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Is Rash a Good Thing with EGFR Inhibitors?
An acne-like rash or dry skin is a very common side effect of the drugs that target the epidermal growth factor receptor, with approximately 3/4 of patients who receive the EGFR tyrosine kinase inhbitor tarceva/erlotinib experiencing skin toxicity. Similar skin toxicities are also seen, but a bit less commonly, with the very similar drug iressa/gefitinib, and also frequently with erbitux/cetuximab, a monoclonal antibody that is less well studied in lung cancer. But since the earliest clinical trials of these agents, there have been questions of whether the rash is something more than just a potentially problematic side effect, but rather a marker of someone likely to do well with these agents.
One initial point we can make is that there is a dose dependency associated with these agents. As shown in the table below for iressa, the more drug you give patients, the more commonly you see a rash.
(click to enlarge)
However, even at doses far beyond what was considered the standard or target dose for iressa (250 mg in general, 500 mg in early studies), not all patients develop a rash. I believe that is important, because it may suggest that some people cannot generate a skin response to even high doses of EGFR inhibitors.
The idea that there may be an association between rash development and how well patients with NSCLC do on EGFR inhibitors traces back to the first reported clinical trial of tarceva in NSCLC, by Dr. Roman Perez-Soler in New York. Among 57 previously treated patients with advanced NSCLC, he reported that survival was best in patients with a moderate or severe rash, worst in the patients with no rash, and in between for the group of patients with a mild rash, as shown here.
(click to enlarge)
In fact, the degree of rash that a patient developed was more predictive of a patient doing well on that trial than their activity level going into the trial. These results were interesting, but it was a single small trial. However, similar trends were seen in other tumor types, as shown in the table below:
(click to enlarge)
And similar results were being seen with erbitux, particularly in colon cancer, and to a lesser extent with iressa. My own study with iressa in BAC showed a correlation as well, although it wasn’t as clear that more severe rash was better than a milder rash. Instead, it did support the idea that patients who did not develop a rash did not do well.
(click to enlarge)
In fact, in both my trial and one with tarceva in BAC, there were no patients who had a favorable response of tumor shrinkage who failed to develop a rash.
The TRIBUTE trial of first-line treatment for advanced NSCLC, in which patients received carboplatin/paclitaxel alone or with tarceva, showed something very interesting. Like other trials, it showed that patients with a rash did better than those who did not, and the worse the rash, the better patients did. But another VERY important point was that the patients who received tarceva but didn’t develop any rash actually did worse than the folks who received chemo and placebo. Here’s the breakdown:
(click to enlarge)
So these results suggest that there’s something particularly unfavorable about not developing a rash, if they do worse than not even getting tarceva at all.
In the BR.21 trial of previously treated patients with advanced NSCLC, rash again appeared to be an important predictive factor. In that trial, the 75% of patients on tarceva who developed a rash had a much better survival than the 25% who didn’t (9.5 vs. 2.2 months, quite a difference!). I have never seen a breakdown by severity of rash. Also interesting was the fact that 17% of patients on the placebo arm developed some kind of rash/skin toxicity, and they did better than the patients on the placebo arm that didn’t develop any skin toxicity!
What can we conclude? Well, we certainly don’t have all of the answers, but there does seem to be a clear and consistent association of rash with better outcomes. It’s not completely clear that a worse rash is associated with better results than a mild rash, but no rash or skin toxicity is associated with worse outcomes. And these results have been seen with multiple agents, in combination with chemo or as single-agents, and in many types of cancers.
But is it how much drug is given or how sensitive a person is? I notice that some patients don’t develop a rash even at very high doses, that the folks who don’t develop a rash actually do worse than the folks getting a placebo, and finally that the folks on the placebo arm of BR.17 who developed a rash actually do better than others, and I conclude that it has to do with immunocompetence/immune sensitivity. However, I’ll admit that nobody understands this especially well, including me at this point.
