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2011 Highlights in Lung Cancer, by Dr. Jared Weiss, Part 1: The EGFR Axis
Apologies for the long wait since our own Dr. Weiss’s upbeat and thoughtful review of the leading stories about lung cancer in 2011. Dr. Weiss covered a lot of ground in his presentation that was followed by a Q&A session, so we’ve broken that up into several short pieces that cover a few highlights at a time. In fact, we’re going to make an effort to have podcasts shorter and easier to digest in the future.
The first part is on EGFR-based therapies, including the EURTAC trial of the EGFR tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) vs. standard doublet chemo in a European, EGFR mutation-positive patient population, followed by work on EGFR TKI/monoclonal antibody combinations: one being the single arm afatinib/Erbitux (cetuximab) for patients with acquired resistance after a good response to earlier EGFR TKI therapy, and the second being Tarceva with either the c-MET antibody MET-MAb or placebo.
Here’s the audio and video versions of the podcast, along with the transcript and figures for this portion of the program.
Dr. Weiss Lung Cancer Highlights 2011 Pt 1 EGFR Axis Audio Podcast
Dr. Weiss Lung Cancer Highlights 2011 Pt 1 EGFR Axis Transcript
Dr. Weiss Lung Cancer Highlights 2011 Pt 1 EGFR Axis Figs
Podcast: Play in new window | Download (Duration: 11:13 — 39.1MB) | Embed
Refining Who Benefits with Erbitux: Can EGFR IHC Score Make a Stronger Case?
The FLEX trial, a European study of cisplatin/Navelbine (vinorelbine) with or without the monoclonal antibody against EGFR Erbitux (cetuximab), was a technically positive study that was initially reported at ASCO 2008. However, showing an improvement in median survival of just 1.2 months, most oncologists came away feeling that the trial illustrated the difference between a statistically vs. clinically significant result. Currently, the use of Erbitux in clinical practice is just a very small percentage of potentially eligible patients, though I think this would change if we could identify patients who are significantly more likely to benefit substantially and spare the others who actually don’t benefit from the cost, weekly infusions, and side effects of it. A recent report suggests that there may be such a method.
One of the most prominent presentations from the World Conference on Lung Cancer last month was a retrospective analysis of the results from the FLEX trial that divided patients based on the extent to which their tumor expressed EGFR protein on cancer cells as measured by the technique of immunohistochemistry (IHC). The investigators developed an “EGFR IHC score” that was a product of the percentage of cancer cells positive for EGFR protein on the cell surface multiplied by the overall intensity of staining (ranging from 0 to 3+), producing a number from 0 to 300.
(click on image to enlarge)
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.
Lung Cancer FAQ: What is EGFR, and what are the molecular tests related to it?
EGFR stands for epidermal growth factor receptor, which is a molecule on the surface of many cancer cells that can be activated to activate signals that promote cell growth and cell division. Though this target may play a role for many kinds of cancer, non-small cell lung cancer (NSCLC) is one type in which this target protein is seen in a majority of people’s cancers. In a minority (about 10% in North America and Europe, but closer to 20-30% in Asian populations) who typically have little or no history of smoking and have an adenocarcinoma subtype of NSCLC, there is a particular mutation that leads to activation of the receptor and the downstream cascade of cellular activity that appears to often do a large part of driving the cancer mechanism. Consequently, drugs that block the EGFR target, specifically oral drugs that inhibit the tyrosine kinase portion on the back end, intracellular (within the cell) portion of the receptor (EGFR tyrosine kinase inhibitors, or TKIs, with examples being Tarceva (erlotinib) and Iressa (gefitinib) can sometimes lead to dramatic and long lasting tumor shrinkage. In a larger proportion of patients with NSCLC, these agents can provide a more modest benefit, consistent with the concept that the EGFR pathway is a contributing pathway for the cancer but not the primary driving force.
Q&A Session with Dr. Ramalingam on Personalizing Treatment Recommendations for Advanced NSCLC
The second podcast from Dr. Ramalingam’s excellent webinar on Personalizing Treatment for First Line NSCLC is the question and answer session that followed it, which includes many questions about EGFR-based therapy, antiangiogenic agents, and other relevant issues for individualized treatments for patients.
Here is the audio and video versions of the podcast, along with the figures and transcript for it.
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-figures
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Dr. Suresh Ramalingam on Personalizing First Line Therapy for Advanced NSCLC: Podcast Available
I’m very pleased to offer the excellent podcast produced from the recent webinar by Dr. Suresh Ramalingam, a leader in the lung cancer field who heads the Thoracic Oncology Program at Emory University in Atlanta. He’s also a good friend I’ve known since our fellowship training days, and he was kind and generous enough to refuse the honorarium we offered for his participation, instead requesting that it be donated back and used for other GRACE programs. Instead, he was happy to do this entirely out of a commitment to the lung cancer community. This is part of a small series of programs supported by an educational grant from Eli Lilly, so we are now enabled to do an additional program because of his generosity.
