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Non-Small Cell Lung Cancer Drug Gets FDA Nod
 
 
  WASHINGTON -- The FDA has approved crizotinib (Xalkori), a novel targeted therapy for late-stage non-small cell lung cancer.

The Pfizer drug, an inhibitor of anaplastic lymphoma kinase, is a twice-daily pill intended for a select group of patients who express the abnormal anaplastic lymphoma kinase (ALK) gene, which causes cancer development and growth.

The FDA also approved a companion diagnostic called the Vysis ALK Break Apart FISH Probe Kid, made by Abbott Molecular, to help determine if a patient has the abnormal ALK gene.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug," Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research said in a press release. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects."

Crizotinib's safety and effectiveness were established in two single-arm studies enrolling a total of 255 patients with late-stage ALK-positive non-small cell lung cancer. One of those studies, published in the New England Journal of Medicine last year, found that crizotinib shrank or eliminated 57% of ALK-positive non-small cell lung tumors.

The most common side effects reported in patients receiving crizotinib included vision disorders, nausea, diarrhea, vomiting, edema, and constipation.

Crizotinib was approved under the FDA's priority review program, which provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists.

Since publication of trial results last October, crizotinib has generated much excitement among oncologists who said genetically-targeted treatments like crizotinib have the potential to change how cancer is treated.

Although no more than 7% of non-small cell lung cancers are driven by the ALK genes targeted by crizotinib, the drug would still benefit as many as 10,000 patients with non-small cell lung cancer in the U.S. alone, Gregory Kalemkerian, MD, co-director of thoracic oncology at the University of Michigan in Ann Arbor, told Medpage Today last year.

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Pfizer Wins U.S. Approval for 'Personalized' Lung-Cancer Drug

bloomberg.com

By Molly Peterson - Aug 27, 2011

Pfizer Inc. (PFE) won U.S. approval to sell a drug targeted at a form of lung cancer caused by a gene defect, as the world's largest drugmaker seeks tumor-fighting medicines to replace sales expected to be lost to generics.

The treatment, crizotinib, was cleared five weeks ahead of schedule for patients with late-stage, non-small cell lung cancer with a rare genetic abnormality, the Food and Drug Administration said yesterday in a statement. Pfizer will sell the twice-a-day pill under the name Xalkori. The agency also approved a companion test made by a unit of Abbott Laboratories (ABT) to determine whether a patient has the abnormal ALK gene.

The drug is among more than 20 cancer medicines that may help New York-based Pfizer offset $11 billion in revenue at risk to generic copies of the best-selling Lipitor cholesterol pill. In a study presented at a conference last year, the drug reduced tumor size in 57 percent of patients and stopped progression of the disease in 87 percent.

"Xalkori represents a new chapter in personalized therapy for lung cancer, enabling physicians to provide the right treatment for the right patient," said Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer's oncology business unit.

The treatment may generate sales of $540 million by the end of 2015, according to the average estimate of four analysts surveyed by Bloomberg.

The drug, the first new lung-cancer treatment approved by the FDA in more than six years, is available immediately through specialty pharmacies, Pfizer said in a statement. Xalkori also is the first lung-cancer treatment developed and approved with a diagnostic test, the company said.

'Targeted Therapy'

"Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects," Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, said in the statement.

About 221,000 cases of lung cancer will be diagnosed in the U.S. this year and the disease will kill about 157,000 people, according to the National Cancer Institute.

The ALK gene abnormality causes cancer development and growth and affects about 1 percent to 7 percent of those with the non-small lung cancer, the most common form of the disease, the FDA said in its statement.

'Breakthrough' Advance

"The Abbott-Pfizer collaboration marks a breakthrough in the advancement of personalized medicine -- and companion diagnostics specifically -- that will help a subset of lung- cancer patients get treatment tailored to their unique genetic profile," said Stafford O'Kelly, head of Abbott's molecular diagnostics business, in a company statement.

Pfizer's drug is the second cancer therapy approved by the FDA this month in conjunction with a diagnostic test. Zelboraf, a skin-cancer drug from Roche Holding AG (ROG) and Daiichi Sankyo Co., won FDA clearance Aug. 17 with a Roche companion test that helps detect whether patients have the gene mutation the drug targets.

