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The Evolving Role of Molecular Markers in the Management of Non-Small Cell Lung Cancer
The Importance of Identifying Molecular Markers in Non-Small Cell Lung Cancer
To understand the importance of molecular markers in the current and future treatment of lung cancer, one should first understand how lung cancer was classified up until the beginning of this decade. Pathologists would look at a sample of a patient’s lung tumor under a microscope, and then make a judgment of whether the cells represented small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Although that is an oversimplification, for all practical purposes, that is what oncologists cared about when it came to choosing treatment. If the diagnosis was NSCLC, then oncologists treated the patient with platinum doublet chemotherapy using one of many standard regimens that were felt to be equally effective. Unfortunately we knew that these regimens only worked in a certain proportion of patients, but we had no way to predict ahead of time who would benefit and who would not.
At the same time pathologists and molecular biologists have know for some time that NSCLC is not really just one disease, but rather a constellation of many diseases that all share the distinction of starting in the lung. For example, major subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma were often reported in pathology reports but did not influence treatment choice. Since 2004 we have taken this one step farther, asking pathologists to tell us not just that the lung cancer is non-small cell but also that it is non-squamous cell, for purposes of safety with Avastin (bevacizumab) and efficacy with Alimta (pemetrexed), but that is the topic for another chapter.
As our understanding of the molecular basis of cancer has grown, we have developed a number of new molecularly-targeted agents with promise in the treatment of lung cancer. However, targeted drugs tend to have limited or no effect on cancers that lack the “target” of the drug, creating a need for markers to guide us.
Differences in Patient Treatment Outcomes by Gender
The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.
There has been a lot of historical data showing that women with lung cancer do better than men with lung cancer, and we don’t really know why, but this has been seen over and over again. These are some earlier trials; one was looking at the registry data (SEER) showing that women with lung cancer did better than men, and another trial done at the Mayo Institute showing that again women do better than men by a small percentage, but a definite statistically significant improvement. Continue reading
Gender Differences in Risk for Lung Cancer
The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.
Let’s move to biological differences of risk of lung cancer between men and women.
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In the table above, this gets right at the question of whether there’s an increase risk of smoking for women versus men. This is some of the data that we have from some of the larger trials, very different types of studies, some were case-control studies where if someone developed lung cancer the investigators would find similar people who matched in every way except that they didn’t have cancer, and then others were cohort studies, in which a large cohort, a defined population, was followed closely over time. Continue reading
Assessing the Causes of Lung Cancer in Never-Smokers
The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.
The real question, of course, is why do people get lung cancer who have never smoked? We don’t really know. We think it could be related to second hand smoke, and perhaps it’s happening in childhood even more so. It might be from vehicle exhaust, and a lot of work is being done there. Cooking fumes have been the culprit in several studies, especially in poorly ventilated kitchens. Occupational exposures including paint in a recent analysis. Radon exposure is a big risk and something especially in the mountain states, people look at radon levels in their house and important, and that can be a thing to test for.
There are a lot of environmental toxins, such as asbestos and arsenic, and then there’s a family risk. It’s much, much lower when we talk about cancer risks like colon cancer families and breast cancer families. It’s not of that magnitude, but there certainly are families where lung cancer tends to run in the family. We see this especially when the lung cancer is diagnosed very early, there’s been a hint that certain genes might be related to family lung cancer — but we have a lot of work still to do on that.
Overall, though, we don’t quite know the reasons why people get lung cancer, but we are starting to understand more about what has happened on a molecular basis, especially in people who never smoked but develop lung cancer.
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Introduction to Lung Cancer in Never-Smokers
The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.
I’ll start with the association of lung cancer with smoking.
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There is no doubt that smoking remains the biggest risk of lung cancer, and what this slide is showing in the green is cigarette consumption and how that started off in the 1900s, gradually increasing until the 1960s ,when the public first became aware of the health risks and as that dropped, lung cancer deaths also started to drop but obviously trailed that.
The gray line is the men, showing that men led early smoking cessation efforts and stopped, and so the death rates in men dropped as the cigarette smoking dropped. Unfortunately for women, we were a little slower to hear that message about health risks from smoking, and we’re only now starting to see a tapering off of lung cancer in women. Still a little bit lower than men, but a real risk.
Afatinib (BIBW-2992, Tomtovok) wins a battle (PFS) but loses the war (OS) for EGFR TKI-sensitive patients
Although the responses we see with a targeted therapy like the epidermal growth factor receptor (EGFR) oral tyrosine kinase inhibitors (TKIs) for patients with the precise target, an activating mutation in the EGFR gene, has redefined our hopes and expectations about what is possible to achieve for at least some patients with advanced non-small cell lung cancer (NSCLC), nearly all of these patients develop a resistance to these agents at some point months or years after often having a very significant response to one of these agents. What to do at that point, whether there is some particular intervention to pursue to get the genie back into the bottle and achieve some similar kind of benefit again, remains unknown.
