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People with specific kind of lung cancer respond to new targeted treatment
By Dross at 2010-10-29 21:45
People with specific kind of lung cancer respond to new targeted treatment

AURORA, Colo. (Oct. 28, 2010) - 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 lymphomaterm 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 adenocarcinomaterm 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 previously presented at the 2010 American Society of Clinical Oncology Annual Meeting.

4 comments | 1902 reads

by gdpawel on Fri, 2011-09-16 10:03
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.


by gdpawel on Mon, 2011-09-26 12:17
By Margot J. Fromer
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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