Xalkori is the third cancer drug this month to win FDA clearance ahead of schedule. The FDA had a Sept. 30 target decision date for Pfizer's new treatment, and an Oct. 28 date for Zelboraf. The agency approved Seattle Genetics Inc. (SGEN)'s lymphoma drug Adcetris on Aug. 19, 11 days early.

All three drugs were evaluated under six-month priority reviews. While the FDA typically takes at least 10 months to rule on drug applications, it grants priority status to therapies that may provide major advances in treatment.

Lipitor, the world's best-selling drug, will face generic competition in the U.S. starting Nov. 30 if Ranbaxy Laboratories Ltd. (RBXY) wins FDA approval to begin selling a copy of the medicine by then.

Watson Pharmaceuticals Inc. has an agreement with Pfizer to start selling a so-called authorized generic on Nov. 30. Pfizer will provide Lipitor to Watson to sell without the brand label as a generic in return for a share of the sales.

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FDA NEWS RELEASE

For Immediate Release: Aug. 26, 2011

Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer Second targeted therapy approved with a test this year

The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.

Xalkori is being approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year.

This ALK gene abnormality causes cancer development and growth. About 1 percent to 7 percent of those with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically non-smokers. Xalkori works by blocking certain proteins called kinases, including the protein produced by the abnormal ALK gene. Xalkori is a pill taken twice a day as a single-agent treatment.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug" said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects."

Xalkori's safety and effectiveness were established in two multi-center, single-arm studies enrolling a total of 255 patients with late-stage ALK-positive NSCLC. A sample of a patient's lung cancer tissue was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy.

In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another, the objective response rate was 61 percent with a median response duration of 48 weeks.

The FDA based its approval of the Vysis ALK Break Apart FISH Probe Kit on data from one of the studies.

Xalkori was reviewed under the FDA's priority review program, which provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists.

Xalkori is being approved under the FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients. The program is designed to provide patients with earlier access to promising new drugs, followed by further studies to confirm the drug's clinical benefit.

Xalkori and the companion Vysis ALK Break Apart FISH Probe Kit were approved ahead of the drug's Sept. 30, 2011, FDA review goal date and the companion diagnostics' Sept. 28, 2011, review goal date.

"The trend in oncology research continues towards targeted therapies," said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA's Center for Devices and Radiological Health. "This test is an example of the important role companion diagnostics play in determining that the safest and most effective treatments are promptly delivered to patients living with serious and life-threatening diseases."

The most common side effects reported in patients receiving Xalkori included vision disorders, nausea, diarrhea, vomiting, swelling (edema), and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects. Xalkori use has also been associated with inflammation of the lung tissue (pneumonitis), which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with Xalkori. The drug should not be used in pregnant women.

In July 2011, FDA issued a draft guidance industry on the agency's policy for reviewing a companion diagnostic and the corresponding drug therapy. The guidance is currently available for public comment.

Xalkori is marketed by New York City-based Pfizer. The Vysis ALK Break Apart FISH Probe Kit is marketed by Abbott Molecular Inc. of Des Plaines, Ill.

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Novel Kinase Inhibitor Promising in NSCLC

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: October 27, 2010

Non-small cell lung cancers and other tumors with a mutation in anaplastic lymphoma kinase (ALK) respond dramatically to a novel agent that "switches off" the faulty gene, according to early trial results.

The experimental ALK inhibitor, crizotinib, shrank or eliminated 57% of ALK-positive non-small cell lung tumors, Eunice L. Kwak, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, and colleagues found in a trial published in the Oct. 28 issue of the New England Journal of Medicine.

Although the 82-patient study lacked a control group, "these results compare very favorably with the reported 10% response with second-line chemotherapy," according to an editorial by Bengt Hallberg, PhD, and Ruth H. Palmer, PhD, both of Umea University in Umea, Sweden.

Action Points

· Explain that crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, led to a complete or partial response in 57% of 82 patients with ALK-positive non-small cell lung cancer.