In the LUX-Lung 1 trial, the irreversible EGFR and HER-2/neu inhibitor BIBW-2992, now named afatinib, with a marketing name Tomtovok (changed from what was previously Tovok), was studied in this population compared with placebo (2:1 randomization to active drug), with all patients also getting supportive care as well. The trial was open to patients with a lung adenocarcinoma, had previously received at least one line of prior chemotherapy, and had gone for at least 12 weeks without progressing on another EGFR inhibitor, either Iressa (gefitinib) or Tarceva (erlotinib). A total of 585 patients were enrolled, and these were clearly closer to the population of the IPASS trial than a general population of folks at the VA hospital: the median age was in the late 50s, 56-58% of the patients were Asian, about 1/4 with no symptoms even after several prior lines of treatment, and nearly 2/3 were never-smokers. This was clearly enriching for a population likely to have an EGFR mutation, though we haven’t seen any analysis of molecular markers for the trial. The median duration of EGFR TKI therapy was about 10 months, and approximately 45% of the enrolled patients achieved an objective response (significant tumor shrinkage), so most of these patients appear to have been the target population that really benefited greatly from an EGFR TKI and then developed acquired resistance to it.
PF299 Continues to Shine…
A couple of months ago I highlighted some very encouraging early work on the novel agent PF299804, an “irreversible pan-HER tyrosine kinase inhibitor”. My previously posts on this agent focused on discussion of it in single arm trials in previously treated patients with advanced NSCLC, and another post comparing it to Tarceva (erlotinib). A new trial just presented at the ESMO Congress by Dr. Tony Mok from Hong Kong highlights its effectiveness in patients clinically selected for a higher probability of an EGFR mutation or else known to have an EGFR mutation. PF299 has the appeal of not only being active in cell lines from cancers with an EGFR activating mutation, but also apparently having activity against cell lines with mutations such as T790M on exon 20 of the EGFR gene, which is seen in about half of patients with acquired resistance to an EGFR inhibitor.
The study enrolled a chemo-naive population of patients with advanced NSCLC who were clinically enriched for having an EGFR mutation (never-smoker or light former-smoker with an adenocarcinoma), either Asian or known to be KRAS wild type (no mutation), or else known to have an EGFR mutation. About 60% (44 of 74) patients were enrolled from one of eight Asian centers, while another 30 patients came from centers in the US; about 80% of patients are never-smokers. Patients received single agent PF299 at 45 mg by mouth daily, until a protocol amendment decreased the starting dose to 30 mg daily, with enrollment still ongoing at this lower dose level.
MetMAb Looking Very Promising for (About Half of) Patients with Advanced NSCLC
We’ve already discussed prior work on Met as a potentially valuable target in NSCLC, as illustrated by work with ARQ-197 combined with the EGFR inhibitor Tarceva (erlotinib) has demonstrated encouraging early results. More recently, Met was the source of a lot of buzz at the European Society for Medical Oncology Congress this past week because of another agent targeting Met, called MetMAb, that has demonstrated compelling evidence of activity, at least in a subset of patients with advanced NSCLC. And this is a subset that includes about half of the NSCLC population.
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Met is a receptor protein that is mutated and overexpressed in many cancers, in which it is typically associated with a worse prognosis, including in NSCLC. Importantly, in the last few years, it has been identified as one of the mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) like Tarceva or Iressa (gefitinib), both from the very start of EGFR TKI therapy (primary resistance), and after an initial response (secondary or acquired resistance).
MetMAb is a single-armed monoclonal antibody (typically abbreviated mAb or MAb) that adheres to and blocks the receptor portion on the outside of the cell without leading to the receptor being stimulated and causing growth, migration, and promotion of survival of the cancer cell. In various cell and animal models, it’s active against many cancers.
An Overview of Molecular Markers in Lung Cancer
Introduction to Molecular Markers
A molecular marker is an identifiable molecular characteristic (usually DNA, RNA, or protein) in a patient or a tumor that can be used to provide prognostic or predictive information about the cancer or about a particular treatment. A prognostic marker is one which indicates a better or worse outcome irrespective of treatment. For example, a mutation in the KRAS gene has been widely regarded as a poor prognostic molecular marker (see below), but does not necessarily guide us in selecting therapy for a particular patient. In contrast a predictive marker indicates a better or worse chance of an outcome for a specific treatment. Identifying this type of marker is a major goal of translational research and forms the basis of “personalized medicine”, which is simply saying that you may be able to determine ahead of time which treatment will or will not work in a specific patient.
In this chapter, I will try and describe the most common molecular markers being investigated in lung cancer, including some tests that are already being used in practice today. Continue reading
Who is Defining the Standard of Care? Clinical Trial vs. Real World Patients with Lung Cancer
The rate of our progress in lung cancer and other settings in medicine reaches a bottleneck in the slow rate at which clinical trials are completed. Nevertheless, only about 3% of patients with cancer in the US participate in clinical trials, and the number is even a little lower for people with lung cancer. There are many reasons for this: many patients don’t have access to clinical trials without traveling significant distances, and others may object to participating in research (misleadingly sensational magazine covers showing a person in a cage, with a headline titled “Are you a guinea pig?” make me cringe), but another factor is that many patients are simply not eligible for our clinical trials. Some recent research looked at this question, important for its relevance for the rate of our progress and the generalizability of clinical trial results in a narrow subset to a much broader population of real world patients.
Dr. Lou Fehrenbacher is a medical oncologist in the large Kaiser Permanente network of Northern California (KPNC) who also conducts a significant amount of important clinical research there. He and collagues there took advantage of the breadth of this network to capture data on 326 consecutive patients diagnosed with advanced NSCLC just in the first quarter of 2005, comparing them to 196 patients who were enrolled on any of the randomized clinical trials that KP participated in over the preceding 10 years. They then presented the results on the differences between these two populations at the ASCO 2009 meeting.
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