His webinar provides a very brief historical overview of NSCLC in general and then advanced NSCLC in particular, including a historical perspective of the evolving standards of care first with chemotherapy alone, and then with the integration of targeted therapies. He describes how our approach now individualizes our treatment recommendations based on such issues as particular NSCLC histology, molecular factors, performance status, and sometimes age to offer what we hope will deliver the best combination of efficacy and safety for a patient.
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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
Correlation of Rash with Survival on FLEX Trial: Predictive or Prognostic?
Completing our tour of clinical factors that we might use for predicting benefit with the EGFR monoclonal antibody Erbitux (cetuximab) in the FLEX trial is the development of a rash. We’re actually discussing rash separately from the other clinical factors from the FLEX trial that we discussed in the prior post for a couple of reasons. First, rash on the treatment isn’t something you can know about until you’ve committed yourself to at least starting the treatment (you can’t have an Erbitux-induced rash before giving Erbitux). Second, it’s not really clear whether this rash is predictive of doing particularly well with Erbitux or prognostic of doing well in general (on Erbitux or anything else).
For years, the EGFR inhibitor side effect of rash has been associated with more favorable outcomes, as I’ve described in one of my earliest posts, on the potential significance of a rash on EGFR inhibitors. The investigators who developed the FLEX trial decided prospectively (pre-planned, not a “fishing expedition”) to look at how patients did as a function of whether they developed a rash in the first 21-day cycle of treatment (all patients alive at day 21 were included). They found that 55% developed a rash to some degree, while 33% developed a grade 1 (mild) rash, 18% developed a grade 2 (moderate) rash, and 5% developed a grade 3 (severe) rash.
It was very interesting to see that the patients who developed a rash on Erbitux did far better than those who did not. In fact, it was also interesting to see that the patients who didn’t develop a rash on Erbitux had a worse median survival than the patients who were assigned to chemo alone:
FLEX Trial Survival by Rash
(click on figure to enlarge)
Clinical Factors on the FLEX Trial: Do Certain Patient Groups Benefit More or Less with Erbitux?
In the last post that presented the highlights of the FLEX trial that tested the benefit of adding Ebritux (cetuximab) to standard chemo. The trial was technically positive, statistically significant, but the results in the overall population of the trial were so marginally superior with Erbitux that a very logical follow-up question is whether we might identify certain subgroups of patients who benefit more, enough to definitely add Erbitux, while not pursuing it for other subgroups that appear to benefit much less.
It’s important to add a word of caution about interpreting information gleaned from patient subsets. Clinical trials are generally designed to have enough patients to show differences in the entire trial with everyone. Nevertheless, when you dissect it ten different ways, the smaller subgroups don’t have adequate numbers to show significant differences, even when they may really exist. At the same time, doing multiple different comparisons escalates the chance that you’ll randomly find differences that aren’t real, and that occur just as a product of random chance. In fact, trials are generally powered to consider a difference as significant only if the probability of the difference happening by chance is less than 5%, but if you slice and dice the results to do ten different subgroup tests, the likelihood of at least one coming up positive just by chance is now 22%.
So these comparisons aren’t really conclusive and are better suited for shaping our ideas for future research than for guiding our treatment decisions. In reality, people (present company included) tend to pick and choose which subgroups they focus on to support their inclinations, while discarding other comparisons.
To provide the general picture, there’s a figure called a forest plot that shows the performance of multiple subgroups simutaneously. Here, the size of the different subgroups is represented by the size of the black ovals, and the position of the oval to the relative to the vertical line shows whether the Ebritux group did better (if the oval is to the left of the vertical line, sometimes referred to as “unity”) or the chemo alone arm did better (if the oval falls to the right).
FLEX Trial Forest Plot
(Click on image to enlarge)
FLEX Trial Redux
I covered the highlights of the FLEX trial, reported at the Plenary Session of ASCO 2008, a full year ago, but in that time, we never showed the survival curves or covered all of the details. It’s time to rectify that, now that it’s actually been published, and we’re left to reflect on whether certain subgroups benefit more or less, and how the subject of the FLEX trial, the EGFR monoclonal antibody Erbitux (cetuximab) should be used in treating advanced NSCLC.
The European sudy compared standard chemotherapy alone to the same chemotherapy with weekly Erbitux in previously untreated advanced NSCLC. It included over 1100 patients, who were screened as needing to have the EGFR protein on their tumor by a test called immunohistochemistry (IHC), because this is the target that the EGFR monoclonal antibody is supposed to bind to. The definition of a positive test for EGFR by IHC was extremely liberal, since only a single cell with the protein was required for patients to be enrolled. Even with such liberal criteria, 15% of the screened patients had no EGFR protein on a single cell and were excluded from the trial.
As with most recent trials with targeted agents, it was degined to give up to six cycles of chemo with or without the novel agent,in patients who didn’t show progresison after six cycles, patients assigned to the experimental arm (with the new agent) would continue on weekly Erbitux as a maintenance therapy. The specific chemo used was cisplatin/navelbine (vinorelbine), a combination rarely used for metastatic NSCLC in the US but a common standard in Europe.
Putting this all together, the trial design is shown here.
FLEX Trial Design
(click on figure to enlarge) Continue reading
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