· Note that approximately 5% of non-small cell lung tumors are ALK-positive and that there is evidence that drug resistance may turn out to be a problem with ALK inhibitors.

The editorial accompanied three studies on crizotinib published in the same issue of the journal.

In the second report, the novel drug also looked promising in another, rarer type of soft tissue tumor with the same ALK mutation. But the third study showed crizotinib to have the same Achilles' heel as other ALK inhibitors -- drug-resistance mutations.

Nevertheless, these early phase results generated enthusiastic responses among oncologists, building on buzz generated over the initial report of the non-small cell lung cancer findings at the meeting of the American Society of Clinical Oncology in June.

"That is a big benefit in the oncology world," Gregory P. Kalemkerian, MD, co-director of thoracic oncology at the University of Michigan in Ann Arbor, commented in an e-mail to MedPage Today and ABC News.

The small proportion of lung cancer patients who stand to benefit -- only 2% to 7% of non-small cell lung cancers are driven by the genetic fusion of EML4 and ALK genes targeted by crizotinib -- wasn't seen as a problem.

"It must be recognized that a small percentage of a very common disease represents a fairly large number of people," Martin J. Edelman, MD, director of solid tumor oncology at the University of Maryland's Greenebaum Cancer Center in Baltimore, pointed out in an e-mail.

Up to 10,000 patients with non-small cell lung cancer in the U.S. alone might stand to benefit from the drug, Kalemkerian noted.

By comparison, imatinib (Gleevec), "considered the biggest success story for molecularly targeted anticancer therapy," is most beneficial in chronic myelogenous leukemia for a population of less than 5,000 a year, he explained.

Moreover, results like these with genetically targeted treatment are changing how we think about cancer, commented Mark Kris, MD, of Memorial Sloan-Kettering Cancer Center in New York City, who was not involved with the studies.

"This concept is extremely important not just to the care of those persons with lung cancer that have that particular mutation but for every patient with lung cancer and every cancer that is driven by a driver oncogene," Kris said in an interview with MedPage Today.

The EML4-ALK oncogene was only discovered in 2007, but since a drug that targeted ALK -- crizotinib -- was already under development for another purpose, clinical studies got under way quickly.

Kwak's group genotyped 1,500 non-small cell lung cancers to find 82 patients with advanced ALK-positive disease, of which 90% had received prior treatment.

After a mean of 6.4 months taking 250 mg oral crizotinib twice daily in 28-day cycles, 47 of the 82 patients met response criteria.

In one patient, all target lesions disappeared, for a confirmed complete response; 46 patients had a partial response with tumor shrinkage of at least 30%, and 27 (33%) had stable disease.

Although most of the patients (77%, 63 of 82) were still taking the ALK inhibitor at the time of data cutoff, the researchers were able to estimate six-month progression-free survival at 72%.

The most common adverse event with the drug was mild nausea and diarrhea followed by mild visual disturbances in 41%.

The researchers noted that these results, both in rate and speed of clinical response, looked as good as those seen with targeted therapy for epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, such as gefitinib (Iressa) and erlotinib (Tarceva).

This similarity "suggests that ALK-positive tumors constitute a second genetically defined subgroup of oncogene-driven lung cancer that is highly susceptible to targeted therapy," they concluded in the paper.

Genotyping is already going on in the clinic for EGFR mutation, which suggests that it might be simple to reuse patients' available tissue in the pathology department to add on a test for ALK, Kris suggested, calling it a "great natural progression" of clinical management.

Testing for multiple mutations at the same time is happening only at large academic centers, noted William Pao, MD, PhD, of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

"The hurdle at this point is not necessarily the testing but getting patients' tumor blocks for the testing," he wrote in an e-mail to MedPage Today and ABC News. "Many patients are diagnosed with just a needle biopsy, so there's not enough tissue for testing."

But "this will change as the physicians who do the initial biopsies are educated about the importance of obtaining larger amounts of tissue," Edelman predicted.

The NEJM editorialists agreed that genotyping should be considered as a standard practice moving toward personalized therapy in non-small cell lung cancer, although other rarer diseases stand to benefit as well.

