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Old 10-29-2010, 10:45 AM
Dross Dross is offline
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Default Crizotinib for ALK-positive advanced non-small cell lung cancer

A study in the New England Journal of Medicine shows more than half of patients with a specific kind of lung cancer are responding positively to a treatment that targets the gene that drives their cancer.

The study shows 57 percent of patients with ALK-positive advanced non-small cell lung cancer responded partially or completely to a tablet called crizotinib, an investigational anaplastic lymphoma kinase (ALK) inhibitor. In some cases, the cancer becomes undetectable in body scans. The data is published in the October 28 issue of the New England Journal of Medicine.

"This study really supports the idea that we should always try to identify the patients that could benefit from a specific treatment in advance. By looking at lung cancer at the molecular level, we were able to find the patients most likely to respond to the ALK inhibitor and put them in this trial," said D. Ross Camidge, MD, PhD, one the of the study's authors, director of the lung cancer clinical program at University of Colorado Hospital (UCH) and the University of Colorado Cancer Center (UCCC).

"At the University of Colorado Hospital, we look after one of the largest groups of ALK positive lung cancer patients in the world. About one in 20 lung cancer patients are ALK positive. Most feel better within days of beginning the drug in the trial and many have returned to active lifestyles with their cancer under excellent control." said Camidge.

There were initially 82 ALK-positive lung cancer patients in the trial of the ALK inhibitor. ALK is believed to be a key driver of tumor development in some cancers.

Updated results from the study were presented earlier this month at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy, reporting on a total of 113 patients and the impressive activity of the drug in these patients remained consistently high. The preliminary median progression-free survival (PFS), the time it takes for the cancer to first start to grow again, was 9.2 months.

"Initially the cancer melts away, but it's still there. And at some point, it usually figures out a way to get around this particular drug. We need to keep looking for new developments so that when this happens, we can supplement or replace the crizotinib with other treatments to help keep the cancer under long-term control," said Camidge.

At the very least, Camidge said it is crucial for anyone diagnosed with lung cancer to get their tumor tested. Several commercially available tests are available but the definitive test that qualifies for entry into the study is only conducted in those centers with the trial. The University of Colorado helped to develop these tests and many others for taking one disease - lung cancer - and revealing that it is, in fact, several different diseases at the molecular level. Each one of the diseases may need a different treatment.

Study Results Published in the New England Journal of Medicine

In the Part 2 expansion cohort study which included 82 patients with ALK-positive advanced NSCLC, 57 percent (n=47)(95% CI 46%, 68%) of patients treated with crizotinib (PF-02341066) at a dose of 250 mg twice daily, had either a complete or partial response to treatment. An additional 33 percent (n=27) met criteria for stable disease, including five unconfirmed partial responses. At eight weeks, the disease control rate (complete response (n=1) + partial response (n=46) + stable disease (n=24)) was 87 percent (n=71). Three patients with stable disease were not included in the disease control rate because their evaluation for response was outside a pre-specified timeframe.

At the time of the analysis, 77 percent of patients (n=63) continued to receive treatment with crizotinib (PF-02341066). The median duration of treatment was 6.4 months, and follow-up is ongoing. As such, the estimated probability of being progression-free at six months is 72 percent (95% CI: 61%, 83%).

Overall, crizotinib (PF-02341066) was generally well tolerated. The most commonly reported all-grade adverse events included nausea (n=44), diarrhea (n=39), vomiting (n=36), and mild visual disturbances (n=34). Grade 3 ALT (alanine aminotransferase) and AST (aspartate aminotransferase) elevations occurred in four patients. One patient experienced a Grade 4 ALT and one patient discontinued treatment due to Grade 3 ALT increases. Tumors in the analysis were primarily of adenocarcinoma histology, and patients tended to be young, and were never or former light smokers. Ninety-three percent of patients (n=76) had received at least one prior therapy and five patients were treated in the first-line setting.This Part 2 expansion cohort study of patients with ALK-positive advanced NSCLC, independent of the number of previous chemotherapies, followed the completion of the dose-escalation study which enrolled 37 advanced cancer patients with various tumors, including NSCLC, colorectal, pancreatic and inflammatory myofibroblastic tumor (IMT) tumors.

These data were presented at the 2010 American Society of Clinical Oncology Annual Meeting.

Note:

Clinical Benefit Rate (CBR) and Disease Control Rate (DCR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. CBR and DCR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether CBR and DCR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR or DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the CBR or DCR are reported suggest that CBR or DCR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient (Curr Opin Investig Drugs. 2010 Dec;11(12):1340-1).

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?

[url]http://www.ncbi.nlm.nih.gov/pubmed/21268434

Last edited by gdpawel : 03-02-2013 at 12:48 AM. Reason: corrected url address
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Old 09-15-2011, 11:03 PM
gdpawel gdpawel is offline
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Default Novel Cancer Treatments — Crizotinib

Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

Recent reports have described the striking activity of a novel Pfizer compound known as Crizotinib. The compound is an inhibitor of an enzyme known as the anaplastic lymphoma kinase (ALK). In approximately 5 percent of non-small cell lung cancer patients, a specific mutation known as the EML4-ALK rearrangement results in activation of this gene and the development of cancer. In those patients who are found positive for this mutation, the response rate to the drug Crizotinib is 57 percent with a disease control rate of 87 percent at eight weeks.

