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Gene Test For Crizotinib To Cost $1,500 Per Patient


gpawelski

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The U.S. Food and Drug Administration (FDA) approved crizotinib (Xalkori), a drug that shrinks tumors in lung-cancer patients with a rare genetic abnormality, the latest molecularly targeted therapy to win a rapid approval from the agency. Patients with this cancer would be identified by a genetic test made by Abbott Laboratories that was also approved, and then take the pills twice a day.

As reported in Forbes, Xalkori will cost $9,600 per patient per month, meaning it could cost $80,000 or more for the average patient. But Xalkori is only effective in about 5% of patients whose tumors have a mutation in a gene called ALK. A biotech executive states the real cost of the drug is $9,600 plus 25 ALK tests, because that's how many patients will need to be screened for one to actually get Xalkori.

Forbes stresses that given those costs, it’s easy to see how DNA sequencing in cancer might have a market in the future. That’s one of the big potential markets for companies like Illumina, Complete Genomics, and Life Technologies, which are sequencing whole human genomes at a cost of $5,000 or less. Those technologies could carry extra pathology costs, too.

The question of whether to consider spending $3,000 or more for a cell-based functional profiling test is interesting, especially with the lastest press release from Pfizer about their new drug Xalkori (crizotinib). The drug will cost $9,600 per patient per month and the gene test for it will cost $1,500 per patient.

There are lots of things which determine if drugs work, beyond the existence of a given target (like ALK for Xalkori). Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

Tumor biology is a lot more complex than we'd like it to be. Cancer is more complex than its gene signature. Many common forms of cancer present as a host of mutated cells, each with a host of mutations. And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment. You kill off the tumor cells that can be killed off, but that may just give the ones that are left a free reign.

The idea of searching for clinical responders by testing for a single gene mutation seems like a nice theoretical idea, but you may have to test for dozens of protein expressions that may be involved in determining sensitivity/resistance to a given drug. Because if you miss just one, that might be the one which continues cancer growth. And at $1,500 a pop, that's a lot of dough, on top of the inflated price of the single drug!

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" pre-testing (is the cell being killed regardless of the mechanism) as opposed to "target" pre-testing (does the cell express a particular target that the drug is supposed to be attacking). While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them, all from the one test.

Source: Cell Function Analysis

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Is there a reason you insist on continuing to promote a testing service that has been unable to show its value for over a decade? If this process had value, it would be a standard practice in cancer treatment. As good as it sounds, the results just aren't there.

I just don't understand why you continue to promote this unless you have a financial stake in one of these companies. I don't bother responding to your posts in general, but I hate that people may get the wrong idea and order these tests based on your misrepresentation of their value. The best oncologists aren't going to base their recommendations on the results of this testing. Therefore, the test is basically one way to separate a patient from their money.

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ts

Even the NCI has concluded that genetic testing cannot be suitable for specific treatments for "individual" cancer patients. They cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for "theoretical" candidates for targeted therapy. That's what conventional cancer medicine has been doing for the last thirty years, and with targeted therapy, still is doing (J Natl Cancer Inst. March 16, 2010).

viewtopic.php?f=28&t=43936

Like I've stated numerous times, I do not have any financial conflicts of interest raising the awareness of the functional profiling technology. On the Internet, my point with respect to this systematic procedure is to educate patients (even doctors) that such techniques exist, and might be very valuable. I receive no financial support from any drug company, laboratory, medical equipment manufacturer, insurance carrier, professional organization, or hospital group. I get nothing out of my endeavors except the satisfaction of knowing that I've helped to increase the knowledge of informed consent. I get no pay, no lectureships, no junkets, not even any free meals.

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  • 2 weeks later...

Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients that have a long way to go before these tests will have meaningful clinical applications.

Dr. Robert Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology. He did an analysis of using the ALK gene test vs a cell-based functional profiling test for Xalkori (crizotinib).

"Let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.

• Their physicians order ALK gene rearrangement $1,500

• And EGFR mutation analysis $1,900

• The costs associated $1,500 + $1,900 x 100 people = $340,000

Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.

Resulting in a cost per correctly identified patient = $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.

• Their physicians order an EVA-PCD analysis $4,000

• The costs associated: $4,000 x 100 people = $400,000

• With 65 percent of patients responding, this

constitutes a cost per correctly identified patient = $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques."

No wonder his group is called Rational Therapeutics.

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Greg - you seem to be contradicting yourself. Firstly you cite the NCI saying this form of testing cannot be used to personalise therapy - then you seem to be saying yes you can but it's too expensive.