The second study, led by Geoffrey I. Shapiro, MD, PhD, of the Dana-Farber Cancer Institute in Boston, described a patient with ALK-positive inflammatory myofibroblastic tumor who maintained a partial response to crizotinib whereas another with the same tumor type but no ALK rearrangement had no effect from the drug.

About half of these soft tissue tumors, which often arise in the lung, involve ALK mutations.

The ALK-positive patient, although pretreated with chemotherapy and imatinib, had a 53% reduction in tumor lesion size after about two months with a partial response that lasted at least six months.

After a debulking surgery because of subsequent growth of three other lesions, retreatment with crizotinib resulted in ongoing complete radiographic remission with only mild side effects.

Still, regrowth of certain lesions while on the drug added to concerns about drug-resistance mutations, the editorialists noted.

The third study by Hiroyuki Mano, MD, PhD, of Jichi Medical University in Tochigi, Japan, and colleagues identified two secondary mutations within the kinase domain of EML4-ALK from a patient who relapsed on crizotinib.

These mutations would likely confer resistance to multiple ALK inhibitors and appeared to have developed independently in different areas of the tumor.

The researchers cautioned that they couldn't determine whether the resistant clones were present initially or developed during treatment.

Primary source: New England Journal of Medicine

Source reference:

Kwak EL, et al "Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer" N Engl J Med 2010; 363: 1693-1703.

Additional source: New England Journal of Medicine

Source reference:

Butrynski JE, et al "Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor" N Engl J Med 2010; 363: 1727-1733.

Additional source: New England Journal of Medicine

Source reference:

Choi YL, et al "EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors" N Engl J Med 2010; 363: 1734-1739.

Hallberg B, Palmer RH "Crizotinib -- Latest champion in the cancer wars?" N Engl J Med 2010; 363: 1760-1762.

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Editorial

Crizotinib - Latest Champion in the Cancer Wars?

Bengt Hallberg, Ph.D., and Ruth H. Palmer, Ph.D.

N Engl J Med Oct 28 2010; 363:1760-1762

Three articles in this issue of the Journal report on the therapeutic potential of a new kid on the kinase inhibitor block: crizotinib, an ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase.

Kwak et al.1 summarize a study involving patients with non-small-cell lung cancer who were enrolled in a phase 1 trial, starting in 2008, hot on the heels of a study in which cell lines derived from non-small-cell lung tumors were shown to be sensitive to NVP-TAE6842 and crizotinib (PF-02341066).3,4 From a cohort of 1500 patients with non-small-cell lung cancer, 82 (5.5%) were found to carry an ALK rearrangement on fluorescence in situ hybridization (FISH). The authors note that not all of these genetic rearrangements were confirmed as EML4-ALK,5 which suggests that other ALK fusions may be present, such as TFG-ALK 6 and KIF5B-ALK.7 Although the best-studied ALK fusion is the nucleophosmin (NPM)-ALK protein found in lymphoma, it is reasonable to expect that a number of the signaling pathways activated by NPM-ALK will also be involved in transformation by variants such as EML4-ALK Figure 1Signaling Pathways Activated by ALK Fusion Proteins.).

Most of the patients with non-small-cell lung cancer who carried the EML4-ALK translocation were nonsmokers and had adenocarcinomas. Even though more than 90% of these patients had undergone at least one previous line of therapy, the investigators observed a 57% response rate to crizotinib, according to Response Evaluation Criteria in Solid Tumors (RECIST), with a rate of disease control of 87% at 8 weeks. Although a control group was lacking in this study, these results compare very favorably with the reported 10% response with second-line chemotherapy. At a mean treatment duration of 6.4 months, 27 patients had stable disease, 46 had a partial response, and 1 had a complete response. All patients tested negative for amplification of MET, another target for crizotinib, which suggested that the therapeutic effect is through inhibition of ALK.

These results raise the question of whether crizotinib will yield equally strong responses as the first therapeutic intervention or whether a combined approach will be more beneficial. At a rate of approximately 5% positivity for the ALK rearrangement, the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone. Clearly, with mutant epidermal growth factor receptor (EGFR), K-RAS, and ALK as important clinical determinants in this type of lung cancer, the use of genotyping as standard practice must be considered as a move toward personalized therapy.

