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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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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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.

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The negative trials don’t get a lot of discussion, but the ZEPHYR trial, a phase III study that directly compared Zactima (vandetanib), an oral inhibitor of EGFR and angiogenesis, vs. placebo, was one that merits some follow-up after my reporting that it failed to show a survival benefit, which was essentially the only thing we learned about the trial prior to ASCO this year.  A more complete report of the ZEPHYR trial was presented at ASCO, and though it suffered the indignity of being the rare phase III trial that didn’t get presented during an oral session, I think the results are important enough in trying to assess the real value of Zactima that the results merit being reviewed.

ZEPHYR was the last of four major lung cancer trials with Zactima to be completed and reported.  The others are summarized in a prior post, and they showed at best equivocal results.   The others are discussed in a point-counterpoint fashion by GRACE member and moderator Neil Berch (arguing that the Zactima glass is half full) and me (taking the less beloved view that the benefits are extremely marginal and probably not enough) — let the record show that, at the present time, his post has been more favored by the people who have added a rating.

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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)

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Here’s a podcast from the webinar presentation earlier this month by our beloved Dr. Weiss, covering the open question of whether we should consider giving an EGFR inhibitor like Tarceva (erlotinib) as an adjuvant (post-operative) therapy following potentially curative surgery for early stage NSCLC.  It’s a setting in which there is a good rationale if we extrapolate from the setting of metastatic NSCLC, at least for patients with an EGFR mutation, but we’ve made incorrect presumptions before when we extrapolate.

Dr. Weiss reviews the pros and cons and the scant relevant data in his podcast.  Below you’ll find the audio and video versions of his presentation with Q&A that followed, as well as the figures and transcripts that go with this.

weiss-adjuvant-egfr-tki-webinar-audio-podcast

weiss-adjuvant-egfr-tki-webinar-figures

weiss-adjuvant-egfr-tki-webinar-transcript

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Podcast: Play in new window | Download

Perhaps the most unexpected clinical trial result in lung cancer over the past 5 years was the finding in the large Southwest Oncology Group (SWOG) 0023 trial that randomized several hundred patients to maintenance therapy with either the oral EGFR inhibitor  Iressa (gefitinib) or a placebo after chemo/radiation concurrently and then consolidation taxotere (docetaxel).  While just about everyone in the lung cancer community expected to see either a significant benefit or, at worst, no real effect from maintenance Iressa, the actual trial was stopped early and demonstrated a statistically and I would say clinically significant decrease in overall survival with maintenance Iressa.  The median overall survival (OS) in the final publication was a full 12 months lower in patients who received Iressa compared with those who received the placebo .

To me, not only did this study demonstrate that giving consolidation EGFR inhibitor therapy was probably a bad idea, at least outside of a clinical trial, it also suggested that we don’t necessarily know as much as we presume we do about how trials will turn out, so it makes sense to do the studies rather than just start a new strategy without the evidence to back it up.

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What we are striving for in cancer care today is personalized medicine. So, if a patient with newly diagnosed NSCLC has an activating epidermal growth factor receptor (EGFR) mutation, we give that patient Tarceva (erlotinib), a tyrosine kinase inhibitor (TKI).  Right?  Well, yes — but it doesn’t always work (the response rate is in the 70-75% range). Why not?  We’re not sure, but it would be nice to learn why we don’t see near a 100% response rate among patients with EGFR mutations, so that we can know to recommend other alternatives.  On the other hand, if a patient does not have the mutation, we don’t really expect much in the way of a dramatic response.   Again, only partly right.   In fact, some studies show a significant minority of patients with normal (“wild type”) EGFR will have at least some response to Iressa (gefitinib) or Tarceva.  So, what’s going on here?

A recent study out of China looked at blood rather than tumor in 84 patients with advanced NSCLC who were all treated with Iressa. The analysis looked at naturally occurring single-nucleotide polymorphisms (SNPs, and pronounced “snips”), in the EGFR gene.  A polymorphism, which basically means “many forms”, can be thought of as small part of a gene which has a different part (nucleotide) from the general population, but is otherwise normal, as best we can tell.  A minority of individuals will have the different nucleotide (polymorphism) while the general population will have the same gene but with a different nucleotide.
In these patients, it was found that having a particular SNP could predict for a better response to Iressa and longer survival than the rest of the group, while different SNP could predict for a poorer response and shorter survival with the drug.  Still another SNP could predict for a greater risk of developing a rash, which we know is also associated with a benefit from these TKIs. This has also been seen with Tarceva.

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I would consider the recently published IPASS trial that compared Iressa (gefitinib) to standard chemo of carbo/taxol (paclitaxel) to be an extremely influential trial in lung cancer that has essentially ushered in a new era of molecularly-defined guidance of our treatment for many patients with advanced NSCLC, and we can expect that this is how we’ll be approaching a much broader population of lung cancer patients.  But there was actually another very similar trial done in Korea that was presented in the Plenary Session of the World Conference on Lung Cancer a couple of months ago in San Francisco that provides another opportunity to directly compare chemo to an EGFR inhibitor.

The First-SIGNAL trial (First-line Single Agent Iressa versus Gemcitabine and cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung) randomized 313 Korean never-smokers with previously untreated stage IIIB or IV lung adenocarcinoma to either Iressa at 250 mg by mouth daily to standard chemo with cisplatin/gemcitabine as initial therapy.  It asked whether first line Iressa would be associated with a significant improvement in overall survival (OS) and also looked at progression-free survival (PFS), response rate (RR), side effect profile, and quality of life between the two treatment arms.  This trial had a rather ambitious goal of showing a 40% improvement in survival and enrolled only about ¼ the number enrolled on the IPASS trial, so the statistics reported here need to be taken with a grain of salt because the study is pretty underpowered to show many meaningful statistical differences.

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