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What I really do: Molecular testing for NSCLC
I’m fortunate to practice at Moffitt, where Dr. Gerold Bepler and Dr. George Simon pioneered a molecularly directed approach to front-line chemotherapy in NSCLC. Data from the phase II clinical trial demonstrated impressive median survival for a platinum-based doublet: 13.3 months. The schema of the MADeIT clinical trial is shown below and I’m happy to say that I am able to put many of my patients on this clinical trial. Dr. West recently posted a podcast featuring Dr. Simon, where he describes the trial in more detail.
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The testing for ERCC1 and RRM1 is performed at Moffitt and turnaround time is typically around a week or less. I consider this a very reasonable interval since patients are unlikely to experience progression or declines in their performance status in a week. A sample from a prior biopsy can be used and fresh tissue is not required. Even when we have to obtain tissue from another institution, we can usually get the patient started in a very reasonable time frame. Right now, we only perform testing as part of the clinical trial. I think this is the right thing to do: although our hypothesis is that molecularly-directed therapy will be superior, we don’t know that for sure yet.
Trial of IGF-1R Inhibitor Figitumumab Combined with Carbo/Taxol Officially Closed
The trial of the insulin-like growth factor-1 receptor (IGF-1R) inhibitor figitumumab in combination with carbo/taxol as first line therapy for advanced NSCLC was officially closed after it was determined that the experimental arm would not have a meaningful chance of appearing superior to standard carbo/taxol with a placebo (“futility analysis”). Dr. Sanborn had previously written about this trial after it was put on hold due to safety concerns with this combination.
Dr. Julie Brahmer on Second Line Therapy: What Treatment and When?
The last of our podcasts in 2009 will also close out the series of presentations given at our September NSCLC Patient Education Forum here in Seattle, which was sponsored by OSI Pharmaceuticals and Swedish Cancer Institute (thanks!). The forum covered everything from initial workup to management principles of early stage NSCLC, locally advanced disease, and advanced/metastatic NSCLC. Dr. Brahmer, a friend for many years now who is a medical oncologist and lung cancer expert at Johns Hopkins University in Baltimore, spoke on treatment of patients after the first line setting, integrating thoughts on both patients who have progressed and also the emerging information on maintenance therapy for patients who have stable disease or have shown tumor shrinkage and no progression after the first line setting.
Her presentation is here, including both the video and audio podcast versions, and the accompanying transcript and figures.
brahmer-second-line-therapy-treatments-and-timing-audio-podcast
brahmer-second-line-therapy-treatments-and-timing-transcript
brahmer-second-line-therapy-treatments-and-timing-figures
Podcast: Play in new window | Download (49.0MB) | Embed
Women, Tamoxifen, and Lung Cancer
One of my areas of interest is studying gender-related differences in lung cancer. Earlier this year, I wrote a post about interesting data that had come out of the Women’s Health Initiative study. This was the landmark study that established that hormone replacement therapy (HRT) for postmenopausal women did more harm than good. When originally presented in 2002, the investigators noted significantly increased risks of breast cancer, cardiovascular disease and stroke. At ASCO 2009, they also reported an increase in lung cancer incidence and lung cancer mortality among postemenopausal women who received HRT compared to those who received placebo.
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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:
(click on image to enlarge)
Vorinostat for NSCLC: Not a home-run, but at least swinging for the fences
Substantial resources are spent on large, expensive trials to demonstrate small survival advantages in lung cancer. For example, 889 patients entrusted their care to the phase III SATURN trial of maintenance erlotinib, following treatment with a platinum doublet. At ASCO, we learned that these patients were rewarded with a one week improvement in PFS, and at World Lung, we learned that they lived a month longer. The FDA’s advisory committee recommended against approving erlotinib for maintenance therapy based on this modest benefit.
I am among many oncologists who take a two-faced view on small advances in care. On the one hand, I use advances with modest benefits in my clinic. I do not consider financial cost/benefit when adding avastin to platinum-based doublet therapy for patients with non-SqCC; I even use cetuximab, with more modest benefits, at times. While I use these small advances regularly in my clinic, I take a very different perspective when talking to other investigators, where I argue that we should be swinging for the fences, not trying to get more base-hits. Along the way, we will make minor advances and should use them, but the real goal should be to either cure cancer, or develop non-toxic drugs capable of turning cancer into a chronic disease.
With this perspective in mind, agents that can potentially overcome resistance in lung cancer are of particular interest to me and the histone de-acetylase inhibitors fit this mold. As I am working on a trial of a histone de-acetylase inhibitor for small cell lung cancer, these agents were already on my mind when I read the results of a new study in JCO.
Dr. George Simon on Individualizing Treatment Recommendations in Advanced NSCLC using Molecular Factors
Dr. George Simon, medical oncologist and Director of the Thoracic Oncology Program at Fox Chase Cancer Center in Philadelphia, has been kind enough to sit down for an interview with me earlier this year, which was made into a podcast several months ago. More recently, he participated in our NSCLC Patient Education, sponsored by OSI Pharmaceuticals and Swedish Cancer Institute, where asked him to speak on molecular factors that are emerging to help us individualize our treatment recommendations for advanced NSCLC. Much of his work over the last few years has been on proteins like ERCC1, RRM1, and others that may allow us to hone our treatment plans with chemotherapy, and he also has a significant interest in molecular markers that are emerging as increasingly relevant with targeted therapies like EGFR inhibitors.
