Can Rash Be Used as a Marker of Treatment Outcome?
by Roman Perez-Soler, MD
Skin-Associated Toxicity and Epidermal Growth Factor Receptor
I am going to try to go in-depth on the pathophysiology of the rash and discuss whether the rash can be used to optimize the use of these agents. This is a controversial topic, maybe less controversial today than 6 months ago, as we have developed more data.
The epidermal growth factor receptor (EGFR) is expressed in the skin, in the epidermis, in the sebaceous glands, and also in the epithelium of the hair follicle. EGFR plays a role in the normal differentiation and development of these 3 areas, particularly the skin follicles and keratinocytes.
There have been some mouse models where the EGFR is removed from the genome of the mice; the lack of EGFR will be a lethal lesion, so the mice will survive only 18 days. There have also been some models of mice where the EGFR has been specifically inhibited or removed from the skin; these mice will develop a necrosis, appearance of hair follicles in the skin, and an inflammatory response. That is similar to what we see in patients when we block EGFR, either by antibodies or by the tyrosine kinase (TK) inhibitors. When there is partial inhibition, the animals are viable and fertile, but they develop hair, skin, and eye abnormalities. Everything that was done in my study suggests that if you are going to transiently inhibit the EGFR pathway, it is going to be feasible but may be associated with cutaneous toxicity.
The EGFR is not the same in mice as in humans; but, in the internal or intracytoplasmic portion, the TK is identical in mice and human. As a result, the TK inhibitors, like erlotinib or gefitinib, would actually inhibit the epidermal growth factor (EGF) pathway on the skin, and then the mice develop skin lesions that consist of diffuse mild-to-moderate thickening of the epidermis and infiltration of acute inflammatory cells in the dermis. In the eyes, they develop dry scabs. The lesions in the skin are similar to the lesions that we see in patients when we block the EGFR pathway.
This slide, pooled by several dermatologists, is their hypothesis for the EGFR inhibitor-associated skin toxicity. Upon inhibition of EGFR at the skin level, there is follicular occlusion due to lack of differentiation of the epithelium there. As a result, there is secretion of inflammatory mediators and cytotaxis of inflammatory cells there, particularly polymorphonuclear cells. There is also an effect on the sebaceous glands that leads to a rosacea-like type of reaction. As a result, there is inflammation that is not always going to be impetiginization or superinfection, but in some cases, we believe it is; in those cases, maybe topical antibiotics will be the way to go, to at least partially treat the rash.
In the clinical trials with EGFR-targeted agents, we have seen that the cutaneous toxicity was predicted, based on the preclinical data I have shown. The primary manifestation is an acneiform skin rash, but we have also seen pruritus without rash and erythema alone. Skin rash is a side effect that has been observed with the TK inhibitors, like erlotinib and gefitinib; the dual inhibitors, like GW2016; and the pan-human epidermal growth factor receptor (HER) inhibitors, like CI-1033. It's also seen with the monoclonal antibodies that block the EGFR pathway, cetuximab, ABX-EGF, and EMD72000. Rash in Phase II Studies of Epidermal Growth Factor Receptor-Targeted Agents
The rash generally occurs above the waist, particularly in the nose area, and is characterized by clusters of monomorphic pustular lesions. The most common histopathologic finding is neutrophilic infiltration of the dermal tissues. There is anecdotal evidence that the rash may spontaneously resolve in some patients after a few weeks.
Here is a picture of the rash, particularly on the cheeks and the face. This is the dermis with infiltration of neutrophils. The neutrophilic infiltration does not mean that there is a bacterial infection of that follicle; it occurs also without infection.
