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Predicting Survival on EGFR Inhibitor Therapy Using Serum Samples
NOTE: ALL FIGURES CAN BE SEEN BY DOUBLE-CLICKING ON THEM, EVEN THOUGH NOT ALL APPEAR AS THUMBNAIL VIEWS PROPERLY.
We’ve discussed various ways of predicting outcomes with EGFR inhibitors like Tarceva or Iressa using clinical variables like smoking status or BAC subtype, as well as molecular markers like EGFR mutations, or EGFR gene amplification or protein expression. These can all be of value, but we know that the clinical markers are quite inexact, while the molecular markers are still a work in progress. Moreover, the molecular testing that has been the subject of most of the work thus far has come from tumor tissue material, which is often hard to come by and usually requires a biopsy or resection to obtain. But a recent article in the Journal of the National Cancer Institute, by a international collaborative group led by Dr. David Carbone from Vanderbilt University, describes their recent success in predicting survival after administration of EGFR inhibitor therapy using serum samples from patients all around the world (abstract here — full article also available from that page).
Dr. Carbone and his team at Vanderbilt have been leaders in the field of serum proteomics, which is the study of the proteins in the serum, the straw-colored fluid that remains after blood has clotted, so the cells and clotting proteins are absent. Obviously, collecting blood, from which serum samples can be analyzed, is much easier than collecting extra cancer cells in a biopsy to send off for studies. The approach they used at Vanderbilt is called matrix-assisted laser desorption ionization (MALDI) mass spectroscopy (MS), or just “mass spec”, which is very complex (code, perhaps, for me saying I really don’t understand it well? we only had to do a year of college physics to get into medical school, you know), but basically it is a way of analyzing a serum sample to report a set of peaks that represent different proteins in the sample:
(Click to enlarge) Continue reading
Is there a Group That Does Particularly Well with Erbitux in NSCLC?
I wrote in a post several months ago about the ongoing study of the monoclonal entibody against EGFR erbitux (cetuximab) in lung cancer, where it’s role is still up in the air. Unlike the EGFR tyrosine kinase inhibitors (TKIs) iressa and tarceva, which showed no benefit when given concurrently with standard chemo, erbitux has a different mechanism and may still be useful when given along with chemo. As I mentioned in my last post, a phase III trial of carbo/taxane chemo with or without erbitux failed to show any improvement in progression-free survival, but it did actually show a higher response rate in the group that received chemo with erbitux. But perhaps there are particular patients who are likely to gain a lot more with erbitux than others, just as we’ve found that certain groups, such as those with EGFR mutations and never-smokers benefit most consistently from the EGFR TKIs.
I previously described the early results on SWOG Trial 0342 (abstract here), in which over 200 patients with previously untreated advanced NSCLC were randomized to two arms. The sequential treatment arm received 4 cycles of carbo/taxol chemotherapy followed immediately by weekly erbitux until progression of disease, while the concurrent arm received the same 4 cycles of chemo along with concurrent weekly erbitux, then followed by weekly erbitux alone. The schema is shown here:
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The early results (abstract here) suggested that perhaps the concurrent arm did a little better, but neither arm did spectacularly, and it was worth debating whether the results were promising enough to commit to larger future studies. This year, Dr. Roy Herbst from MD Anderson Cancer Center presented more updated results (abstract here). With longer follow-up, the two arms converged together, both looking pretty good, with a median progression-free survival (PFS) of 4 months and overall survival (OS)of 11 months. You can see that the survival curves for the two groups are basically on top of each other:
Trial of Chemo with or Without Erbitux in Advanced NSCLC Negative
It’s a little sad that you can get more cancer information from the business websites than from the medical ones, but if you checked a story on Forbes.com today you learned that Bristol-Myers Squibb (BMS) provided a press release that one of their important Erbitux (cetuximab) trials didn’t meet its primary endpoint of improved progression-free survival for chemo with Erbitux compared with the same chemo alone.
Erbitux is another inhibitor of the epidermal growth factor receptor (EGFR), similar to Iressa and Tarceva, but unlike those oral pills, Erbitux is an IV drug that is actually a monoclonal antibody to the part of the receptor that is on the outside portion of the cancer cell (extracellular). Erbitux definitely has activity in some cancer types: it’s FDA-approved in treating colon cancer and head and neck cancer. But there have been some negative studies with Erbitux as well in other tumor types, including a large trial of chemo with or without Erbitux in pancreatic cancer that showed no benefit to the Erbitux combination (abstract here). It’s also been studied in lung cancer, primarily in NSCLC, with some modestly encouraging results, but definitely not a slam dunk. I’ve described some of this work in a prior post. Continue reading
Biologic and Molecular Correlates of Clinical Benefit in French Trial of Iressa in BAC
The study I was just discussing, the French trial of Iressa at 250 mg daily for advanced BAC (abstract here), provided interesting clinical information, especially when viewed in the context of previous work on EGFR inhibitors in BAC. But in 2007 we’re also interested in the next generation of questions, including trying to identify which patients are more or less likely to benefit from Iressa or other EGFR tyrosine kinase inhibitor therapy. In addition to the clinical portion of the trial, the French investigators evaluated several clinical, pathologic, and molecular variables that were associated with disease control (DCR: response or stable disease) vs. progressive disease (PD) in a separate reported part of the study (abstract here).
