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.
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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.
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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:
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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.
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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:
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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.
posted by Dr. West @ 8:41 pm link to this post
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December 7th, 2007 at 12:22 am
[…] Rashes from EGFR inhibitors: we like to see them, because we know that many trials have shown that skin toxicity on drugs like tarceva is associated with better survival (see prior post), but the fact is that sometimes a rash is more than an inconvenience and can really make people miserable, or at least pretty unhappy, as described in the comments and questions from a discussion forum thread today. I’ve described some general management principles for rash in another prior post, but in truth, oncologists aren’t well trained in rash management, and we’ve generally had to learn as we go along, because EGFR inhibitors have introduced this as a new problem in oncology. Tarceva is a well established treatment at this point for lung cancer, and while the monoclonal antibody Erbitux has been used primarily in colon cancer and head and neck cancer thus far, a major lung cancer trial with erbitux was also recently reported as positive (post here), so there’s a strong possibility that erbitux, which is also associated with very significant rashes (and better survival correlated with that), will also be used increasingly for lung cancer. […]
April 12th, 2007 at 11:56 pm
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
April 12th, 2007 at 9:24 pm
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
April 12th, 2007 at 8:04 am
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.
November 28th, 2006 at 5:00 pm
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.
November 28th, 2006 at 9:18 am
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?