His brief introduction to the field is included here, with the audio and video versions of the podcast, as well as the accompanying set of figures and the transcript from his presentation.
simon-individualizing-rx-adv-nsclc-molec-factors-audio-podcast
simon-individualizing-rx-adv-nsclc-molec-factors-figs
simon-individualizing-rx-adv-nsclc-molec-factors-transcript
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Picoplatin for SCLC — Another One Bites the Dust
A few weeks ago, I received an email from a colleague at an affiliated hospital with the title, “Another one bites the dust.” Now I love Queen as much as the next guy, but I don’t like seeing this line in reference to new oncology drugs. In this case, the drug was picoplatin.
Picoplatin is a novel platinum drug, somewhat like cisplatin or carboplatin. Like most chemotherapy, it works by poisoning DNA, causing rapidly dividing cells to die. As you can see, it shares the common platinum core with our old “friend” cisplatin, but the shape has been modified. The idea was that the drug might work in tumors that were resistant to cisplatin.
Picoplatin
Cisplatin
Picoplatin looked good in early studies, even earning attention on GRACE. Last year, Dr. West outlined the vital stats for the phase II of 77 patients for this new compound in 2nd line SCLC:
- Good side effect profile
- 10% response rate
- Median progression-free survival of 10 weeks
- Median survival of 27 weeks
Lung Cancer Screening: Dr. West shouldn’t be the only one with a bulls-eye on his chest (and no, I don’t torture puppies either)
On March 24, 2009, Dr. West wrote,
Lung cancer screening is one of my least favorite topics to discuss because it’s probably one of the biggest areas where there is a gulf between the medical establishment’s party line and the expectations of many patients and advocates. I tackled a discussion of screening a few years ago that included the anticipated benefits as well as the challenges with LC screening (nowadays really focusing on low dose, spiral CT). That was probably about the most frustrating topic I’ve pursued, initially heralded after my post on the arguments in favor of screening, but feeling like I was being vilified as a kitten torturer in the responses I received after my post about the thorny issues with it.
Dr. West’s last post is relevant to the conversation that member cards7up and I have been having on the discussion thread from my piece on November 30, 2009. The gist of the conversation is about whether to screen, and if so, how to do it.
On the “if” question, I consider my father’s desire for pan-scans to look for occult cancer (he quit smoking about 20 years ago). Every now and again, he hears on the radio ads for commercial enterprises offering pan-scans for a fee to screen for cancer. Even though he can afford it, I don’t let him go—I feel that he’s more likely to be harmed by the test than helped. Dr. West addressed this issue in his discussion about PSA and prostate cancer:
But last week, the story emerged that PSA screening for prostate cancer appears to provide somewhere between little and no survival benefit for men. One large trial suggested a very small benefit, in which nearly 50 patients would need to be treated to save the life of one from prostate cancer, and another trial didn’t show a survival benefit. After lung cancer, prostate cancer is the next most common focus of my practice, and I can assure you that I find this very easy to believe. I see many men who are exceptionally likely to do well, begging the question of whether they underwent surgery or radiation or some other alternative for no benefit, but who have had a permanent compromise of their sexual function, urinary continence, and other issues important to their quality of life (and I probably see only a small minority of the patients who are exceptionally likely to do well and never even see an oncologist). I also see men with prostate cancer who undergo aggressive treatments for prostate cancer but have a virulent enough cancer that even screening efforts and timely, aggressive interventions can’t save them from their cancer. In between, the numbers suggest one in 50 men may be saved from a truly life-threatening cancer.
Dr. Alan Sandler Provides General Intro to Treatment of Advanced Non-Small Cell Lung Cancer
Dr. Alan Sandler is an international leader in the lung cancer world, also identified as among the most down to earth and funniest people in the field (and though that might not sound like much, he travels with an audio clip of a rim shot to play after his jokes). His talks are light-hearted, but he’s so highly regarded because he has also been deeply involved in several of the pivotal research activities that have helped shape our current treatments. He led the original study that led to the approval of gemcitabine in lung cancer, and more recently he led the ECOG 4599 trial that was published in the New England Journal of Medicine and established the benefit of Avastin with carbo/taxol for advanced lung cancer.
Dr. Sandler recently moved from Vanderbilt to my corner of the world (more or less), where he leads the Division of Hematology and Oncology at Oregon Health & Science University in Portland. He was kind enough to participate in our NSCLC Patient Education Forum, where he provided a general introduction to the biggest questions of managing advanced NSCLC: does treatment really help, and how much? He also provided an overall review of the landscape in how we approach first line therapy for metastatic NSCLC, from someone who has been a big part of developing those standards.
Here is the audio and video versions of his presentation, along with the accompanying figures and transcript.
sandler intro to first line treatment of advanced nsclc audio podcast
sandler-intro-to-first-line-treatment-of-advanced-nsclc-figures
sandler-first-line-treatment-of-advanced-nsclc-transcript
I’m trying to leverage my proximity to Dr. Sandler, as well as my longtime friendship with him, to get him to involved with more of our GRACE activities. Fortunately, he’s been very gracious and generous with his time, so get more of his perspective , and maybe even some good jokes, from him in the future as well.
Podcast: Play in new window | Download (36.2MB) | Embed
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