From the 88 eligible patients enrolled on the BAC trial, they had tissue submitted from 65, of whom the expert pathologists felt that 50 had BAC or adenoBAC, evenly split between mucinous (M) and non-mucinous(NM) BAC, while the others didn’t have tumor tissue in their submitted specimen or had an adenocarcinoma that the experts didn’t think could be called BAC (this is typical — expert reviews of pathology submitted as “BAC” from various hospitals often show high rates of disagreement, with a less strict definition in the “real world”). Not suprisingly, the patients with tissue submitted, like those on the trial in general, had a higher rate of non-smokers (>40%, and from France, no less!), and more than half of the BAC patients were women (pretty much the only lung cancer setting where we see this). The tumor tissue was tested for EGFR by protein expression (immunohistochemistry, or IHC), gene amplification (by a process called FISH, and another called CISH), and also for EGFR mutations; they also checked for ras mutations, which I described in a prior post as being likely associated with a lower likelihood of benefit on EGFR inhibitors. Finally, they checked for thyroid transcription factor-1 (TTF-1), which is a marker of thyroid and lung tissue that helps us determine whether a cancer is actually from the lung or thyroid vs. another part of the body (they can tell the difference between lung and thyroid from other protein stains in the unusual cases where there’s a question between those sites as the primary tumor site). About 70% of lung adenocarcinomas express TTF-1.
First, the investigators compared the M-BAC to NM-BAC tumors and found differences in several regards. Although there were no gender differences and never-smokers were found in similar proportions between the two types of BAC, NM-BAC was much more likely to be associated with TTF-1 expression, EGFR protein overexpression (by IHC; about 35%) and gene amplification (by FISH and CISH; 10% range)) and EGFR mutations (12% of the population) than M-BAC tumors. They didn’t differ in their frequency of ras mutations (about 1/4 of both groups). So they have some differences that might explain differences in how the different types of BAC tumors respond to EGFR inhibitor therapy.
And when they looked at the characteristics of the patients who achieved disease control vs. those who showed PD, they saw that the patients who had stable disease or better were significantly more likely to be women, never-smokers, have NM-BAC, have a tumor that expresses TTF-1, and also a higher likelihood of having an EGFR mutation. In contrast, those with ras mutations were more likely to be the ones who showed progression. Here’s the summary:
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This isn’t a large enough study to say anything definitive, but it’s a step forward in giving us hints about biological differences between M-BAC and NM-BAC, and it also helps provide some insight about why people with NM-BAC may be more likely to respond better and have longer survival on Iressa and Tarceva trials. In addition, this biological information may be useful outside of BAC. Perhaps the patients with TTF-1 positive tumors are the ones more likely to respond to EGFR inhibitors. We’ve never really looked at that, but that marker is a routine part of testing lung tumors. It’s readily available everywhere, and it doesn’t take days or weeks to obtain, unlike the mutation work. There are several other interesting leads here, so we need to follow up and see what holds up in other studies of EGFR inhibitors.
The Variability of Bronchioloalveolar Carcinoma (BAC): Non-Mucinous and Mucinous BAC
One of the themes that we’ve covered in some of the posts introducing the clinical entity of BAC is the variability in its natural history. In fact, much of what we’ve been learning about BAC has been in the last several years, and we’re still learning more about it all the time. One of the things we’ve struggled with is the range of outcomes, that some patients can experience rapid deterioration and no response at all to EGFR inhibitors, while other patients can have a remarkably slow progression, and they sometimes will have an astounding regression of disease from EGFR inhibitors. It sometimes seems as if there are at least a couple of diseases being labelled as BAC. In fact, that’s the case, and it’s been part of the confusion in why some people don’t fit a simplified view of what is supposed to happen in BAC. So let’s talk about mucinous and non-mucinous BAC.
Non-mucinous BAC is the largest group, accounting for about 40-60% of the patients, while perhaps 30-40% have mucinous BAC, and about 10-15% fall in between and are classified as mixed or indeterminate. In truth, this is pretty high-level classification that is not always (or even often) mentioned in pathology reports of BAC, and I would consider it relatively unreliable if read from a small amount of tissue and/or read by a pathologist without much expertise in lung cancer. In truth, even expert pathologists differ in how they interpret BAC diagnoses. Here’s a slide of BAC and adeno subtypes under the microscope:
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Mucinous BAC is the subtype that is associated with a cough productive of thick sputum, and it tends to appear more localized and pneumonia-like on CT scans than non-mucinous BAC, which appears most commonly as a buckshot appearance of lots of tiny, diffuse nodules:
Smokers and Tarceva: Is More Better?