I also challenge you math - as it is widely accepted that alk/egfr/Kras are mutually exclusive with the alk/egfr pair you only need to perform one not both.

However I Wholeheartedly support the use of pcd - go figure!

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macleanb

How about "the NCI has concluded that genetic testing cannot be suitable for specific treatments for "individual" cancer patients" and "it's too expensive?" Molecular profiling is not effective in personalizing therapy.

Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have 'backup systems' that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.

Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

The functional profiling platform can explore multiple signaling pathways from the same test. It doesn't have to test for each and every signaling pathways there are.

There are many pathways to altered cellular function. Testing for these pathways, those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. In testing for all "known" mutations, if you miss just one, it may be the one that gets through.

And it's not just only targeted drugs that may be effective as first-line treatment on your individual cancer cells. Cancers share pathways across tumor types. There really is no lung cancer chemos, or breast cancer chemos, or ovarian cancer chemos.

There are chemos that are sensitive (effective) or there are chemos that are resistant (ineffective) to each and every "individual" cancer patient, not populations. There are chemos that share across tumor types.

The functional profiling platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death.

Finding what targeted therapies would work for what cancers is very difficult. A lot of trial-and-error goes along trying to find out. However, finding the right targeted therapies for the right "individual" cancer cells can be improved by the functional profiling platform.

Identifying DNA expression of individual proteins (that measure of RNA content, like Her2, EGFR, KRAS or ALK) often examine only one component of a much larger, interactive process. Gene (molecular) profiling measures the expression only in the "resting" state, prior to drug exposure. There is no single gene whose expression accurately predicts clinical outcome. Efforts to administer targeted therapies in randomly selected patients often will result in low response rates at significant toxicity and cost.

Functional profiling measures proteins before and after drug exposure. It measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology "when it comes to drug selection." The endpoints of molecular profiling are gene expression. The endpoints of functional profiling are expression of cell death (both tumor cell death and tumor associated endothelial [capillary] cell death).

In testing for all "known" mutations, if you miss just one, it may be the one that gets through. And it's not just only targeted drugs that may be effective as first-line treatment on your "individual" cancer cells. Cancers share pathways across tumor types.

Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.

Clinicians have learned that the same enzymes and pathways are involved in many types of cancer. However, understanding targeted treatments begins with understanding the cancer "cell." In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in the cell.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.

All the gene amplification studies, via genetic testing, tell us is whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack. They don't tell you if one drug is better or worse than another drug which may target a certain mechanism/pathway. Cell-based functional analysis can accomplish this.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway, or even a few targets/pathways.

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By Margot J. Fromer

ASCO Post

September 1, 2011, Volume 2, Issue 13

If the clinical trials endeavor in oncology is falling short of its goals and if targeted agents have not kept their promise, can a new approach to drug development provide a solution?

Very possibly, said John Hohneker, MD, Chair of the Workshop Planning Committee for the conference, “Facilitating Collaborations to Develop Combination Investigational Cancer Therapies,” held in Washington in mid-June and sponsored by the Institute of Medicine (IOM) National Cancer Policy Forum. He is also Senior Vice President and Global Head of Development, Integrated Hospital Care, Novartis.

Dr. Hohneker said that the purpose of the workshop was to talk about the many barriers to this new approach to cancer treatment. “Combining investigational products early in their development is thought to be a promising strategy, especially when they target multiple pathways (or more than one step in a pathway), thus conferring greater benefit than therapy directed at a single target.”

Unfulfilled Promise

Jane Perlmutter, PhD, founder of the Gemini Group, a consulting company, added, “The problem with the way cancer research is conducted is that the biology of the disease is so complicated that, although technology keeps advancing, personalized medicine is still mostly only a promise.”

Targeted agents for cancer haven’t panned out to the extent hoped. Although a few might work sometimes or for a short time, the effects have not been significant or durable. And many are more toxic than expected. “Their regulation is confusing and/or interpreted too conservatively, and despite the great need, there is limited incentive for pharmaceutical companies to collaborate with each other,” said Dr. Perlmutter.

Advances in genomics and cell biology have paved the way for increasingly sophisticated targeted therapies, but cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.

The traditional path to drug development, even targeted therapy, has been one at a time. Sometimes a new drug is added to a standard regimen and then compared to the standard alone, but regardless of how or with what it is used, it has to work on its own.

Cooperative Development

This system is no longer completely viable in cancer and needs to be modernized. A new approach would provide the flexibility to evaluate combination regimens in a single development program that can screen all tumors for their pathway dependencies, resulting in efficacy based on screening results and experience with patterns of resistance.

