|
|
|
FAQ: I started an EGFR inhibitor two weeks ago but haven’t developed a rash. Does this mean it’s not working?
The short answer is no.
Since the introduction of the targeted agents that inhibit the epidermal growth factor receptor (EGFR), both the oral EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) or Tarceva (Erbitux), and the monoclonal antibody therapies against EGFR like Erbitux (cetuximab) have been identified as often having a rash as a leading side effect. Though often annoying and sometimes very difficult to manage, the development of a rash has also been identified as somewhat of a double-edged sword, as several early trials identified development of a rash as being associated with a better result on oral EGFR inhibitors, and even that there may be a correlation with best outcomes in patients who develop a more severe rash. Moreover, this same trend has also been seen in patients who receive Erbitux for lung cancer as well as for colon cancer.
Meanwhile, other corroborating tangents included the finding that smokers on Tarceva had fewer side effects and have also been consistently identified to not do as well with oral EGFR inhibitors as never-smokers or ex-smokers, very possibly related to faster metabolic breakdown of these agents in current smokers. It remains a possibility, though still not well studied and unproven, that a higher dose of EGFR TKI therapy may be more effective in current smokers.
Are There Significant Differences Among EGFR Mutations?
Since we’ve come to appreciate the presence of distinct activating EGFR mutations associated with a very high probability of responding to an oral EGFR inhibitor, the question has emerged about whether there are significant differences in outcomes between the two most common ones, which are a deletion in exon 19 and a “point mutation” in exon 21. Some retrospective work in smaller aggregated series has suggested that patients with an exon 19 deletion tend to do best, but other work has suggested no difference between these two most common mutations. The recently reported trio of prospective trials of patients with an EGFR mutation receiving first line chemo or an EGFR inhibitor provide a good opportunity to evaluate this question.
The studies are actually pretty consistent in conveying that there is a modest trend toward the most favorable progression-free survival (PFS) in people with an exon 19 vs. an exon 21 mutation, but the differences aren’t great. Here are the PFS curves directly comparing the two main types of mutations in the Japanese trials with Iressa (gefitinib):
(Click on image to enlarge)
So while the curve for exon 19 deletion is on top by a small margin, both activating mutations appear to follow a very similar trajectory overall, with no significant difference.
Post-ASCO Discussion of the BR.19 Trial
Here’s the first of a series of posts on key presentations on lung cancer from ASCO 2010, as reviewed by myself and Dr. Nate Pennell of our faculty here several weeks ago.
The first topic we covered was the very interesting if troubling Canadian BR.19 trial of post-operative Iressa (gefitinib) vs. placebo, as summarized by Dr. Pennell.
Dr. Pennell: So this is certainly one of the most important presentations at ASCO this year, I think, if nothing else to show us that we aren’t nearly as smart as we think we are. Gefitinib, as I’m sure most of our GRACE community knows, is an EGFR tyrosine kinase inhibitor very similar to Tarceva, which is the approved drug here in the United States. And back in the early 2000s there was a lot of enthusiasm for exploring the potential for gefitinib in the adjuvant setting for patients with early stage disease to see if it improved cure rates essentially.
And so the BR.19 trial was launched in the first half of that decade in resected patients with stage I-B through IIIA non-small cell. These patients could receive adjuvant chemotherapy as appropriate, I think, once the adjuvant chemotherapy trials in 2003 and 2004 came out and then were randomized in one-to-one fashion to either two years of daily gefitinib or to placebo.
(click on image to enlarge)
Never-smoker vs. “ever-smoker”? It’s not quite that simple…
For the last several years, we’ve known that never-smokers are more likely to have a significant and long-lasting response to EGFR inhibitors. Since then, we’ve learned that EGFR mutation status is quite correlated with smoking status and is the more important, likely driving factor, but all of this work has led to a new focus on never-smokers and smoking history in general. In fact, prior to about 5-10 years ago, we didn’t consistently record much of a smoking history for patients because it wasn’t appreciated as being relevant. Now, not only do we realize it’s an important factor, but we’re moving beyond the over-simplified view that smoking history is just a “yes/no” answer. We couldn’t expect that it would be that simple. Continue reading
SATURN Survival Results: What Can We Say About “Maintenance” Tarceva?
Shortly after ASCO 2009, Dr. Pennell provided the highlights of the early report of the SATURN trial, conducted primarily in Europe, that randomized patients to maintenance tarceva (erlotinib) or placebo after four cycles of first line chemotherapy. The early report described a modest but statistically significant improvement in progression-free survival (PFS), but overall survival (OS) wasn’t reported at ASCO. Frankly, the modestly favorable results in terms of PFS were overshadowed at ASCO by the maintenance therapy trial with alimta (pemetrexed), which showed a significant improvement in both PFS and OS.
One of the more interesting presentations with new data at the World Conference on Lung Cancer in San Francisco a few weeks ago was an update of the SATURN trial results that included OS results. It revealed a significant improvement in OS, with a difference in median OS of one month (11 vs. 12 months, measured from the time of randomization, so patients had generally received about three months of treatment before then). The survival curves are shown below:
Maintenance Tarceva Trial Positive for Overall Survival Benefit
At ASCO a little over a month ago we learned the preliminary results of the SATURN trial that compared “maintenance” Tarceva (erlotinib), the oral EGFR inhibitor, to an oral placebo in patients who showed no progression after four cycles of first line chemotherapy. The results of the ASCO presentation, which showed a statistically significant improvement in progression-free survival but didn’t include any information about overall survival, are summarized in a prior post about the SATURN trial.