As I’ve described in a prior post, one of the most consistent findings in the work with the EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib) is that never-smokers are far more likely to demonstrate a response and survival benefit than patients who do smoke or did smoke. Here, for instance, is the set of survival curves separated by smoking status for the large randomized trial of tarceva vs. placebo in previously treated patients with advanced NSCLC (abstract here):
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We really haven’t explored why that as, and that’s partly because there is a lot we don’t know. We do know that never-smokers are far more likely to have mutations than current or ex-smokers with lung cancer, but it’s really not all or nothing. The likelihood of having an EGFR mutation is higher in ex-smokers than in current smokers, and it’s also a gradually higher likelihood with a longer period since patients quit smoking, and with less overall tobacco exposure in terms of pack-years, the product of the number of packs smoked per day (PPD) x the number of years smoked, so 2 PPD x 20 years would be a 40 pack-year history. You can see that between never-smokers and major smokers are a population of patients who fall in between in terms of their smoke exposure and likelihood of having an EGFR mutation (abstract here):
But it’s probably not all about EGFR mutations, which are still only seen in a minority of patients with lung cancer, somewhere in the 5-15% range in the US (more in Asia). It’s quite possible that one of the more important issues may be the metabolism and different pharmacokinetics (the way a drug is processed by the body, specifically the changing levels in the blood over time) between smokers and non-smokers, which may mean that what is an optimally effective dose in a smoker may be higher than the optimal dose in a non-smoker. Continue reading
Ras Mutations and EGFR Resistance
Most of the focus on predicting response to EGFR inhibitors has been on identifing molecular markers that are associated with major response to this kind of treatment. But we know that there is a group of patients who get no benefit from these expensive drugs, and in these patients, EGFR inhibitors would just lead to side effects and keep them from a potentially more effective therapy for them. As you can see, the overall survival and progression-free survival curves from the BR.21 trial (abstract here) show that there are a group of patients clustered on the right side of the curve who do no better than the placebo group. In addition to detecting which patients are going to be the greatest beneficiaries, we need to identify which patients will get no benefit at all from EGFR tyrosine inhibitors like Tarceva.
Ras (rhymes with mass) is a gene and protein product that are involved in molecular signalling and very important in many cancers. There are several related genes in the family, and most of the focus is on k-ras. Mutations are seen in a significant minority of lung cancers and are far more likely to be seen in smokers than in non-smokers (abstract here). As you can see from the tables below, ras mutations are consistently more common in smokers than in non-smokers in multiple case series, and they are essentially mutually exclusive with EGFR mutations that have been associated with a high response rate to EGFR tyrosine kinase inhibitors like Iressa and Tarceva.
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Continue reading
Single-Agent Erbitux Studies in NSCLC
Yesterday I reviewed a series of studies of the EGFR monoclonal antibody cetixumab, or Erbitux, combined with chemotherapy. Overall, these trials are modestly encouraging, without what I would consider to be a potential antagonistic effect when chemo and EGFR tyrosine kinase inhibitors (TKIs) like Iressa or Tarceva. However, we still don’t have studies big enough to establish any role for erbitux. Today, I’ll cover the very limited experience of single-agent Erbitux in advanced NSCLC. Continue reading
Targeted Therapy for Selected Populations in NSCLC
In my last post, I described the somewhat disappointing results for tarceva compared with chemotherapy in a trial of unselected advanced NSCLC patients with a marginal performance status. However, EGFR tyrosine kinase inhibitors like iressa and tarceva were developed as targeted therapies, so perhaps they might prove to be more effective if used selectively, in a targeted population. That targeting might be based on clinical characteristics like using it in never-smokers or bronchioloalveolar carcinoma (BAC), or it might be based on molecular markers like mutations in the EGFR gene or overexpression of the number of copies of the EGFR gene, as determined by fluorescence in situ hybridization, also known as EGFR FISH testing. All of these methods have been employed in early but very promising studies of iressa or tarceva in selected populations. Continue reading
Targeted Therapy in Older and Sicker Patients: A Replacement for Chemo?
The emergence of targeted therapies provides a goal of treating the cancer more selectively, thereby minimizing side effects, while hopefully achieving results as good as or better than standard chemotherapy. Although this is important in the entire population of cancer patients, this is a particularly welcome benefit in patients who may be reluctant to or not healthy enough to receive standard chemotherapy. As I mentioned in my last post on the association of age and benefits of chemotherapy, chronological age is not nearly as important as performance status, at least up until around age 80, where we have very few patients on clinical trials to help tell us what to expect. Regardless, there have been several studies of tarceva/erlotinib in older patients, and other trials specifically looking at patients with marginal performance status regardless of age, asking whether we can do as well or better with tarceva as with conventional chemotherapy in these patients. Continue reading
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