Importantly, we have not yet seen ANY good evidence that you can convert a non-responder to a responder on EGFR inhibitors by increasing the dose (so please don’t start doubling your dose!!). There are a few studies of dose escalation to get to developing a rash, being looked at for years, but I’ve never heard any results from them, which makes me believe that there’s nothing promising there. Nor is there any evidence that patients who develop a major rash do any worse after reducing dose to manage the rash better. I think that someone’s tendency to develop a rash is more intrinsic, and that you can’t change that.
Finally, this is a correlation, and it’s definitely NOT perfect. I’ve had patients do very well with no skin reaction, and I’ve had patients with very bad rashes who had their lung cancer progress through them
I’ll talk more about managing the rash, and perhaps how dose and rash and smoking status may interact, in future posts. In the meantime, I welcome your comments, questions, or objections.
16 Responses to Is Rash a Good Thing with EGFR Inhibitors?
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Hi Dr. West–
Just registered after seeing your post on the NSCLC list. I’m on Tarceva alone and I have a rash that I’d say varies from mild to moderate (without knowing the clinical criteria for evaluating the rash). I am doing quite well with Tarceva. I feel very well and my tumor shrank at first and is now stable.
I have a question. On your second graph in this article, it looks like “Median Survival” is highest with no rash, and lowest with with more rash. Am I reading this wrong or is it an error?
I look forward to your post about managing the rash…!
Leslie
Leslie,
Good pick-up! There was an error on the original slide I had received, and I subsequently changed it in later slide presentations I did, but the figure that you saw had that mistake. The figure is actually correct but the legend was not.
The post now includes a corrected version. Thanks for noticing and asking.
I’ll look forward to your participation and will hope to have more information to offer you.
Thanks!
-Jack
Dr. West -
What’s your thoughts on Iressa/Tarceva response in spite of being biopsied and tested for “the” mutations with no mutations found?
How about returning to Tarceva after a recurrence, this time with Avastin (after 6 rounds of Avastin with Alimta)?
And, any thoughts on high doses of celebrex? (especially in concert with Tarceva).
I was dx’d in 2003, stage IV. A never smoker. Did carbo/taxol with Iressa. Complete response by 7/04. Stayed on Iressa alone.
Recurrence in 4/05. Stopped Iressa. Started high doses of Celebrex (400mg, 2x daily) while awaiting a June biopsy and mutation testing. Started Tarceva (continued the Celebrex) on July 7, 05. Moderate rash within days. Had a PET/CT on July 13. A 30% SUV reduction! Stuck with Tarceva. Dec 05 PET showed an additional 90% SUV decrease.
Stuck with Tarceva until recurrence in 5/06. Stopped Tarceva and celebrex.
Just completed 6 rounds of Alimta with Avastin. Now on Avastin alone. Thinking of adding Tarceva and perhaps celebrex. Stable so far.
It’s been a wild ride so far as I seem to defy conventional wisdom that later shows promise in trials (ie: celebrex with Tarceva, Tarceva response with no mutations).
Any insight is appreciated.
Tom
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Tom,
You’ve described quite a fascinating adventure. I’m gratified, as I know you are, that you’ve been doing so well for so long.
I definitely would not say that you have to have a mutation to do well with iressa or tarceva. It is possible to miss some of the activating mutations, there may be ones we don’t know about, and it also may be possible to respond if you have high gene amplification (expressed by FISH testing, or fluorescence in situ hybridization). We definitely DON’T know everything about predicting who will benefit, and I think your story should be instructive for any reader to recognize that it is likely not a good idea to exclude EGFR inhibitor therapy just because you don’t have a mutation.
We in the lung cancer community have been debating whether there really might be any benefit to giving tarceva after a patient has progressed on iressa. I think the evidence shows that tarceva is a better agent, at least at the standard doses that have been used, but it hasn’t been clear that switching from one to another will help. Your case seems to show that you can have at least some convincing response after switching from iressa to tarceva. Good for you, and it’s valuable for all of us to know.
You asked about celebrex/celecoxib, and I’d have to admit that I’m not convinced and actually skeptical. Results of the combination of iressa and celebrex didn’t look better at all than iressa alone. I know that there has been a lot of buzz about the UCLA study of celebrex and tarceva, and perhaps it will really pan out to something terrific on a larger scale, but I wouldn’t change my practice on the basis of this small study, since celebrex has had plenty of less exciting results that nobody could get excited about, and they just haven’t been talked about.