As with the kinase inhibitors already in use, such as imatinib and EGFR inhibitors, kinase inhibition frequently leads to the appearance of drug-resistance mutations within the target kinase itself. Although Kwak et al. do not address this issue, it is possible that in a number of ALK-positive patients who had a limited response in this study, such mutations may have developed either before or during treatment with crizotinib. This factor is clearly illustrated in a study by Choi et al.,10 who describe mutations in EML4-ALK that confer resistance to crizotinib. Their data support the independent appearance of mutations leading to C1156Y and L1196M coding changes in a patient with non-small-cell lung cancer who had an initial strong clinical response to crizotinib. On the basis of structural considerations of the crystal structure of the ALK kinase domain,11,12 L1196M represents a mutation of the gatekeeper residue, similar to the T790M gefitinib-resistance mutations observed in EGFR and T315I mutations in ABL, and it would be predicted to prevent crizotinib binding to ALK. The effect of the C1156Y mutation is unclear, since it appears unlikely to have a direct effect on crizotinib binding. Further studies will be required to establish the mechanism of action behind C1156Y resistance. Choi et al. found that these EML4-ALK mutants are less sensitive to crizotinib than is wild-type EML4-ALK when expressed in Ba/F3 cells, in agreement with the loss of clinical response in this patient. The resistance of the C1156Y variant to crizotinib was not as great in vitro as in vivo, suggesting that this mutation may require interaction with additional factors in the cell to have strong drug sensitivity.

The appearance of crizotinib-resistance mutations in this patient indicates that additional ALK inhibitors will be required to target EML4-ALK mutants that are insensitive to crizotinib in a clinical setting. This brings clinical reality to the predictions from a recent prospective mutagenesis study on NPM-ALK in which strong resistance to ALK inhibitors in mouse tumor models was observed with the NPM-ALK mutant L256M, which is in the same residue as L1196M of EML4-ALK.13 Thus, a familiar story line emerges, highlighting the need for basic scientists and clinicians to work together to plan a step ahead of the evolving tumor. It is encouraging that some progress in this area has already been made, and a number of such drugs are in the pipeline, including a new ALK inhibitor.14

Although patients with ALK-positive non-small-cell lung cancers make up the largest group of patients who may benefit from crizotinib, other patients with rarer diseases, such as those with ALK-positive non-Hodgkin's lymphoma or inflammatory myofibroblastic tumor (IMT), also stand to benefit. This is illustrated in a study by Butrynski et al.,15 in which the authors describe two patients with IMT, one of whom carried the RANBP2-ALK fusion protein. Both patients were treated with crizotinib, with the ALK-positive patient having a strong response for several months. However, there was subsequent identification of growth in three lesions, which were resected before resumption of crizotinib postoperatively. A complete radiographic remission was reported in June 2010. It will be interesting to understand more about the nature of the masses that were surgically removed, since it is possible they carried crizotinib-insensitive RANBP2-ALK variants. Therefore, ALK-positive IMT, like non-small-cell lung cancer, appears to have an Achilles' heel when it comes to inhibition of ALK signaling.

One major problem for cancer drugs, including kinase inhibitors, is toxic effects. Both Kwak et al. and Butrynski et al. report that crizotinib produced only grade 2 side effects in patients when used at the therapeutic dose of 250 mg twice daily. This is good news for patients facing the prospect of long-term cancer therapy.

Together, these three studies provide an optimistic view of the successful treatment of ALK-positive cancers. One positive offshoot is the potential use of crizotinib in treating neuroblastoma, a devastating childhood cancer, in which ALK gain-of-function mutations have been reported in approximately 10% of patients.16 Clearly, in groups of patients with cancers in which ALK is implicated, a standard genotyping approach will be important for a more personalized therapeutic protocol. Future clinical studies of crizotinib and other ALK inhibitors will tell us whether they will be the latest champions in the cancer wars.

 
 
 
 
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