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Update on Evidence of CALGB 30406 Trial: Chemo/EGFR Inhibitor vs. EGFR Inhibitor Alone in Never-Smokers
Just prior to ASCO, I mentioned the early results of the Cancer and Leurkemia Group B (CALGB — Group A long-since defunct) 30406 trial. This study enrolled 181 people with advanced lung adenocarcinoma who had either never-smoked or had a rather minimal smoking history of 10 “pack-years” or fewer, and who were randomized to receive the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) alone or in combination with standard chemo of carboplatin and Taxol (paclitaxel) as first line treatment. The idea of this trial was that the selection of patients by the clinical factor of smoking status was meant to enrich for a higher probability of such patients having an EGFR mutation, and it had also been recognized that never-smokers (less than 100 cigarettes in their lifetime) or “oligo-smokers” (oligo meaning few, so the term means those ex-smokers who had a light smoking history but didn’t qualify as never-smokers) in many clinical trials of EGFR inhibitors appeared to be the greatest beneficiaries of an EGFR inihibitor like Tarceva or Iressa (gefitinib). At the same time, there was reason to question whether combining chemo with an EGFR inhibitor might provide additional benefit, have no effect, or might even be detrimental.
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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.
Round Table Case-Based Discussion — Drs. Laskin and Sandler on Molecular Testing in a Never-Smoker
Here is the first podcast of what we plan will be an ongoing series of round table discussions with cancer experts about real case scenarios and how we make decisions in practice. My guests for the discussion are Drs. Janessa Laskin, medical oncologist from British Columbia Cancer Agency in Vancouver, BC, and Alan Sandler, medical oncologist and Director of Hematology/Oncology at Oregon Health & Science University in Portland.
The first case we discussed is a relatively young Asian never-smoking woman with an advanced lung adenocarcinoma, focusing first on the changing standards for sending tissue for molecular testing, as well as the limitations of that. Here is the video version, audio, transcript, and associated figures.
round-table-laskin-sandler-never-smoker-mutn-testing-audio-podcast
round-table-laskin-sandler-never-smoker-mutn-testing-transcript
round-table-laskin-sandler-never-smoker-mutn-testing-figures
Podcast: Play in new window | Download (0.3KB) | Embed
Evidence of the Impact of Environmental Tobacco Smoke in Never-Smokers: Correlations with EGFR Mutations
It seems obvious: environmental tobacco smoke (ETS)/passive smoke exposure from being around smokers, can be harmful and may cause cancer in never-smokers. A new paper in the Journal of Clinical Oncology by Lee and colleagues from Korea actually offers some evidence that highlights this, showing that never-smokers in Korea were less likely to have an EGFR mutation if they were exposed to ETS.
Lee and colleagues from Korea assessed ETS in 179 consecutive never-smoking Korean patients with NSCLC by using trained interviewers who reviewed the number of smokers either living or working with a patient and the duration of their shared exposure. This led to a measurement of “smoker-years” that was the product of the number of smokers by the number of years living or working together (in their paper, the term “never-smoker” was actually assigned to those who not only never smoked personally but also had no significant direct exposure to smokers or tobacco.
Similar to the demographics of the famous IPASS trial of Asian never-smokers (or 6% light former smokers), the patient population skewed far younger than a typical lung cancer patient (58 in this study, vs. about 70 in broad populations) and was overwhelmingly female (>80%).
Though the proportion of patients they found with EGFR mutations was a little lower than was seen in the IPASS trial, (44% vs. 60%), the key finding was that patients with a history of ETS exposure were less likely to have a NSCLC tumor associated with an EGFR mutation than those with ETS exposure (38% vs. 61%), and there was a stepwise decrease in probability of having an EGFR mutation with gradually increasing ETS exposure. And the same pattern held true whether that exposure is in childhood or as an adult, at home or at work:
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Iressa vs. Chemo in First Line Treatment of Korean Never-Smokers: The First-SIGNAL Trial
I would consider the recently published IPASS trial that compared Iressa (gefitinib) to standard chemo of carbo/taxol (paclitaxel) to be an extremely influential trial in lung cancer that has essentially ushered in a new era of molecularly-defined guidance of our treatment for many patients with advanced NSCLC, and we can expect that this is how we’ll be approaching a much broader population of lung cancer patients. But there was actually another very similar trial done in Korea that was presented in the Plenary Session of the World Conference on Lung Cancer a couple of months ago in San Francisco that provides another opportunity to directly compare chemo to an EGFR inhibitor.
The First-SIGNAL trial (First-line Single Agent Iressa versus Gemcitabine and cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung) randomized 313 Korean never-smokers with previously untreated stage IIIB or IV lung adenocarcinoma to either Iressa at 250 mg by mouth daily to standard chemo with cisplatin/gemcitabine as initial therapy. It asked whether first line Iressa would be associated with a significant improvement in overall survival (OS) and also looked at progression-free survival (PFS), response rate (RR), side effect profile, and quality of life between the two treatment arms. This trial had a rather ambitious goal of showing a 40% improvement in survival and enrolled only about ¼ the number enrolled on the IPASS trial, so the statistics reported here need to be taken with a grain of salt because the study is pretty underpowered to show many meaningful statistical differences.