Avastin and tarceva is a different story. I don’t know if the combination will prove better than tarceva alone, but there have been a few trials that look encouraging and show that the combination is at least as safe, and potentially a better toxicity profile, than chemo and avastin.
Overall, there is no clear best choice here, but those ideas are very reasonable. And clinical trials with any promising new approach are also always appealing, if you can find them.
Thanks for telling us about your “wild ride”!
I have been on Tarceva for 15 months, initially in combination with carbo/taxotere then on Tarceva alone for about a year. I did not develop a rash, a mild one at that, until 3 months ago. Is there any significance to having a delayed reaction? So far, the drug seems to be working, as my scans show I am stable. BWS
BWS,
No, it’s unusual, but sometimes people do get delayed responses. I don’t think anyone has ever analyzed the time to developing a rash vs. how patients did. I’ve had at least one other patient like you. We’ll have to see if other people have a delayed, minimal skin reaction and are still doing well for a long time.
I guess we should be thankful you’re doing well with just a very mild, delayed skin reaction. For most of the folks on tarceva, even a more significant rash is worth the trade-off for doing well against their cancer.
Great update on this. I started T-150 10 days ago. I developed a “mild” rash on neck, face and back of head after a few days. It seems to have stabilized so far (had lots of small white puscules which are now turning to red sores). I look forward to your post on treatment options for this.
I like others thank the Lord and you that you take your valuable time to share with others your wisdom and experience.
Dr. West,
I had stage IV lung cancer with a pleural effusion. I was given Carboplatin, Taxol and Tarceva 100mg all at the same time. This was my first line treatment. In three months there was nothing but scar tissue. I have been cancer free since November 2005. I still take Tarceva and expect to stop the Tarceva after two years.
I had a very slight rash when I first started treatment. I could hardly notice it, but my wife said that she could see a slight rash. I had no bad side effects from any of my treatment. Does this mean that the Tarceva is not what worked for me or am I just an isolated case?
I did and still do take a lot of supplements and herbs, but of course no credit is ever given to them. Two that I take are AHCC 6 grams a day and Melatonin 20mg a day.
I was wondering what your thought is on this. If there is something that I am doing that I could give to someone else I would sure like to know what it is.
Thanks for joining us at Lung Cancer Support
Stay positive,
Ernie Puckett
Ernie,
Congratulations on doing so well. That’s remarkable, and I hope all of us in the field can learn more about what makes the major responders do so well.
I must admit that I am also somewhat skeptical about the role of diet and supplements, but I’ll admit that this is my slight bias. I struggle to be very evidence-based in my conclusions, and most of the work with supplements is not tested the same way that chemo or tarceva or other targeted therapies are studied. If I do have look at supplements with a bit of a negative eye, it is because it frustrates me that they are given so much credit without actually proving their benefit in the right way. Like just about everyone on this site (and Lung Cancer Support), I’m dealing with lung cancer every day and am not satisfied with how we’re doing, so I would welcome ANYTHING that can help. Taxol is from the bark of the Pacific Yew tree, and many other effective anticancer therapies are natural products, so I actually think that there isn’t a fundamental difference between “conventional treatment” and “complementary treatment”. But I didn’t recommend Tarceva before it had good evidence in a big trial to prove the survival benefit, and I wouldn’t give another approach an automatic pass whether it is AHCC or a numbered compound from a pharmaceutical company.
And in your case, it is hard to tell whether it’s the tarceva or the chemo (or possibly the combination, but I’ve already said that this isn’t my preferred approach). Please keep me informed on your progress. Whether it’s chemo, tarceva, AHCC, or anything else, I would love to have more patients responding like you.
Thanks for bringing up such a thorny topic. I am always glad to mull over different points of view. Life would be boring if we all thought the same things.
My wife beat IIIa lung cancer in 2000 through chemo.,chemo& radition then surgery. In mid 2005 it started again but wasn’t id’ed until recently. She started Traceva this month after nine days on 150 doseage she was so weak that the oncologist took her off for 7 days. She restared and has been on it for five days on day three the weakness returned . She has no rash.Should she continue until the 30 days are finished and then have a CT scan or stop now?
