Lung Cancer / Mesothelioma
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There was some evidence that patients with adenocarcinomas received a little more benefit with erbitux than the patients with squamous cancers, as shown in the table below (which also highlights the race-based difference)
(click on image to enlarge)
However, many patients with adenocarcinomas are also eligible for avastin, which has been associated with a two month advantage in median overall survival and is FDA approved already in this same setting. I think that for patients in whom you might be particularly worried about bleeding risk but are still technically avastin-eligible, such as the patients with central cavitary tumors or a history of coughing up small amounts of blood, erbitux may be an attractive alternative. There are also some patients who develop problematic side effects on avastin, whether with nosebleeds or kidney problems or high blood pressure, who might switch from avastin to erbitux.
But I think that the easiest transition of use of erbitux will be in patients with squamous tumors, despite the rather modest median overall survival advantage of 1.3 months. There are several real challenges, including the problematic rash, the weekly infusion schedule, and other potential side effects, including higher risk of fevers with low white blood cell counts (known as febrile neutropenia) that we usually hospitalize patients for. There is also a cost that will average tens of thousands of dollars per patient (which for many patients amounts to a very significant co-payment with each treatment), which may be considered to be too expensive to gain what many will perceive as relatively little. I think it will be worth a discussion with patients, but many doctors may recommend that it doesn’t offer enough benefit to a general population to justify adding it, that the juice may not be worth the squeeze.
The equation could change, though, if we could better identify a target population. One factor that I think could emerge as extremely important is selection by EGFR gene amplification, detected by a lab test called fluorescence in situ hybridization, or FISH. I described this very provocative issue in a prior post, in which it appeared that within the limited subset of patients who had received carbo/taxol chemotherapy combined in some way with erbitux in whom tumor tissue was available for EGFR FISH testing, both the progression-free and overall survival were markedly greater (doubled, in fact) in patients who were EGFR FISH positive vs. EGFR FISH negative (pretty evenly divided between two categories). Those are small numbers and not enough to change practice at this point, most experts would agree, but additional tumor tissue from ongoing trials is being tested in the coming months. If that work supports the same conclusion, it would support adding this variable into future trials and arguably using this factor as a clinical decision-making tool.
Another concept that may be relevant here is the presence or absence of a K-Ras mutation (see prior post), one of the important cancer-inducing factors, in the tumor. One of the biggest stories at ASCO this year was work that clearly demonstrated that patients with colon cancer who have a K-Ras mutation in their tumor are very unlikely to benefit from erbitux. There has been work in lung cancer that has shown that patients with K-Ras mutations (about 20-30% of lung cancer patients overall, and usually correlated with smoking more) have almost no chance of responding to tarceva, and they also do very poorly with chemo – so it’s not clear what would be a useful treatment for these patients. I don’t think we’ve seen any work yet on the topic of K-Ras mutations correlating with benefit on erbitux in the setting of NSCLC, but that’s a subject we need to address.
I’ll just close by saying that this work, whether talking about differences between patients with adenocarcinomas or squamous tumors, or considering EGFR FISH and K-Ras testing, all require a reasonable amount of tumor tissue. After years of settling on the smallest amount of tumor tissue possible, often with a fine needle aspirate that collects just a few cells, we need to use larger bore needles to perform core biopsies or even remove entire lymph nodes, so that we can collect enough tissue to more reliably determine the histology (type of lung cancer) and molecular features of a cancer. Accounting for these variables, we may well be able to focus on a narrower population of patients who can gain a more clinically significant benefit from drugs like erbitux, and potentially others.
Next, I’ll turn to some of what we learned about alimta in the previously described trial about maintenance (or early second line) chemotherapy after four cycles of first line chemo. This work could change clinical practice and also provided further information about alimta working in some NSCLC subgroups but not others.
Posted in: Chemotherapy, Epidermal growth factor receptor (EGFR)-based therapies, First-line treatment, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Stage IV/Advanced/Metastatic NSCLC, Targeted Therapies, Activity and Side Effects, Targeted therapies, Treatment
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Dr. West,
I’m curious, were there Latino and/or African-American subgroups as well? This is not a political question. I was just reading the data and it struck me I wonder how those groups faired?
texatl
Dr. West:
Erbitux is of particular interest to me because I have Squamous cell carcinoma AND have had pulmonary embolism so in need of blood thinner (am on Lovenox). I was also, however, a heavy smoker.
I have not been tested for EFGR or K-Ras because up to now, my oncologist and I have been working our way down through chemos that have lesser side effects (initial chemo was cisplatin/etoposide followed by first docetaxel session, which had to be dropped due to my overall condition (pulmonary embolism, radiation pneumonitis, etc.)).
I was never NED and in 12/07 tumor and lymph nodes began growing again. Tried Tarceva with no luck and am currently on Alimta (with low expectations).
My oncologist is looking at Erbitux next (following which, we might take a stab at docetaxel again since I only had 1 tx), but given severity of side effects, I will first be measuring “quality of life” vs. “buying time,” raising the question as to whether I should bother with Erbitux at all if I’m EFGR-negative or have the K-Ras mutation?
Note: I have no idea at this point whether my insurance (Medicare Advantage thru Kaiser) will cover biopsy or specialty drugs as I’ve been taking this one step at a time, although I’m probably willing to invest in myself (pay for testing and/or drugs) if I have to.
