Archive for the ‘ALK’ Category

Taking a Leap in Cancer Diagnostics: Clarient Enters New Era in Molecular Tumor Testing, Drug Discovery Research

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Posted 13 Mar 2012 — by James Street
Category ALK, Biomarkers, BRAF, Diagnostic, EGFR, genetic research, Kras, Molecular, PI3K
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Anita T. Shaffer
Published Online: Friday, March 9th, 2012

When Kenneth J. Bloom, MD, began his career in pathology more than 25 years ago, the field of genomic and molecular diagnostics in cancer therapeutics was virtually nonexistent. Today, the sector is exploding and Bloom is at the forefront of efforts to develop new oncologic tools and bring them to clinical practice.

Bloom is the chief medical officer of Clarient, Inc, a once-fledgling company that GE Healthcare acquired in December 2010 for $425 million.

Clarient provides more than 350 diagnostic tests to assess and characterize tumors, including tests for BRAF, KRAS, and EGFR gene mutations, as well as the recently launched Clarient InsightDx Mammostrat test for breast cancer recurrence. The company also offers PATHSITE, an Internet-based service where physicians can view and manage digital images, patient case histories, and test results.

In December, Clarient announced a partnership with ACORN Research, LLC, a network of community oncology practices and hospitals, through which tumor-specific biomarker data for each new patient will be collected and analyzed under standardized protocols. The data will be used to personalize treatment for individual patients, as well as to build a databank of information about particular tumor types that can be used in clinical trials and other research.

Such developments are likely to mean a big jump forward not only for the Aliso Viejo, California-based company, but also for patients, according to Bloom.

“This is the perfect storm,” Bloom said in an interview. “All of the things that are necessary are coming together as one. We can really start bringing the highest level of care to every patient anywhere within the United States, and then eventually anywhere in the world. It is incredibly exciting.”

“It’s something that five years ago nobody could have contemplated,” he added. “If you were sick in rural Georgia, you would have to go to Atlanta. But those days are changing. You’re going to be able to get access to the same level of care no matter where you are.”

Bloom said GE ownership will boost Clarient’s ability to expand internationally, while the ACORN partnership will enable the company to compare outcomes with clinical trial results and conduct drug discovery research.

“To me, when we talk about personalized healthcare, it means giving healthcare locally,” he added. “It means you don’t pick up and travel 200 miles to some other institution where your family and friends can’t visit you and you undergo therapy in isolation. If that care could be given locally with your family and friends around you, that would be hugely advantageous. I think that’s what we’ve really been striving for all along, and it’s achievable.”

To me, when we talk about personalized healthcare, it means giving healthcare locally. It means you don’t pick up and travel 200 miles to some other institution where your family and friends can’t visit you and you undergo therapy in isolation. ”
–Kenneth J. Bloom, MD

Growing With Community Oncologists in Mind

The trends now shaping the cancer diagnostics field in some ways mirror the trajectories of both Bloom’s career and Clarient’s corporate evolution.

Now, as a result of the sequencing of the human genome and advances such as polymerase chain reaction and microarray technology, the options in genomic and molecular testing in cancer diagnostics are expanding dramatically.

“When I went through medical school, molecular pathology didn’t exist,” Bloom said. “So I got zero molecular pathology in medical school, zero molecular pathology in residency. It’s really only the last 10 or 15 years of my practice that molecular pathology has come to the forefront.”

Bloom, who became a member of the College of American Pathologists in 1987, held a number of positions related to oncology at Rush-Presbyterian- St. Luke’s Medical Center, now Rush University Medical Center, in Chicago, Illinois, for more than 20 years before joining US Labs as senior medical director in 2002.

Within a few years, the Irvine, California, cancer diagnostics company was purchased by industry giant LabCorp. Bloom, who moved on to Clarient in August 2004, said he shared Clarient’s philosophy of partnering with local pathologists rather than supplanting them with a centralized lab.

Clarient itself has grown from a small company launched in the early 1990s to develop medical imaging technologies into a 400-employee business focused on diagnostics.

General Electric Company, which operates GE Healthcare, said in its 2010 annual report that Clarient was a “leading player” in a rapidly growing market, and that its purchase of the company would accelerate GE’s presence in the field. The demand for cancer diagnostics is expected to grow from $15 billion in 2010 to $47 billion by 2015, GE said.