OSI Pharmaceuticals, the makers of Tarceva, have just put out a press release that there is also a significant improvement in overall survival among the recipients of maintenance Tarceva compared to placebo. Though no details were offered, the press release notes that more information will be presented at the upcoming World Conference on Lung Cancer in San Francisco at the end of this month. I’ll be there, so readers should expect more information as soon as the data are made public.
The Unsettling Evidence of Tumor Heterogeneity
We know that cancer cells mutate over time — in fact, that’s how they became cancer cells. In fact, oncologists see the heterogeneity of cancer cells in our daily practice every day. Although there are certainly many reasons why patients have some of their cancer cells respond and others not (blood supply, local microenvironmental factors, etc.), one of the important factors is genetic heterogeneity within the cancer cell population — some cells die and others don’t. Moreover, the typical gradual shift from a cancer responding to a treatment and then showing an acquired resistance and progression after several cycles is presumably mediated by an ongoing evolution of the tumor itself to selective survival of cancer cells with a new resistance mechanism.
I suppose it should come as no surprise, then, that EGFR mutations are also subject to tissue heterogeneity. This is demonstrated by a paper in this month’s Annals of Oncology by Gow and colleagues, out of Taiwan.This paper checked for EGFR mutations in tumor tissue from 67 patients who underwent some form of surgery of biopsy or resection of NSCLC in Taiwan that included removal of some tissue from both the primary tumor and a metastatic lesion. Those 67 paired patient samples came from a pool of over 900 surgical samples over an 8 year period; none had received an EGFR inhibitor at the time that tissue was collected.
Polling Lung Cancer Experts: Metastatic NSCLC, Squamous Subtype
Several weeks ago, I described the results of a survey I sent out to several colleagues who are lung cancer experts around the country, asking how they would manage a case of a newly diagnosed Caucasian never-smoking patient with advanced NSCLC, adenocarcinoma, and asymptomatic subcentimeter brain metastases, treated with whole brain RT before starting systemic therapy.
I then asked these same experts the question but now with the patient being an ex-smoker with a squamous NSCLC tumor. The basic sketch is that it’s a 61 year old Caucausion woman with a very good performance status, no limitation on health or motivation for treatment, and a metastatic NSCLC, squamous subtype . As in the prior case, she had treated asymptomatic brain metastases and was presenting for consideration of first line treatment. What would various experts recommend as a plan for the next few months?
One major difference was that, unlike the never-smoker with an adenocarcinoma, very few experts now favored sending tissue for an EGFR mutation. The vast majority had favored checking this in a never-smoker, who might be considered for up-front EGFR inhibitor therapy, but when the case was an ex-smoker with a squamous tumor, only 6 of 20 were interested in any molecular testing: 3 for KRAS mutation, 1 for EGFR IHC before considering erbitux (cetuximab), and two who still wanted to check for an EGFR mutation. Most were inclined to make a treatment recommendation without any molecular testing.
VeriStrat Test for EGFR Test: Initial Impressions after Sending a Few
A few weeks ago I described a blood test for predicting survival after getting an oral epidermal growth factor receptor (EGFR) inhibitor that is just becoming commercially available. This is called the Veristrat test and from company called Biodesix. As I noted previously, this technique looks at the protein patterns in a patient’s serum and reportedly can reliably predict whether a patient is likely to have a prolonged survival after receiving an EGFR inhibitor. The company gave me the opportunity to send off a few of these tests at no charge, and after a few weeks of trying it in a handful of patients, I’m finding that it seems to do what it says it does, for better or for worse.
What they specifically say is that, by separating serum samples into the two thirds that will have a “good” survival and the one third that will have a “poor” survival after getting an EGFR inhibitor, clinicians can use this test to determine which patients shouldn’t get an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. The test may well be great for this, but I haven’t had the opportunity to send this test off in the last few weeks for this purpose.
Instead, what I was hoping we might use this test for is to get a faster answer about whether a patient will do well with an EGFR inhibitor. Even though I and many other lung cancer experts are increasingly becoming converts to the idea that EGFR mutations are quite relevant and override clinical predictors of benefit with EGFR tyrosine kinase inhibitors (TKIs), these mutations aren’t always very accessible. Only a minority have enough tumor tissue from their original biopsy to send off for mutation testing, and the test itself takes 3-4 weeks, which is long enough that many patients will not be inclined to sit around and wait for a month before starting treatment.
New Podcast on the ABCs of BAC
Here’s a video slide presentation that provides a basic introduction to bronchioloalveolar carcinoma (BAC), including the demographics, natural history, imaging appearance, and patterns of response that make it a unique subpopulation within lung cancer. The audio only version is below the video.
[display_podcast]
In addition, we’ve got the final slides in pdf form, so people can follow along with the audio or just study them at your own pace, along with the transcript from the presentation:
| Follow us on... |    |
||
Copyright ©2012 GRACE |
|||