Here I have shown the incidence of rash in a variety of trials with the TK inhibitors, erlotinib and gefitinib, and also in some trials with the monoclonal antibodies. Cutaneous toxicity is new to oncology. We have not, in the past, had agents where cutaneous toxicity is the main form of toxicity. In these trials, we have been slowly learning how to grade our cutaneous toxicity. Some of the terminology used is different for different trials. But in general, we have seen that about two thirds of the patients on the TK inhibitors will develop rash or some form of cutaneous toxicity. The monoclonal antibodies will also show the same side effect in a similar proportion of patients. Maybe the exception is the ABX-EGF antibody, where with the dose of 2.5 mg/kg, all the patients developed a skin rash. What is also clear for all these studies is that the rash is dose dependent. As you increase the dose of the agent -- if you can (for some of the TK inhibitors that may not be possible because of diarrhea) and if you do not have diarrhea or any other side effect -- you will eventually develop a rash on most of the patients, if not all.
This shows the incidence of rash in the erlotinib (Tarceva) studies. There were 3 phase II studies: one in non-small cell lung cancer, one in head and neck cancer, and one in ovarian carcinoma. The bars on the far right show the summary of all studies. This slide shows the proportion of patients who develop rash. Approximately one-a third of the patients develop a grade 1, another third develop a grade 2, and then a minority of patients develops a grade 3 or grade 4 rash.
Is the rash related to response? This shows, just for erlotinib, that rash was associated with response in these 3 studies. The bars (far right) where you see the summary show, basically, that almost all patients who had an objective response had grade 2 rash; a minority had grade 1 rash; and no patients had a response if they didn't have any rash. So, at least for erlotinib -- maybe not so clearly for some of the other agents -- response was associated with rash.
How do we treat the rash? This is a new entity. In oncology, we are still learning, and there are no clear guidelines for rash management. Treatment options include antibiotics -- that was with the assumption that some of these lesions are superinfected. The results have been mixed, but in some cases, topical or systemic antibiotics have worked. Retinoids have been tried. Short-term corticosteroids can be used, if there is a very severe acute inflammatory reaction; but, in general, most dermatologists will not recommend that. In general, for severe rash, we do not really have a well-established way of treating it. Based on the current toxicity criteria, it is difficult to grade the rash appropriately, as this rash will never affect 100% of the body -- it only affects, in general, one third of the skin. We have to probably modify toxicity criteria to have a better definition of the intensity or severity of the rash. There is no question that further studies are required to understand the etiology and to develop rational therapies for these side effects. Survival by Grade of Rash in Trials of Erlotinib
Does inhibition of EGFR-associated rash correlate with response/survival? I have shown some data for response indication of erlotinib. Let's look at the survival data. I think there are more and more studies reporting a positive correlation between the occurrence of rash and the survival, and it is not only for erlotinib, but also for some of the monoclonal antibodies. We also have data for some of the other TK inhibitors.
Maybe the most impressive results were obtained in our non-small cell lung cancer study. These are survival data on those 57 patients. There is a very statistically significant difference between the survival of individuals who have a grade 1 rash and no rash, and certainly between those who had grade 2/3 rash and those with no rash. The horizontal axis is the median survival in days.
This was also true in the head and neck phase II study with erlotinib and in the ovarian study with erlotinib. This shows the median survival in days of the patients who did not have any rash and those who had grade 1 or grade 2. There is a doubling in survival between grade 1 and grade 2 in the head and neck study. The doubling in survival in the ovarian study is between no rash and grade 2. In any case, the same trends -- maybe not as impressive as in the non-small cell lung cancer study -- but still very significant.
This graph shows the survival for the erlotinib studies, all 3 studies. The main difference, when you pool the patients, is between the survival of patients who had grade 1 rash and those who had no rash, and it is about a 2-fold difference again. Survival by Grade of Rash With Other Agents
What happens with the other agents? For gefitinib we have limited data presented. For cetuximab, there is a clear correlation between rash and survival. We have no data for CI-1033. There are very few data for ABX-EGF, and there are no data at this point for EMB72000, the other antibody.
Here are the results of the correlation between rash and survival presented by Saltz at the 2003 American Society of Clinical Oncology (ASCO). It shows 4 trials -- the original Erbitux (cetuximab) plus irinotecan in colorectal cancer; the study of the single agent in colorectal carcinoma; the study of combination cetuximab and cisplatin; and the study in pancreatic carcinoma with gemcitabine -- almost 300 patients. The trend is there all the time; the higher the degree of rash, the median survival goes up. We also now have about 200 or more patients on the erlotinib. That is a lot of patients where the trend is emerging and with a very high statistical significance.