However, despite the potential benefits of such a scheme, uncertainty and risk abound. First, it is usually impossible to characterize the effects of the individual components. Second, combinations would probably yield considerably less information about safety and efficacy than would have been available had they been developed individually. Third, patients and physicians must not only be informed of more-than-usual risk, they must be willing to accept it. Fourth, there should be a compelling biologic rationale for their use and substantial reasons why the agents cannot be developed individually.

The Science Is Complex

James Doroshow, MD, Deputy Director for Clinical and Translational Research, NCI, discussed the scientific challenges facing development of combination targeted therapeutics:

The mechanisms of action for a growing number of targeted agents that are available for trials are not completely understood.

Lack of the right assays or imaging tools means inability to assess the target effect of many agents, and assays are not standardized.

Preclinical models to evaluate efficacy, dosing schedule effects, biomarker utility, and toxicity are not available for combination therapies.

Clinical trials methodology remains unclear with regard to numbers of patients, tumor biopsies, relevance of histologic homogeneity, and pharmacokinetic interactions.

Intellectual property and regulatory matters are daunting.

Dr. Doroshow also discussed mechanism of action (or mechanism of resistance) studies in early-phase trials. Problems include the evaluation of actual vs presumed sites of target engagement, evidence to support further development, demonstration of the relationship between dosing schedule and systemic exposure to target effects, and relevance of biomarkers.

“In addition, we need to investigate the molecular effects, toxicology, and other safety signals of combination agents in surrogate tissues,” said Dr. Doroshow. “This is a huge undertaking, and unfortunately it is not necessarily predictive of clinical benefit. That requires larger, later-stage trials.”

Michael T. Barrett, PhD, Associate Professor and Head of the Oncogenomics Laboratory, TGen, added that cancer is extremely genetically unstable, resulting in highly karyotypically and biologically individual malignancies. Thus, each patient’s cancer could require its own specific therapy. Even if this were possible and practical, the treatment could ultimately be thwarted by emergence of a resistant variant genetic subline.

Dr. Barrett also noted that each genome has unique sets of selected aberrations and mutations, of which multiple populations can be present at biopsy. These mutations can be asymmetric; they can progress and metastasize, and thus resist treatment. He warned that application of genomic tools to combination therapy has to be based on unbiased profiling of biopsies, as well as identification of therapeutic vulnerabilities in all patients.

Kurt Bachman, PhD, Head of Translational Medicine and Biology, GlaxoSmithKline, added, “The challenge is to identify the tumor types most likely to respond, to find biomarkers that predict a response, and to define the relationship of the predictors to the biology of the inhibitors.”

Disclosure: Dr. Hohneker is employed by and owns stock in Novartis. Dr. Barrett has a current research contract with AstraZeneca. Dr. Bachman is employed by GlaxoSmithKline. Dr. Perlmutter reported no potential conflicts of interest. Dr. Doroshow reported no potential conflicts of interest.

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In a conference sponsored by the Institute of Medicine, scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted cancer agents.

In a periodical published by the American Society of Clinical Oncology (ASCO) in their September 1, 2011 issue of the ASCO Post, contributor Margo J. Fromer, who participated in the conference, wrote about it.

One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.”

James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.”

He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . . in surrogate tissues,” and concluded “this is a huge undertaking.”

Michael T. Barrett, PhD, of TGen, pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.”

What they were describing was precisely the work that clinical oncologists involved with cell culture assays have been doing for the past two decades. One of those clinicians, Dr. Robert Nagourney felt that there had been an epiphany.

The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms.

The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and whole-cell experimental models had gained the hegemony they so rightly deserved.

Source: Dr. Robert A. Nagourney, medical director, Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted about this on his blog.

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  • 6 months later...

Implications of a New Target in NSCLC

The incidence of ALK gene rearrangement in patients with NSCLC is in the range of 2-4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. And now we have the ROS1 rearrangement in patients in the range of 1-2 percent, with another report of ALK rearrangement in the range of 1-2 percent (Bergethon, et al, J Clin Oncol. 2012; 30:863-870).

Dr. Howard (Jack) West told Medscape Oncology that "with a growing battery of extremely uncommon but potentially highly relevant markers in NSCLC, what is needed is a multiplex platform to test a broad range of targets simultaneously, using a limited amount of tissue, and for a reasonable price. If such testing capability is not readily available, we will soon reach a breaking point where it is not feasible to seek a series of separate $1500 mutation tests from multiple laboratories in search of patient subgroups totaling 1%-3% of the larger patient population."

http://www.medscape.com/viewarticle/761569

Yet with an objective response rate of 10 percent (Von Hoff, et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients, it doesn't seem to be a very accurate or validated methodology to use in patients with advanced NSCLC.