Although the acquisition is an example of the consolidation in the industry, Bloom believes Clarient maintains a business model that preserves both local pathologists, and helps the community oncologists and hematologists with whom they work.

“We really had a passion of bringing cancer testing directly to local pathologists and hence local oncologists,” Bloom said. “The idea was that we would never compete with the local pathologists. The things that a local pathologist knew how to do, and do well, they should do.

“But all of the advanced things that they should be doing but didn’t have access to, either because they didn’t have the space, the resources, the training, or the technicians, we would not only provide that test to them, but we also would engage them in the process, and we would educate them along the way,” he said. “And that’s been an incredibly successful model.”

The GE Healthcare acquisition gives Clarient the resources to expand its model worldwide and to pursue original research, Bloom said. “Now we can lead the charge and develop the next generation of tests that will lead the way to personalized healthcare,” he said.

The Clarient InsightDx Mammostrat

The Clarient InsightDx Mammostrat

Emphasizing Role of Pathologists Amid Change

As the options in cancer diagnostics grow in number and complexity, Bloom believes oncologists will be bombarded with choices they might not be equipped to evaluate. That is why he feels pathologists are vital members of the treatment team.

“Probably the biggest question for oncologists is, ‘How do I deal with all these new tests that are coming on the market?’” he said.

“To me, it’s not obvious that just because there’s a new test, that everybody should instantly understand how that test works and how to apply it,” Bloom said. “There’s going to have to be experts that understand how to do that.”

In Bloom’s view, local pathologists should supply that expertise by working with oncologists and with labs such as Clarient that offer advanced testing.

“The pathologist can be your biggest tool, because they are charged with understanding all of the tests, monitoring the performance of those tests, and discovering why laboratory A might be better than laboratory B for a more consistent and a more robust test result,” Bloom said.

“That would be the single biggest thing that I would tell oncologists to do,” he noted. “You need to become partners with a local pathologist, even if your local pathology lab doesn’t perform the test.”

Top Tests Available at Clarient

Combining innovative diagnostic technologies with world-class pathology expertise, Clarient’s state-of-the-art laboratories provide advanced oncology testing and diagnostic services to assess and characterize cancer. Using a wide range of methodologies, including flow cytometry, IHC, ISH, FISH, cytogenic karotyping, immunofluorescence, microarray, and molecular testing, these are the 7 leading tests Clarient performs:

Mammostrat Breast Recurrence Assay

Methodology: Immunohistochemistry
Highlights:

  • Mammostrat is a novel test for estimating the risk for recurrence in hormonereceptor positive, early-stage breast cancer.
  • Mammostrat stratifies breast cancer patients into low risk (patients have a 7.6% chance of distant recurrence over a 10-year period); moderate risk (patients have a 16.3% chance of distant recurrence over a 10-year period), and high risk (patients have a 20.9% chance of distant recurrence over a 10-year period).

ALK Rearrangement

Methodology: FISH
Highlights:

  • ALK mutations have been identified in 3% to 7% of patients with non-small cell lung cancer (NSCLC).
  • The presence of ALK gene rearrangements may help treating physicians select more effective therapies for patients with NSCLC.
  • ALK gene rearrangements define a distinct molecular subset of NSCLC that is mutually exclusive from EGFR and KRAS mutations.
  • The FISH test results should be used in conjunction with other clinical information.

BRAF

Methodology: Real-time polymerase chain reaction
Highlights:

  • BRAF mutations account for approximately 12% to 15% of colorectal cancer cases.
  • BRAF mutations are biomarkers of nonresponse to anti-EGFR therapies.
  • BRAF mutations are highly predictive of nonresponse to therapy with cetuximab or panitumumab in combination with chemotherapy and as monotherapy.

BRAF V600 Mutation

Methodology: Real-time polymerase chain reaction
Highlights:

  • Approximately 60% of melanomas harbor activating mutations in BRAF V600E as identified by the cobas 4800 test.
  • The cobas 4800 test is the first FDA-approved diagnostic test to help identify patients with the BRAF V600E mutation.
  • Patients with BRAF V600 mutation-positive melanoma as detected by the cobas 4800 test showed dramatic results with vemurafenib.