I hope you are keeping in close contact with her oncologist. In addition to potentially taking breaks from tarceva, there are lower dose tablets of tarceva. It is possible that she will do better with 100 mg, and sometimes patients need even lower doses (they come in 25 mg tabs as well). Profound fatigue is an unusual side effect from tarceva, but it happens occasionally.
Hi,
My husband started on Tarceva 3rd April 2007 150mg. Whithin Three days he had the rash and pain free day 4, had no pain at all and his breathing is great too. The rash however is severe, his nose is swollen and weeping puss. The Dr has told him to stop until rash improves and then start back on a lower dose 75mg.Then increase it again. I have read through your article with great intrest about the worse the rash the better the response. I am now however worring becasue he has to reduce the dose.
Hi,
I just finished my 8th bottle of 150mg of Tarceva and finally had to take a break because of severe rash on arms, legs, and chest – the rash on my face is about the same as always but the itching is driving me crazy. I am hoping a week break will be enough and I can start back on the Tarceva, but if I am still itching I may need a longer break – I had been using minocycline but switched to bactrim about 6-8 weeks ago when I developed a rash on my eyebrows when they were falling out. The rash on the eyebrows has improved, but I think I may have developed a problem with the bactrim and that might be what is causing my itching – I am also allergic to penicillin so it was a concern that I might have a reaction. I have had such great success on Tarceva that I really don’t want to not take it, and my oncologist always encourages me about my rash saying the worse the rash the better the Tarceva is working – I do believe that because I was only stable prior to going on Tarceva, I had 6 nodules and now only have 2, 1 is stable and the other is only half of its size. My skin peels and sheds frequently and I was wondering if this is normal – it is almost like my skin has been sunburned only I haven’t been in the sun the way it peels. I have been using Sarna and Aquaphor for itching and trying to keep it moisturized. Do you have any better recommendations for helping for the dryness and itchiness? Any suggestions would be greatly appreciated.
Pamee
First, while it’s true that there’s an overall trend for the population that indicates that people with skin toxicity on tarceva tend to do better, there isn’t evidence that you need to continue to experience severe side effects to do well. We don’t understand this association extremely well, but my sense is that it’s an epiphenomenon, that the skin problems are some kind of window of how active the drug is in patients, but it’s not that skin toxicity drives the good effects. We really want to titrate the dose so that someone is getting an effective amount but not so much that the side effects are potentially dangerous, especially for an agent that can be taken on a daily basis for years. It sounds to me like your father’s side effects are quite severe, and your doctor’s advice sounds very prudent. Remember that, as Angela’s father’s situation illustrates, it’s possible to get the skin side effects under better control and then carefully adjust the dose with greater support for the skin toxicity. However, there’s no evidence that the patients who have excessive skin toxicity at 150 mg and need to drop the dose do less well than patients who stay at 150 mg. If you’re very sensitive to tarceva, 100 mg or 75 mg may just be as much as you can tolerate safely and on a potentially chronic basis. I wouldn’t consider it any significant detriment to hold drug temporarily and/or drop dose in order to find the maximal dose that works for long-term use in a particular patient.
Pamee,
I agree that bactrim, with its sulfa component, is a common allergy and is a real consideration as a source for itching. I wish I had a great idea, but mainly it’s emollients and perhaps benadryl or atarax as medications to help with itch. As my comments above would suggest, I have somewhat of a “less is more” approach, and one question I think is worth considering is whether you could get the same results with fewer side effects on a lower dose, like 100 mg. If the side effects are manageable, then I’m all for staying at 15o mg daily, but if it’s really harming your quality of life, I can assure you that I have several patients who are doing well for months and months, and in a few cases more than a year, after a dose reduction. It is always possible to re-escalate to a higher dose if there is progression at a lower dose.
Anyway, even though I do agree with the general relationship of rash development and outcome on tarceva, I don’t think the rash drives the better results, so I’m not sure it’s necessary to suffer at a higher dose rather than find the lowest dose possible to keep disease from progressing.
-Dr. West
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