And those patients who do test negative for ALK and EGFR are left to the same guesswork that has provided responses in the range of 30 percent and survivals in the range of 12 months. It's interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient molecular testing.

If you don't have the mutant gene, why would you want the same treatment? It's like saying, a friend had a son who was not doing well in math and got a math tutor who greatly improved her son's grades. My son does not have a problem with math, but would like to do better in basketball, can I get the same tutor?

ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers.

J Clin Oncol. 2012; 30(8):863-70 (ISSN: 1527-7755)

Bergethon K; Shaw AT; Ignatius Ou SH; Katayama R; Lovly CM; McDonald NT; Massion PP; Siwak-Tapp C; Gonzalez A; Fang R; Mark EJ; Batten JM; Chen H; Wilner KD; Kwak EL; Clark JW; Carbone DP; Ji H; Engelman JA; Mino-Kenudson M; Pao W; Iafrate AJ

Department of Pathology, 55 Fruit St, Massachusetts General Hospital, Boston, MA 02114-2696.

PURPOSE:

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement.

PATIENTS AND METHODS:

Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort.

Results:

Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response.

CONCLUSION:

ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.

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The ROS1 mutation is a gene for DNA repair and the tyrosine kinase binding portion (the part that gets turned on to set off a cascade of downstream intracellular events) for ROS1 is very similar to ALK (ALK inhibitors can also inhibit ROS1). It seems like the results with Xalkori in some ROS1 mutation patients are very encouraging so far.

The ROS1 mutation occurs in about 1% of the lung cancer population, patients who are never-smokers, have poorly-differentiated and higher grade adenocarcinoma with bronchiololoalveolar cell carcinoma, and negative for EGFR, KRAS or ALK.

A published report to characterize the frequency and clinical features of the ROS1 rearrangement came from Massachusetts General Hospital and Vanderbilt University. The article looked at the molecular features of 1073 tumors from patients and found that 18 (1.7%) had the ROS1 rearrangement and 31 (2.9%) had the ALK rearrangement.

Both ROS1 and ALK patients share some clinical features, like a much younger median age than the broader NSCLC population. If testing for these few mutations has any significance, then use those tests for those "mutation targeted" drugs, but in the meantime, we've got the other 97.1% to 98.3% of chemotherapy in NSCLC patients to worry about.

According to Research To Practice, Massachusetts General (MGH) published a mutation paper focused on the new translocation called ROS1 (a receptor tyrosine kinase of the insulin receptor family). The article has been released electronically by the JCO and details the genetic and clinical characteristics of ROS1-positive tumors and also describes the case of a 31-year-old man who, according to Dr. Tom Lynch, was “on his deathbed” when he was found to have a ROS1 rearrangement.

Prior in vitro work, also conducted by the MGH group, had shown ROS1 cells to be sensitive to ALK inhibitors, so the patient was treated with Xalkori (crizotinib) as part of a newly launched Phase I trial. The patient experienced rapid tumor shrinkage with a near complete response and almost a year later he remains on that agent with no evidence of recurrence.

The ROS1 translocation is found mainly in younger never smokers with adenocarcinoma. Like ALK, it is detected by FISH assay and has some sequence homology to ALK — perhaps explaining why Xalkori (crizotinib) is effective in vitro and in at least one patient. Of particular interest, this rearrangement has also been observed in glioblastomas and cholangiocarcinomas, but the impact of an agent like Xalkori (crizotinib) is unknown.

Winter Lung faculty member Dr. Pasi Jänne wrote an accompanying JCO editorial and commented during the meeting that oncologists must be on the lookout for nonsmokers who test negative for EGFR and ALK, and while ROS1 is thought to occur in only about 2% of non-small cell cases, this translates to approximately 4,000 people a year in the United States alone.

The appearance of yet another potentially “druggable” target in NSCLC should be no surprise considering recent research demonstrating that so-called driver mutations occur in perhaps as many as 60% of pulmonary adenocarcinomas. As a result, we are now approaching or have arrived at a situation very similar to breast cancer with ER, HER2 and the 21-gene Recurrence Score, in that the treatment algorithm changes dramatically based on the results of tissue assays.