EGFR Mutation Analysis

Methodology: Molecular polymerase chain reaction
Highlights:

  • EGFR mutations can be seen in approximately 10% to 15% of patients.
  • The development of selective tyrosine kinase inhibitors is an important area of drug discovery for the treatment of a variety of solid tumors such as breast, ovarian, and colorectal cancers, NSCLC, and carcinoma of the head and neck.
  • Patients with EGFR mutations respond more favorably to EGFR tyrosine kinase inhibitors than non-mutation carriers.

KRAS Mutation Analysis

Methodology: Real-time polymerase chain reaction
Highlights:

  • KRAS mutations can be detected in approximately 30% to 40% of patients with colon cancer.
  • Patients with wild-type KRAS have shown much greater benefit to anti-EGFR therapies.
  • Identification of mutations along the KRAS gene suggests that anti-EGFR therapies will not be efficacious in most patients.

PI3K

Methodology: Molecular polymerase chain reaction
Highlights:

  • The PI3K pathway plays an important role in many cancers, including colorectal, breast, and lung cancers.
  • The presence of activating mutations in the PIK3CA gene, which encodes PI3K, can occur in 20% to 30% of cases.
Source: Clarient Inc’s website www.clarient.com.

Crizotinib Is ‘Major Breakthrough for Genomic Medicine’

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Posted 01 Sep 2011 — by James Street
Category ALK, Finance and Politics of cancer research and treatment, genetic research, Lung Cancer

Roxanne Nelson

September 1, 2011 — The US Food and Drug Administration (FDA) recently granted accelerated approval to crizotinib (Xalkori, Pfizer) for the treatment of patients with advanced-stage nonsmall-cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive.

A companion diagnostic test — the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc.) — was approved concurrently. It is designed to detect rearrangements of the ALK gene, which are found in about 4% to 5% of patients with NSCLC.

This is the first targeted agent to be developed with an accompanying diagnostic test, said Mace Rothenberg, MD, senior vice president of Pfizer’s Oncology Business Unit.

The first target discovered was the epidermal growth-factor receptor (EGFR), but at the time the technology wasn’t available to test which patients would benefit most from anti-EGRF therapies, he explained during an expert panel discussion sponsored by Pfizer.

Paradigm Shift

Paul Bunn, MD, professor of medicine and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, in Aurora, who was on the panel, noted that the approval of crizotinib is part of a paradigm shift in the care and management of lung cancer.

“It used to be that everyone with lung cancer was treated the same, but then about 30 years ago, it was discovered that some patients with small-cell lung cancer could be cured with chemotherapy and radiation therapy,” said Dr. Bunn. “So lung cancers were then divided into small cell and nonsmall cell.”

“More recently, it has been appreciated that lung cancer is a group of heterogeneous diseases with different molecular origins,” he explained. “It was then recognized the some lung cancers were driven by EGFR mutations — about 10% to 15% in Western countries. But then in 2007, it was recognized that some lung cancers are driven by the ALK oncogene, which is activated not by a mutation but by a breakage in chromosome 2 and a refusion of the 2 genes in the opposite direction.”

The current paradigm is that the molecular features of a tumor have to be considered, not just histology, to select patients for the appropriate treatment, Dr. Bunn emphasized.

There are now 2 molecular subsets of lung cancer patients with specific therapies, namely those with EGFR and ALK mutations.

The question is, will we go 10 for 10?

Research coming out of the Lung Cancer Mutation Consortium has shown that almost 60% of patients with adenocarcinoma have 1 of 10 genomic abnormalities for which there is a drug. “We have 2 drugs approved now for 2 molecular abnormalities. The question is, will we go 10 for 10?” he asked.

There is also the question of being able to test patients for all 10 molecular abnormalities, but Dr. Bunn pointed out that technology is now moving as fast as drug development. “It is possible now to test for all 10 at a cost that is cheaper than it used to cost for testing for 1 in the past,” he said.

Fantastic Development

Mark G. Kris, MD, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York City, noted that this is a “fantastic development.”

I see this as a delivery on the promise of personalized medicine.

“I see this as a delivery on the promise of personalized medicine and genomic medicine,” he said during the panel discussion. “Clinical trials have shown that virtually every patient with an ALK fusion who received crizotinib has had some benefit. It is very effective.”

By testing for the ALK fusion gene, it is almost guaranteed that there will be some benefit, although the degree of benefit can vary, he noted. Conversely, if a patient lacks the ALK fusion gene, then crizotinib is not likely to demonstrate any efficacy. “This will be sparing individuals side effects, as well as not wasting time and resources for taking a drug that is not going to help them,” he said.