The EML4-ALK Mutation Enters the Lung Cancer Clinic
Dr. Pinder previously summarized the early story of the newly identified EML4-ALK mutation in NSCLC, which traces back only a couple of years. Amazingly, in that short time, treatments targeting this mutation have already been identified and administered to patients who are benefiting from these novel agents at this very moment. Still, one of the leading issues with this story of progress is that the EML4-ALK mutation appears to be present in less that 5 percent of the overall NSCLC population, so people may ask how valuable this discovery really is.
That really depends on a couple of factors. First, screening for an EML4-ALK mutation will be much more appealing and feasible if we have some hints of which pateints are more or less likely to have one of these mutations. Second, we need to have a treatment that helps the people we screen who have the ALK mutation.
Looking for Genetic Differences in Never-Smokers who Develop Lung Cancer
Last year I highlighted a research program out of Memorial Sloan-Kettering Cancer Center in NYC that has been trying to identify molecular genetic factors in never-smokers who develop lung cancer that can help provide explanations and even perhaps a better sense of why anyone, including smokers, may be at higher risk for developing lung cancer than others. The study involves just a questionnaire about tobacco and other exposures, and also collecting a couple of vials of blood that can be drawn at your local doctors office and then sent, postage paid, to a lab for genetic analysis.
I saw the investigator leading this effort, Dr. William Pao, at the World Conference on Lung Cancer this past week. He has since been recruited from Memorial Sloan Kettering to Vanderbilt University Medical Center in Nashville, TN, where he’s leadinga growing lab-based effort to better understand the genetic underpinnings of lung cancer. The blood collection and genetic analysis is bearing fruit, and he and his colleagues are in the process of writing some of their early findings from this project. They’ve enrolled many people who found out about this work here, and I’ve also told my never-smokers about it and encouraged them to consider participating. Who wouldn’t want to help understand why some people are at a higher risk for developing lung cancer.
You can find out more information at the website www.vicc.org/neversmokers or by e-mailing neversmokerswithlungcancer@vanderbilt.edu.
One new development is that the survey is now available online, making it even easier.
Video Presentation on Never-Smokers with Lung Cancer
Here’s a video presentation on never-smokers with lung cancer, a population that has been a subject of great interest to me for the past several years. Ten years ago, we really didn’t focus on smoking status as a relevant issue and didn’t break out never-smokers as a group within our lung cancer trials. Over the last few years, and largely on the basis of differences in outcomes that became more clear with the introduction of the EGFR inhibitors, we’re coming to recognize that never-smokers with lung cancer may really represent a distinct disease, with different demographics, pathology subtypes, response to treatments, and overall survival. This video provides a brief overview of the highlights of what we know about never-smokers with lung cancer.
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A Non-Scientific Assessment of Better Lung Cancer Outcomes
This week I happened to see a man in my clinic who I had first met at the time of his diagnosis with metastatic lung cancer more than five years ago. He’s from another part of Washington state, and this was his first time back with me to revisit treatment options. For me it was a time to take a step back and reflect on how well he’s done, with the real question being whether this represented a real change in what we can expect from lung cancer or whether he represents an outlier and that our so-called progress is really modest (as suggested by some of the sobering statistics described in a recent New York Times article). But from the standpoint of an oncologist with a particular interest and expertise in lung cancer, I feel like I’m seeing more lung cancer patients doing better and better than the numbers would indicate.
The gentleman I saw this week is now in his late 50s and is lifelong never-smoker who presented with brain mets (immediately treated with whole brain radiation) and a good amount of disease in his chest. Since meeting me during his initial workup, he’s been managed by a very good community-based general oncologist in a small town in eastern Washington. He was treated with initial platinum-based doublet chemo (old school cisplatin/gemcitabine, actually), then taxotere (docetaxel), and both of these approaches were associated with mild benefit, though nothing spectacular. He started tarceva (erlotinib in early 2005 and had a great response that lasted about three and a half years, then had some new areas of bony metastatic disease. His oncologist actually added alimta (pemetrexed) to his tarceva, an approach I don’t really favor (my take on the evidence is that there may well be an antagonistic effect between EGFR inhibitors and at least some if not most standard chemo approaches used for NSCLC).
Though he’s showing evidence of mild progression again, what’s limiting his activity is degenerative joint pain in his hip and a need for a hip transplant (he had one last year that helped a lot). Otherwise, he’s a genuine cowboy and is planning to literally get back in the saddle after surgery, which I strongly encouraged. And we talked about a bunch of options, but what impressed me most is the thought that we could be revisiting treatment options for him over many years to come. And this from a man who presented with multiple brain metastases over five years ago.
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