In terms of gefitinib, there are little data presented. However, there was a study published by Cohen in the Journal of Clinical Oncology -- in head and neck cancer, a phase II study with 52 patients -- where there was a clear correlation between skin toxicity and response, between skin toxicity and progression-free survival, and between skin toxicity and overall survival. There was another study of carboplatin/Taxol (paclitaxel) and gefitinib -- a phase II, a small study -- where there was no correlation, but this combination has not been shown to be superior to carboplatin/paclitaxel alone; so there is no enhanced activity. No correlation has been observed in a phase II study, again quite small, where gefitinib was combined with 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX-4); gefitinib is inactive in colorectal cancer. Of the 3 studies (looking at the information), the only one that is relevant is head and neck cancer, and this is, obviously, an indication where gefitinib has activity; we saw a correlation between rash and survival. There have not been data presented for the Iressa (gefitinib) Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2 studies, and we hope that in the future they will be analyzed and that we will see the data.
What are the clinical implications if there is a rash/survival relationship? The first one is that maybe you are dosing at the maximum tolerated dose (MTD) -- the dose that is the maximum that patients can tolerate -- which could increase the incidence/severity of rash and potentially improve the response and survival of these patients. The other would be to use the rash as a surrogate marker; so that, if we don't see the rash in a patient at a certain dose, we could increase that dose until the patient develops rash -- provided that we can do that and no other toxicities occur. That would be a case where we would use the rash as a tool to maximize the response or the chances for a response and survival.
To answer some of these questions, a phase II study of erlotinib is being proposed and will be started soon. The rationale is that the dose will be escalated in patients with less severe skin toxicity to try to increase response/survival. This will be a single-arm, phase II study starting soon that will take previously treated, stage IIIB/IV non-small cell lung cancer patients. The starting dose will be 150 mg/day, and the dose will be escalated until the patients develop grade 2 or worse toxicities. The primary endpoints will be response and duration and will be analyzed in relation to the grade of rash. Severity of Rash and Pharmacokinetic Parameters
Does the rash correlate with the pharmacokinetic parameters or with the levels that we accomplish in plasma with the exposure of the skin to the drug? We have limited data for that, but I'll show some of the data that are available.
This is in the context of a phase II study of erlotinib in breast cancer where only 1 patient responded out of 50. There was a trend for a higher area under the curve (AUC) when the grade of rash was higher. This shows the average AUC in the patient who had grade 2 or more rash vs grade 1 and 0. These barely make statistical significance, but there is a nice trend here that shows that the higher exposure of the skin to the drug, the higher the incidence of rash.
Here is the relationship between erlotinib exposure, in the same study, and time to onset of rash. The median time to onset of rash in the highest exposure group was 8 days vs 14.5 days. The graph depicts the time to rash with the greatest grade. The more exposed patients get the highest grade of rash about day 12, and the least exposed patients get the highest grade of rash on day 28. So, it seems that dose or exposure AUC would correlate with the severity of rash, as well as with the rapidity by which you develop the rash.
What are the clinical implications of the rash? This pharmacodynamic observation could be the result of a pharmacokinetic variability or some genetic susceptibility factor that predetermines that you are going to develop the rash at a certain dose level. But, it seems that it probably may be overcome just by increasing the dose, if you can do that. Maximizing exposure may increase severity of rash and time to onset, potentially improving clinical outcome.
In conclusion, rash appears -- in most cases -- to be necessary but not sufficient to achieve a clinical response. That is true for erlotinib and cetuximab, and we do not know yet if it is true for the other agents. In particular, with erlotinib, there is a consistent trend between higher grades of rash and increased response/survival. Rash may be, therefore, a valuable tool to improve outcome with erlotinib. Further studies are needed, and I think we also need retrospective analyses of previously completed studies to see if the association between rash and clinical benefit is real. *** POSTED JULY 27, 2004 *** |
