Journal of Medicine by Italian researchers reported that two patients with ALK-positive anaplastic large cell lymphoma who had previously failed chemotherapy responded to Xalkori.
Pfizer is also studying Xalkori as an inhibitor of c-Met. "One role of crizotinib as a Met inhibitor may be in lung cancer tumors that have become resistant to the first-generation EGFR inhibitors," the Pfizer spokesperson said. In a Phase I/II trial, Pfizer is comparing the safety, efficacy, and pharmacokinetics of Xalkori in combination with Genentech's EGFR inhibitor Tarceva versus Tarceva alone. In another Phase I trial, Pfizer is studying how patients respond to a combination regimen including Xalkori and PF-00299804, an investigational pan-HER inhibitor, aiming to block both c-MET and EGFR pathways in an effort to overcome potential treatment resistance.
In clinical trials, many ALK-positive lung cancer patients treated with Xalkori who responded to the drug eventually developed resistance to the drug. As such, published studies have suggested that targeting C1156Y and L1196M mutations within the kinase domain of EML4-ALK may be a way to address resistance against Xalkori. Additionally, research has suggested that for patients with F1174L mutations, increasing Xalkori's dose, or giving the patients HSP90 inhibitors or other ALK inhibitors, may be a successful strategy against drug resistance.
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