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Interview with IPASS Trial & Leading Lung Cancer Researcher Tony Mok
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.
Q&A With Dr. Sequist
The third and last podcast from our discussions with Dr. Lecia Sequist, of Massachusetts General Hospital and Harvard Medical School, covers the question & answer session that followed her excellent webinar on acquired resistance to EGFR tyrosine kinase inhibitors, as well as the update I did with her on the latest information from their experience of re-biopsying lung tumors over the course of treatment.
Here are the audio and video versions of the podcast, as well as the transcript.
sequist-qa-session-audio-podcast
Podcast: Play in new window | Download (35.1MB) | Embed
Heterogeneity in Population of NSCLC Patients with Acquired Resistance to EGFR Inhibitors: T790M is Key Predictor
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.
Trifecta of Clinical Trials Show Major PFS Benefit for First Line EGFR Inhibitor Over Chemo for EGFR Mutation-Positive Patients with Advanced NSCLC
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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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.
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.
(click on image to enlarge)
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
Lung Cancer FAQ: I have advanced NSCLC and have been told I don’t have an EGFR mutation. Does this mean I won’t benefit from an EGFR inhibitor?
There is no question that the recognition of an activating mutation in the gene for the epidermal growth factor receptor (EGFR) has revolutionized our understanding of why some patients with advanced/metastatic NSCLC develop a profound benefit from the class of oral EGFR tyrosine kinase inhibitors (TKIs). We know that the response rate to EGFR TKIs among patients with an EGFR mutation is in the 60-75% range in many trials, but does this mean that the entire benefit of these drugs is explained by the minority of patients with an EGFR mutation (about 10% of patients in North America and Europe, vs. 20-30% range in Asian populations)?
Put simply, the answer is definitely no, that the larger population of patients who don’t have an EGFR mutation (also known as EGFR wild type in genetics terminology) experience an improvement in overall survival despite a much lower response rate. The evidence in many studies of EGFR TKIs demonstrates consistently that those patients who don’t have an EGFR mutation demonstrate significant tumor shrinkage defined as a partial or complete response in our strict criteria only about 1-5% of the time, a much more sizable fraction of patients without an EGFR mutation have a prolongation in the duration of their cancer demonstrating stable disease that translates to a modest improvement in survival. The benefit is clearly of a lesser magnitude than the benefit seen from EGFR TKIs in patients who have an activating EGFR mutation, but this modest benefit clearly exceeds the benefit seen with placebo, making Tarceva (erlotinib) and possibly Iressa (gefitinib) an appropriate consideration for previously treated patients with advanced NSCLC, even if they are known to not have an EGFR mutation.
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.
Lung Cancer FAQ: I’ve just been diagnosed with advanced NSCLC. What treatment should I be starting with??
The initial or “first line” management of advanced NSCLC has evolved quite a bit over the past 10 years, in that time moving from a much more uniform approach of very similar treatment for just about everyone to a revised approach that is far more individualized. First, we assess key issues like the subtype of NSCLC, focusing largely on whether it is squamous cell or non-squamous NSCLC, because treatment tends to diverge very early based on this factor. Second, a patient’s performance status is another important issue, as patients who are frail often need a customized approach, because a more aggressive standard approach may be prohibitively difficult and even harmful. Third, a minority of patients (about 10% in North America and Europe, closer to 1/3 in Asia) will have a particular molecular marker, specifically a mutation in the epidermal growth factor receptor (EGFR), that is associated with a high probability of having a dramatic and long-lasting response to targeted therapy that inhibit the EGFR pathway. This particular activating mutation is most typically seen in never-smokers or people with a minimal, remote prior smoking history who also have an adenocarcinoma subtype of NSCLC.
Recommendations for first line therapy are most typically for a two drug chemotherapy combination, often with the drug Avastin (bevacizumab) — a targeted therapy that blocks the blood supply to the cancer — added for many patients who don’t have squamous NSCLC. However, for patients with an EGFR mutation identified before they have started treatment, several recent studies have demonstrated that the rate of significant tumor shrinkage and the time before the cancer progresses are significantly longer with an oral agent that works as an EGFR inhibitor, such as Iressa (gefitinib) or Tarceva (erlotinib). Consequently, one of these agents is increasingly recognized as a very appealing first line treatment approach.
Elderly patients are often treated the same as younger patients if they have minimal limitations in their activity level. In contrast, frail patients are sometimes recommended to receive single agent chemotherapy rather than a multi-agent combination that may be prohibitively difficult to tolerate. The available evidence suggests that elderly and frail patients who have an EGFR mutation also typically have a very significant response to EGFR inhibitor therapy.
Further information is available through the following links:
Podcast on introduction to first line chemotherapy for advanced NSCLC
Podcast on personalization of first line therapy
Reference library summary on selecting optimal first line treatment for advanced NSCLC
Using molecular markers to guide treatment: The IPASS trial
Alimta (pemetrexed) benefit is histology-specific
Treatment approaches for first line therapy in frail patients with advanced NSCLC
Podcast discussion of managing advanced NSCLC in the frail and/or elderly
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