Dr. Kris pointed out that there has been a lot of attention focused on the fact that only a small percentage of patients have the ALK fusion gene. “But in terms of lung cancer, even though the percentage is small, the numbers are quite large,” Dr. Kris explained. “It is estimated that in United States alone, there are somewhere between 6,000 and 11,000 new patients each year who have an ALK fusion gene. To put that into perspective, that’s more people than would have Hodgkin’s disease, more patients than would have testicular cancer, and more patients than would have chronic myelogenous leukemia — all serious diseases where we have made important inroads.”

Safety and Efficacy Established

The safety and efficacy of crizotinib were established in 2 multicenter, single-group studies that enrolled 255 patients with locally advanced or metastatic ALK-positive NSCLC: a phase 2 study (PROFILE 1005) and a part 2 expansion cohort of a phase 1 study (Study 1001).

In PROFILE 1005 (n = 136), the objective response rate (ORR) was 50%, and that included 1 complete response and 67 partial responses. The median duration of treatment was 22 weeks, and 79% of objective tumor responses were achieved during the first 8 weeks of treatment.

In Study 1001 (n = 119), the ORR was 61%, and that included 2 complete responses and 69 partial responses. The median duration of treatment was 32 weeks, and 55% of objective tumor responses were achieved during the first 8 weeks of treatment.

Expensive But…

Like many targeted therapies, crizotinib comes with a hefty price tag. According to Geno Germano, president and general manager of specialty care and oncology at Pfizer, the drug will cost $9,600 per month, or $115,000 per year.

But Mr. Germano pointed out that with the approval of crizotinib, treatment will be improved. “We are going to be treating patients more effectively and avoiding treatments that don’t work,” he said.

He also noted that Pfizer has devised a number of programs to help with the cost. “We realize that we have to be attentive to the individual needs of each patient,” he said.

Pfizer’s initiatives would cut some patients’ share of that cost significantly. The company is offering copay assistance of up to $24,000 per year with a program that would have privately insured patients pay only $100 per prescription. For example, if a patient has a 20% copay, that would cover a full year of treatment.

Pfizer has said it will also help patients who are uninsured or insured by Medicaid or Medicare figure out how to cover the cost of crizotinib. However, the assistance programs do not help payers cover their costs.

ALK Gene Test

The companion diagnostic test approved along with crizotinib uses Abbott’s fluorescence in situ hybridization (FISH) technology to detect rearrangements of the ALK gene on the 2p23 chromosome.

It offers clinicians a standardized, clinically validated method of identifying the patients most likely to benefit from the therapy. Experts have predicted that the simultaneous FDA approvals will change clinical practice for the diagnosis and treatment of patients with NSCLC.

“The Abbott ALK FISH test was developed in conjunction with Pfizer and the clinical trials for crizotinib,” said Kathryn B. Becker, PhD, director of Abbott Molecular Oncology. “It was configured to work specifically in NSCLC patients, and we have ensured that it is a very high-quality product that is reproducible.”

The cost of the test is in line with other clinically validated assays of this type, and will be less than $250 per patient. “We believe that the test brings an extremely high value to this patient population and the outcome of the therapeutics,” Dr. Becker said.

Dr. Becker also feels that this test will eventually be widely used. “In the clinic today, a number of biomarkers are commonly being tested for,” she said. “We believe that the Abbott ALK FISH test will become a standard part of testing for nonsmall-cell lung cancer patients, along with EGFR mutations and KRAS status.”

Both the diagnostic test and crizotinib were accelerated approvals. “The fact that Pfizer and Abbott were able to work together, in concert with the FDA, to bring both the therapeutic and the diagnostic to approval so early is a testament to the way that Pfizer and Abbott have communicated and collaborated throughout this whole process,” she added. “It has been a great pleasure working with Pfizer. We had a really interactive collaboration; without that, we may not have been that successful.”

Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.

Pfizer Wins U.S. Approval for Tumor-Fighting Medicine to Treat Lung Cancer

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Posted 26 Aug 2011 — by James Street
Category ALK, genetic research, Lung Cancer, Personalized, Targeted Cancer Therapy, Xalkori (crizotinib)
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.

To contact the reporter on this story: Molly Peterson in Washington at mpeterson9@bloomberg.net

To contact the editor responsible for this story: Adriel Bettelheim at abettelheim@bloomberg.net