Continued from part 1

Dr. West: You have a huge portion of your patients who have an EGFR mutation and we know that over time patients develop acquired resistance. So how do you approach the patients who have a great response initially, have a known EGFR mutation, and then you see that slipping away at slow progression? Do you continue the EGFR inhibitor?  Do you add something to it?  Do you change the dose? How do you approach that?

Dr. Mok: I think this is one area where we still have a lot to learn.  First of all, let’s define resistance, or progression. If you use the Jackman criteria (Jackman, J Clin Oncol 2010), that still incorporates the RECIST criteria, which mean if the lesion that has increased by about 30%, then it’s progression. But then one factor we didn’t look into was in the rate of progression within this definition. The second concern is about the occurrence of a new lesion that’s also progression. Now, whether this is directly applicable to a targeted like Tarceva or another EGFR TKI or not, I have some doubts, because simply from your experience and my experience, some of these patients get a new nodule, but they can take a long time to grow and the patient lives a normal life. And we also know the fact that if we take them off the TKI, the disease can progress rapidly. So some of these are slow progressors, then we just keep them on a TKI. Read the rest of this entry »

A few weeks ago I had the chance to speak with Dr. Tony Mok, who is a professor in the Department of Clinical Oncology at the Prince of Wales Hospital in Hong Kong and the Chairman of the Hong Kong Cancer Therapy Society.

He is also the principal investigator and lead author for the pivotal Iressa Pan ASian Study (IPASS), which was published in the New England Journal of Medicine in the fall of 2009.  I started by telling him that I consider that study to be arguably the most influential over the last 5-10 years in the field of lung cancer, because it highlighted that molecular predictive factors trump clinical markers in determining who is likely to do best with a targeted therapy, specifically an EGFR tyrosine kinase inhibitor like Iressa (gefitinib) or Tarceva (erlotinib).  Here’s the first part of our conversation about what we’ve learned about how best to use these EGFR inhibitors and the potential differences in practice between Asia and the US.

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A few weeks ago, Dr. Lecia Sequist, Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital (MGH), joined us for a live webinar we did in partnership with LUNGevity Foundation.  Dr. Sequist and her colleagues at MGH have been at the forefront of research in EGFR mutations: her group was among the first to identify activating mutations and observe the correlation with response to EGFR tyrosine kinase inhibitors (TKIs), and they continue to do much of the leading clinical research on acquired resistance — the development of progression after an initial good response — and potential mechanisms for reversing this.

In the presentation below, provided in video and audio podcast forms (along with the associated transcript and figures), she provides an outline of the issue and some of the identified mechanisms for resistance.  In addition, she discusses several attempts to manage this and current and emerging clinical trial options for this setting.

sequist-acquired-resistance-to-egfr-tkis-audio-podcast

sequist-acquired-resistance-to-egfr-tkis-transcript

sequist-acquired-resistance-to-egfr-tkis-figures

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Podcast: Play in new window | Download

Over the past several years, probably the biggest development in the field of NSCLC has been the recognition of the importance of molecularly-defined subgroups that help define the clinical patterns of how patients are likely to do with various treatments.  We’ve seen this clearly illustrated with EGFR mutations vs. EGFR wild type (no mutation), and more recently with the very uncommon but clinically important ALK rearrangements.

One newly defined clinical setting that has emerged has been the group of patients who experience a very good response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib) or Iressa (gefitinib), generally but not necessarily those with an activating EGFR mutation (most typically on exon 19 or 21, as described in this great summary by Dr. Nate Pennell) who respond for a period of months or years and then develop resistance.  Why does it happen, and what are the leading options for managing this situation?

Early work on this problem of acquired resistance (as opposed to primary resistance, which is the situation in which a person starts out by not being very responsive to an EGFR TKI), largely out of the Harvard hospitals in Boston and Memorial Sloan-Kettering Cancer Center in New York City, have shown that about half or slightly more develop a resistance mutation called T790M on exon 20 (and a minority of people with an activating EGFR mutation also have this from the beginning, likely helping to explain why the response rate with one is not 100% but more like 70-75%).  Another 10-20% or so are found to have over-expression of c-MET (targeted by agents like ARQ-197), reflecting a pathway that can bypass the EGFR signaling cascade as a mechanism for resistance.