Carole
Dr West;
Who ever coined the original term “targeted therapy” sure knew what they were talking about. To a lay person like myself, Merck KgaA sure seems it hit the target with the FLEX trial now it’s up to the onocological community to aim the arrow so we can hit the “bulls- eye”. It’ll take time, but it will happen and then we can claim we made another step towards turning cancer into a chronic disease instead of a death sentence.
I have to commend Merck in its selection of the patient population. To include everyone including ps2 patients knowing that this trial would be compared to the ecog trial was suicide to begin with. But it was the right thing to do.
You mentioned the Kras trials that were presented at Asco and their effect on Erbitux. If you saw the presentation’s OPUS and CRYSTAL you’d see that in colorectal cancer they just got their “arrow” much closer to the bull’s-eye. While the headline numbers didn’t set the world on fire, both trials showed that 40% to 45% of the patients literally flat lined into the 12 month pfs mark. That gave the trials PFS hazard ratios in the .5 and .6 range and that’s remarkable. Now the goal is to identify what’s unique to that population and they can hit the bull’s-eye.
It’s funny but at times like this that we realize that “the more we learn the less we know”.
Thank you
jb
jbogd1
I’ll start by saying that the presenters didn’t report any data on racial groups that didn’t fit into Asian or Caucasian, I suspect because there were too few in this European study to draw any meaningful conclusions. The whole question of breaking down by race is very new, but the relevance of racial differences, particularly differences between Asian adeno NSCLC (with such a low frequency of smoking history in this group) just highlights that this may be a very different disease. Breaking down by race is a very new concept, but probably very relevant, and it requires large numbers to make subsets of meaningful size. I don’t think US-based, Asian, or European studies have enough African American or Hispanic patients to say much. But we’re starting to see reports that profile how EGFR inhibitors do in understudied populations like Indian and other groups that really don’t necessarily fall in as East Asian or Caucasian.
For Carole, I think it’s going to be very personal how to apply the FLEX data for individual patients. As you’ve probably concluded, many of our treatments appear to work particularly well in patients with adenocarcinomas (EGFR inhibitors, avastin, alimta), except that the cisplatin/gemcitabine combination looked particularly favorable in patients with squamous tumors and has led me to give extra consideration to gemcitabine for patients with squamous tumors (although I’ve been pretty pleased with the balance of effectiveness vs. often very mild side effects in a broader NSCLC population). Erbitux has looked pretty favorable in combinations with platinum/navelbine and also platinum/gemcitabine (smaller trial), and I’d give consider a combination of erbitux in combination with any of these, such as navelbine/erbitux or gemcitabine/erbitux. However, I’d have to tell a patient that there is no good evidence yet of the value of erbitux with these drugs in previously treated patients, so it’s just something to consider when we don’t have a clear best choice. I think advanced NSCLC is going to be more of a free for all than it’s been in the past, with so many agents to potentially mix and match, but not enough evidence of how best to combine them. (I hope you weren’t expecting a real answer of what to do — since I’m not your doctor, I couldn’t say that, but let me clarify that I don’t know and I don’t think anyone could really say anything definitive).
And JB, I agree that while many of our drugs have provided modest improvements by using these drugs in untargeted ways for most patients, the real hope is to define the test(s) that will separate the beneficiaries from the people who will only experience side effects and extra costs from these drugs. I came away from the FLEX presentation feeling that the lung community desperately needs to know two things:
1) Can EGFR FISH results discriminate the beneficiaries to identify a group of half the patients who get a major benefit and the other half who get no benefit and shouldn’t bother with Erbitux?
2) Can the presence of K-Ras mutations predict who won’t benefit? At 20-30% of NSCLC cases, it’s a smaller proportion than in colon cancer, but it would still be helpful to hone the drug to be used toward a population more likely to benefit.
We should get more information in the next 6-12 months, I hope. In the meantime, some docs are going to seek these tests to help make these decisions even without much evidence to go on right now. Given how modest the benefits are in a relatively untargeted population, I can see the appeal of doing whatever we can to feel our way while we grapple in the dark.
-Dr. West
I am surprised that there is apparently no subgroup analysis by gender or smoking history as this has been very relevant for tarceva that works in a similar fashion. My wife recently had to stop avastin due to a pulmonary embolism and is now on arixtra. Her oncologist is considering adding erbitux to replace avastin and continue with the carboplatin and taxotere that she is on. She is a neversmoker and had a major 1 year response to tarceva. She had a significant rash problem and had to use a reduced dose of tarceva. I would assume this probably means she would also have a major rash problem with erbitux. Thank you again for your insights.
hubbie
The ASCO presentations are only about 10-12 minutes, so there’s only so much information you can squeeze into a brief report, even if you’ve done it. But I believe that the analysis alluded to a similar degree of benefit being seen across many variables, including patient sex. I would say that the issue of smoking status hasn’t been addressed as systematically for erbitux as it has with the EGFR TKIs. I haven’t come to the conclusion that the same association applies, but I actually need to say that I really haven’t come to any firm conclusions with Erbitux based on the limited information available thus far.
I would imagine that there is likely to be a strong correlation of degree of rash/skin toxicity on erbitux vs. an EGFR TKI, but I have never seen data to either support or refute that.
-Dr. West
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