In cancer medicine, the new paradigm establishing a requirement of a companion diagnostic as a condition for approval of new targeted therapies. However, it puts such great pressure that the companion diagnostics that are approved often have been mostly or totally ineffective at identifying clinical responders to the various therapies. That is because genomics are far too limited in scope to encompass the vagaries and complexities of human cancer biology.

Pharmacogenomics is defined as the study of how a person's genetic makeup determines response to a drug. Although any number of labs and techniques can detect mutant genes, this area of pharmacogenomics was ripe for proprietary tests, invented alongside the drug and owned by the drug developer and/or a partner in the diagnostics field.

This business opportunity evolved as more drugs were approved with companion diagnostics. Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. There is still a lot of trial-and-error treatment going on.

Top pharmaceutical firms specializing along disease management lines: in-licensing or co-marketing portfolios of personalized, smaller-market drugs as a package deal to physician specialties, along with a test or two. Drug and diagnostic companies working together, with drug targets perhaps based on a diagnostic marker - not the other way around - could grease the wheels for personalized medicine.

Pharmacogenomics relies on the marriage of pharmacology and genetic testing. Where cell function analysis finds the optimal treatment or combination from an array of possibilities, pharmacogenomics normally focuses on one or more genes targeted by a single drug. Gene-based tests lend themselves to the drug/diagnostic brand of personalized medicine.

Functional profiling methodology maintains cancer cells in their native state, making analysis of "targeted" compounds more reliable. Cellular tests have the advantage over genetic tests because the complexities and redundancies of human biology are beyond the ken of genomics.

As we enter the era of personalized medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed actually matching treatment to the patient (not statistical guesstimates).

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

In this new era of pharmacogenomics, genetic and phenotypic analysis, prognostic molecular marker testing, and cell function analysis all share a role in the development of "personalized" patient care.

Literature Citation:

BMJ 2007;334(suppl 1):s18 (6 January), doi:10.1136/bmj.39034.719942.94

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

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ROS1: New Marker of Small Population with Apparent Big Benefit with XALKORI?

Functional analysis response rates for Tarceva (erlotinib) as a single agent are superior to the response rates for patients selected based on EGFR mutational analysis. In addition, secondary mutations have already been identified that confer resistance to Xalkori (crizotinib), which likely confound durable remissions for this and related targeted drugs.

While the selective application of drugs like Tarceva for EGFR mutants, and Xalkori for ALK or ROS1 mutants seem much more effective in patients with these gene expressions, these are a select few examples of linear thinking, in that this gene is associated with this disease state and can be treated with this particular drug.

Most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if they first know the gene of interest and second know that its over-expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways, the "targets" of these drugs.

The address these complexities, functional analytic platforms examine outcomes, not targets. This bottom-up approach has enabled cell-based functional profiling assay labs to explore the activity of novel compounds. When investigators develop "small molecule" targeted drugs, these labs examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms.

There are lots of things which determine if drugs work, beyond the existence of a given target (like ALK or ROS1 for Xalkori). Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

Tumor biology is a lot more complex than we'd like it to be. Cancer is more complex than its gene signature. Many common forms of cancer present as a host of mutated cells, each with a host of mutations. And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment. You kill off the tumor cells that can be killed off, but that may just give the ones that are left a free reign.

The idea of searching for clinical responders by testing for a single gene mutation seems like a nice theoretical idea, but you may have to test for dozens of protein expressions that may be involved in determining sensitivity/resistance to a given drug. Because if you miss just one, that might be the one which continues cancer growth. And at up to $1,500 a pop, that's a lot of dough, on top of the inflated price of the single drug!

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" analysis (is the cell being killed regardless of the mechanism) as opposed to "target" analysis (does the cell express a particular target that the drug is supposed to be attacking). While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them, all from the one test.

Sometimes the genetic signal may not be the driver mutation. Other signaling pathways, like passenger mutations, could be operative. Driver mutations are the ones that cause cancer cells to grow, whereas passengers are co-travellers that make no contribution to cancer development. It turns out that most mutations in cancers are passengers. However, buried among them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought.

Cells speak to each other and the messaages they send are interpreted via these intracellular pathways. You wouldn't know this using analyte-based genomic and proteomic methodologies. However, functional profiling provides the window. It can test various cell-death signaling pathways downstream.

While most scientists use genomic or proteomic platforms to detect mutations in these pathways that might result in response to chemicals, cell-based functional profiling platforms have taken a different tack. By applying functional analysis, to measure the end result of pathway activation or deactivation, they can predict whether patients will actually respond.

The cell-based functional profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

J. Clin Oncol 28:7s, 2010 Abstract No. 7617

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