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Doublet vs. Single Agent Chemo in the Elderly with Advanced NSCLC: France Offers a Definitive Answer
Although the ASCO Plenary session presentation on ALK inhibition with crizotinib was a darling of the entire conference and led to a post I wrote about on the way back from the meeting, there was actually a second presentation on lung cancer in the plenary session that received far less attention, including by us here at GRACE. It asked the question of whether doublet therapy or single agent chemo for elderly patients with advanced NSCLC leads to better outcomes, and specifically superior survival. Without a novel targeted agent, it’s been overshadowed, but it demonstrated a clear answer to a question that is very relevant, so it’s high time to review its findings.
Dr. Quoix from France reviewed the IFCT-0501 trial, which randomized previously untreated stage III or IV NSCLC patients of age 70-89, with a good or more marginal performance status, to either carboplatin/Taxol (paclitaxel), with carbo all on the first day and the Taxol divided into three weekly doses every 4 weeks (4th week being an off week), vs. a single agent chemo arm of either Navelbine (vinorelbine) or Gemzar (gemcitabine) as two weekly doses in a three week cycle (3rd week being an off week), at the treating physician’s discretion. All patients were to received Tarceva (erlotinib) as planned second line therapy.
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Lung Cancer FAQ: I’m coming to the end of my first line chemo for advanced NSCLC. After 4 (or 6) cycles are done, should I take a break or continue with some form of maintenance therapy?
The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).
Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.
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
Expert Round Table with Drs. Hensing & Jackman: Molecular Markers & Sequence of Therapy for An Asian Never-Smoker with Advanced Lung Adenocarcinoma
The third and final part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a presentation of an Asian never-smoking woman with an advanced lung adenocarcinoma, the demographic picture most closely associated with potentially but not necessarily having an EGFR mutation or ALK rearrangement.
We cover the question of whether, in someone with a significant probability of one of these particular molecular markers, it’s worth obtaining tissue and delaying treatment to tailor treatment on the basis of these results. We also discuss the range of options for maintenance therapy in someone who has many alternatives for continuing one or more agents from the first line setting or switching to a new treatment. Finally, we turn to the question of managing treatment for a patient who has a prolonged response to an EGFR inhibitor and then develops an acquired resistance to that therapy.
Podcast: Play in new window | Download (47.4MB) | Embed
Local Therapy for Metastatic Disease: Why Might We Break the Rules?
One of the most common questions. we receive is why people are told that surgery isn’t an appropriate option for metastatic disease. If you can see the areas where there is active cancer, why can’t you just take it out?
The problem is that it’s very rare for a metastatic cancer to be limited to the areas that we can see. If a cancer spread from the lung to the liver, adrenal gland, brain, bones, or the other lung, it got there by having microscopic cancer cells (micrometastases) travel through the bloodstream to get there. Because this almost always means that there are many other micrometastases in the bloodstream, we’re fighting not just the cancer we can see, but the potential future areas of cancer we can’t see because they’re in the bloodstream, with the ability to settle in new places and grow into new lesions. So the general treatment strategy is systemic (whole body) treatment that travels through the bloodstream to reach cancer cells that may be distributed throughout the body.
Picoplatin for SCLC: Review of Data Presented at ASCO
Here is the discussion about the study of picoplatin vs. placebo for relapsed SCLC, from the post-ASCO review that I did with Dr. Pennell. Unfortunately, this work was an overall disappointment, not quite beating placebo in a setting for which we already have a more active alternative. Here’s the transcript and figures from that portion of the discussion.
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Dr. West: So we’ll turn to the SPEAR trial. This is a small-cell study with picoplatin which has been one that has been on the radar for small cell for several years at this point. And this is a randomized trial, a 2 to 1 randomization, of patients who had previously received chemotherapy for extensive small-cell lung cancer, and this was for patients who had relapsed within six month,s with the thought being that the patients who actually progressed beyond six months would often get their prior chemo instead.
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So patients were randomized to picoplatin with supportive care or one third of patients getting supportive care alone, and the trial looked primarily at overall survival.
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