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The IPASS trial that randomized never-smoking Asian patients with a previously untreated advanced lung adenocarcinoma to either standard chemo with carboplatin/Taxol (paclitaxel) or the oral EGFR inhibitor Iressa (gefitinib) was a pivotal study that changed how many of us thought about NSCLC.  Clinical factors such as patient race, smoking status, tumor histology, and potentially patient sex have historically been useful in predicting which patients are most likely to benefit from an oral EGFR inhibitor (with Asian, never-smoking status, adenocarcinoma and especially bronchiooloalveolar carcinoma (BAC), and women being prevalent features of major responders).  However, the IPASS study showed that the molecular marker of EGFR mutation is clearly more important than these clinical factors: in those patients who have an EGFR mutation, Iressa was associated with a far better response rate (RR) and progression-free survival (PFS), as well as a trend toward a more favorable overall survival (OS).  On the other hand, in those who don’t have an EGFR mutation, even among Asian never-smoking women with an adenocarcinoma, chemotherapy was a clearly superior option.  It is worth noting that this is specifically for the question of first line therapy, for which chemotherapy is the default standard therapy — the results comparing chemo to EGFR inhibitor therapy as second line treatment have been very comparable in broad populations.

Eligibility on the IPASS trial was based on clinical selection for patients more likely to benefit from EGFR inhibitor therapy, and it was only in a planned retrospective analysis that the importance of the very different results by EGFR mutation status became apparent.  A slightly different question emerges if you know that a patient has an EGFR mutation before you start treatment.  The IPASS trial strongly suggests that patients with an EGFR mutation will be better served by receiving first line EGFR tyrosine kinase inhibitor (TKI) therapy, and this has now been confirmed in three independent prospective randomized trials.

One pivotal study of this concept was done by the North-East Japan Study Group, performing a remarkably similar trial to that done by IPASS: carbo/Taxol or Iressa as first line therapy in patients with a prospectively identified EGFR mutation, using PFS as the primary endpoint.  Though it was designed to enroll 320 patients, it closed early, when an interim analysis showed such a remarkably superior improvement in PFS that the Data Safety Monitoring Board considered that continuing to randomize patients on the trial would be unethical:

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   One of the trials presented at the Chicago Multidisciplinary Symposium in Thoracic Oncology last month was the TITAN trial, one of a pair of studies conducted in Europe to test the oral EGFR inhibitor Tarceva (erlotinib) in patients with chemotherapy pre-treated advanced NSCLC.  The other trial, SATURN, was designed to test Tarceva as a maintenance therapy vs. placebo in patients who had shown a response or stable disease after four cycles of first line chemotherapy (without the VEGF inhibitor Avastin (bevacizumab)) has been summarized previously and ultimately led to the approval of Tarceva as a maintenance therapy in this patient population.  But what happened to the significant fraction of patients who progressed by the time of the repeat imaging after four cycles of first line platinum-based doublet chemotherapy?  They were directed to the TITAN trial, which was a head to head comparison of Tarceva vs. either Taxotere (docetaxel) or Alimta (pemetrexed), both well studied and commonly used second line agents for advanced NSCLC.  The trial looked for an improvement in overall survival with Tarceva.

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    The trial closed earlier than planned, due to slow enrollment, with just 424 patients, which leaves it quite underpowered to detect a difference even if there really is one between the two treatment approach.  Still, there may be some conclusions that can be drawn from what they saw, even if limited by smaller numbers than needed to say anything definitive.

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We’ve recently received a series of questions on the question of whether it makes sense to give an oral EGFR inhibitor like Tarceva (erlotinib) or Iressa (gefitinib) concurrently with radiation.  This is really a poorly studied question, but a paper just published in the Journal of Thoracic Oncology describes a clinical trial that helps to address this question.  Unfortunately, for reasons that aren’t very clear, the results didn’t look very favorable overall.  But let’s explore this in more detail.

The Cancer And Leukemia Group B (CALGB), one of the three main cancer cooperative groups in the US, noted that EGFR inhibitors were apparently active for at least some patients with NSCLC and with often modest side effects, most typically rash and a tendency toward diarrhea.  The investigators from CALGB started trial 30106 to ask a slightly different question in two different clinical populations:

1) For patients with a good performance status (PS) and unresectable stage III NSCLC, does adding daily Iressa to initial chemo followed by concurrent chemo/radiation lead to more favorable results than would be expected from this approach without Iressa?

2) For patients with a marginal PS and unresectable stage III NSCLC, does adding daily Iressa to initial chemo, giving Iressa with radiation instead of chemo/radiation lead to favorable results?

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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.

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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. (Click on image to enlarge)

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In the last decade, the treatment of NSCLC has evolved very significantly, and one of the leading ways has been that we’ve gone from having no established role for treatment after initial, first line therapy to having multiple agents with a proven benefit.

It’s worth clarifying that as maintenance therapy is increasingly being considered as an option after first line therapy, a distinction between this and second line therapy. Maintenance therapy is given to prolong the period before someone who has achieved a response or stable disease on first line treatment demonstrates progression for the first time, while second line therapy is the term more commonly reserved for treatment after someone has demonstrated evidence of progression for the first time after first line therapy.

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