Hailed as an unprecedented response rate by Anil Potti, MD, associate professor of medicine at Duke University, these results reflect the power of pre-selection of candidates for treatment. The drug is reasonably well tolerated and represents a true advance. Taken in context, however, these results are not superior to those that we recently reported using conventional chemotherapies pre-selected by functional analysis. Indeed, our results with a response rate of 62 percent, a time to progression of 9.5 months and a median overall survival of 20.3 months are actually better. More notably, our results were obtained with conventional chemotherapeutics, not novel compounds.

What is most striking about the Crizotinib results is the capacity of pre-selection to demonstrably improve response rates. Yet, these results only apply to a distinct minority of patients. The results that we reported at ASCO reflect the activity of chemotherapy applicable to the remaining 95 percent of NSCLC patients. It is also highly likely that functional analysis will select Crizotinib candidates as well, or better, than the mutational analysis utilized for patient selection in the study reported. For comparison, our response rates for erlotinib (Tarceva) 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 Crizotinib, which likely confound durable remissions for this and related drugs.

While I applaud the results of this interesting trial, my team and I feel it important that all lung cancer patients have the benefit of pre-selection. Whether they fit into the 5 percent described in this report, or the 95 percent covered in our clinical trial.

[url]http://www.medscape.com/viewarticle/731330
[url]http://robertanagourney.wordpress.com/category/asco-2010-lung-cancer/
[url]http://hopepracticedhere.wordpress.com/2012/05/02/persistence-over-acceptance/
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Old 09-26-2011, 01:17 AM
gdpawel gdpawel is offline
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Default Research in Combining Targeted Agents Faces Numerous Challenges

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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Old 09-26-2011, 01:18 AM
gdpawel gdpawel is offline
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Default Targeted Therapies for Cancer Confronts Hurdles

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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Old 12-22-2011, 11:11 AM
gdpawel gdpawel is offline
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Default Dermatologic Adverse Events Induced by Molecularly Targeted Cancer Agents

Dr. Mario Lacouture from Memorial Sloan-Kettering Center Center in New York and his colleagues from the Northwestern University Feinberg School of Medicine in Chicago, have suggested in a new study that painful rashes and other skin-related side effects of newer targeted cancer drugs may jack up treatment costs.

The average cost of treating each cancer patient who came into a dermatology clinic with skin, hair and nail complaints was almost $2,000, the researchers reported. That included expenses related to doctors' appointments, dermatology medications and lab tests. And some patients with skin problems may have to delay or alter their treatment regimen if side effects are too severe.

According to Dr. Lacouture, dermatologic side effects including skin irritation and dry skin are the two topmost concerns that patients have that they did not expect during therapy. Patients are prepared to get hair loss, they are prepared to get some nausea and diarrhea, but they aren't expecting to get is all these skin issues.

Lacouture and his colleagues tracked costs related to skin reactions in 132 patients being treated with targeted cancer-fighting drugs at their dermatology clinic between 2005 and 2008. The majority of those patients had colon or lung cancer and the most common drug treatments included Erbitux (cetuximab) and Tarceva (erlotinib).

Patients came in with a range of dermatology-related complaints, including painful acne, lesions and blisters on the hands and feet and nail infections. Those conditions cost anywhere from $21 to almost $11,000 to treat, depending on the patient.

The average total cost of medications, clinic visits, treatment procedures and lab tests such as blood work and wound culturing for each patient was $1,920. Dermatology drugs accounted for the greatest chunk of that, costing an average of about $840 per patient, according to findings published in the Archives of Dermatology.

Lacouture said that more than half of patients may have skin, hair and nail reactions to newer drugs that treat some of the most fatal types of cancer. That's because along with their cancer-fighting action, the drugs also attack proteins on the skin.

If skin reactions are severe, especially with certain cancer drugs including Nexavar (sorafenib) for kidney cancer, doctors may have to adjust dosages or take patients off those drugs for a period of time. While most of the extra costs would be covered by patients' insurance, skin problems also mean more time and transportation for appointments and co-payments.

It adds to the out-of-pocket costs for the patient and to the already ballooning cost of cancer. Those costs should be taken into consideration when evaluating new cancer drugs. The most important thing for patients is to be aware of how common these problems are and know that the sooner they are diagnosed and treated for side effects, the less likely it will interfere with cancer treatment and the quality of life.

Source: Archives of Dermatology, December 19, 2011.

[url]http://archderm.ama-assn.org/cgi/content/abstract/147/12/1403

Skin problems are the most common adverse effects from new anti-cancer drugs. Ralf Gutzmer, from the Hannover Medical School (MHH), and co-authors now summarize the current state of knowledge in the recent edition of Deutsches Aerzteblatt International (Dtsch Arztebl Int 2012; 109(8): 133-40).

Adverse effects of the skin include rashes, nail problems, and the hand-foot syndrome. The substance class of multikinase inhibitors causes such cutaneous adverse effects in up to 34% of patients. The proportion of patients with adverse effects is even higher for the selective kinase inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors and inhibitors of mutated BRAF, with up to 90% affected, and for immunotherapeutics such as the CTLA-4 antibody, with up to 68% affected.

Such adverse effects can be severe, painful, or lead to psychological discomfort due to their localization on visible areas of the body, and this can affect patients' willingness to continue treatment. However, adverse effects can also be associated with a patient's positive response to therapy, as is the case for the EGFR inhibitors.

Early recognition and treatment of cutaneous adverse effects are critical to successfully implementing anti-cancer drug therapies. Achieving this requires on the one hand the primary treating physician, and on the other, an intensive, interdisciplinary collaboration involving dermatologists.

Deutsches Aerzteblatt International

http://www.aerzteblatt.de/pdf.asp?id=122847
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