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EGFR Inhibitors Iressa and Tarceva: A Tale of Two TKIs (Part I)
I haven’t really covered the history or issues of directly comparing the two oral inhibitors of the epidermal growth factor receptor, or EGFR, which are Iressa (gefitinib) and Tarceva (erlotinib). This is really because over the last few years, gefitinib has had disappointing results in some important trials and is no longer readily used or available, while the remarkably similar drug Tarceva has been approved by the US FDA and is a standard treatment for patients with advanced NSCLC that has previously been treated with chemotherapy. So you already know where we are in the story in early 2007. While it appears that Iressa for lung cancer is no longer very relevent for clinical management of lung cancer in the US, several trials of Iressa are still emerging that compare it to chemotherapy, so it’s important to review the similarities and differences of Iressa and Tarceva as we consider whether the effects with Iressa can be generalized to the “class” of EGFR inhibitors.
We’ll step back for a moment to say that the molecular target for both drugs is EGFR, which is expressed on some normal body tissues, including skin (it’s an epidermal growth factor), but it’s also expressed on 40-80% of NSCLC tumors and many other kinds of cancers. In fact, in lab studies using test tube as well as animal models, activating the receptor leads to activities in cancer cells that lead to cancer cell growth and division, as well as decreased likelihood of the cancer cell dying and a higher chance of it invading tissues and spreading elsewhere in the body.
(click to enlarge)
In people, several types of cancers that have high degrees of expression of the protein on the tumor cells have been shown to be more aggressive and be associated with more aggressive behavior and worse survival outcomes. On the other hand, drugs that inhibit EGFR, which can be antibodies that block EGFR on the outside of the cell (such as Erbitux (cetuximab) and Vectabix (panitumumab) or tyrosine kinase inhibitors (such as Iressa and Tarceva) that act on the inside of the cell on the back end of the receptor, block the cancer-promoting effects of an activated EGFR molecule. So Iressa and Tarceva act on the same part of the EGFR molecule.
Direct Comparison of EGFR Inhibitor Therapy vs. Chemo in Previously Treated NSCLC Patients
Although EGFR tyrosine kinase inhibitors and chemotherapy agents have been tested in previously treated patients with advanced NSCLC, and tarceva, alimta, and taxotere are all approved by the US FDA in this setting, we haven’t had studies directly comparing chemo to targeted therapy. However, we’re starting to get the first glimpses of information, including a randomized Phase III trial out of Japan that gave previously treated advanced NSCLC patients either iressa or taxotere. In addition to the results being put out in the public domain on the internet last week (here, but in Japanese only), one of the leading lung cancer experts in Japan, Dr. Nagahiro Saijo from the National Cancer Center Hospital, described the results (in English).
The trial (known as V-15-32), which started back in 2003, was done in several countries but enrolled largely from Japan, and the design is shown here:
(click to enlarge) Continue reading
EGFR Inhibitor Therapy as Maintenance Therapy in Stage III NSCLC: A Cautionary Tale
The oral EGFR inhibitors Iressa and Tarceva both have activity in advanced NSCLC, with proven responses in a minority of patients and improvements in cancer-related symptoms as well. While Iressa ultimately did not prove to have a significant survival advantage over a placebo in previously treated advanced NSCLC patients (ISEL trial abstract here), and is therefore no longer used in the US outside of trials or in patients who have already shown a response, Tarceva did show a significant survival benefit compared to placebo (BR.21 trial abstract here) and is one of our more commonly used agents in previously treated advanced NSCLC.
Patients and physicians have noted that in the advanced/metastatic NSCLC setting, the potential improvements are limited. While some fortunate patients have a very prolonged response or non-progression, the average improvement in survival on the major tarceva trial was two months. If we turn to earlier stage, potentially curable NSCLC, can we add EGFR inhibitors to actually improve the cure rates? The studies thus far have been limited but have at this point mostly highlighted how much we still need to learn about these agents.
Timing EGFR Inhibitors and Chemo: Why I Don’t Give Them Concurrently
Both standard chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) have been approved in NSCLC, and other anti-EGFR agents like erbitux/cetuximab and vectabix/panitumumab are also commercially available for treating other cancers and are being studied in lung cancer. Iressa was previously approved as a single agent in previously treated patients with advanced NSCLC, and Tarceva is now available but approved also as a single agent therapy. However, some oncologists give EGFR inhibitor therapies in combination with standard chemo. I don’t favor that approach, but I think it will be helpful to review the issue and my rationale for avoiding concurrent chemo and EGFR inhibitor therapy, at least until there is some evidence suggesting a benefit of combined therapy.
It’s fair to say that treatment combinations are a key cornerstone of medical oncology. The idea of combining anti-cancer drugs with different mechanisms of action and non-overlapping side effects has been central in our field for decades, and combinations are now standard therapy that often are far superior to single-agent approaches. Targeted therapies like EGFR inhibitors, specifically Iressa and Tarceva initially, generally have very different side effects than chemo and were shown to be active as single agents in the second and third line settings and beyond for chemo-pretretaed patients. So there was a great deal of hope that we could improve clinical outcomes for advanced NSCLC patients by adding Iressa and/or Tarceva to standard chemo doublets in previously untreated patients. There were several clinical trials done to test this idea, and the entire lung cancer community was disappointed to see no benefit for combined chemo and EGFR TKI therapy. Continue reading
Management Approaches for EGFR Inhibitor-Induced Rash
After describing the association of a rash on EGFR inhibitors with overall better outcomes on this class of agents, we can now take a step back and recognize that the rash can be an annoyance at the very least and sometimes a real problem. While there are no established guidelines, both treating physicians and patients have developed experience with the rash over the past few years that we should be able to use to minimize the impact for the majority of patients and reduce the proportion of people who need stop a potentially helpful agent due to this toxicity. Continue reading
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.
Are EGFR Inhibitors Only Useful in Certain Patient Groups?
Since the earliest clinical trials of EGFR inhibitors in NSCLC, certain clinically defined patient subsets became identified as more likely to show a benefit than others. Such studies suggested that women, patients with adenocarcinomas rather than squamous cell carcinomas, Asian patients, and never-smokers compared with current or former smokers were the patients who would do well with EGFR tyrosine kinase inhibitors like gefitinib (Iressa) or erlotinib (Tarceva). Since that time, we have been debating whether these targeted therapies should be used primarily or exclusively in selected populations or whether they should be used in general lung cancer populations. The correlation of rash with better outcomes is another interesting issue that is a big enough topic I’ll discuss it separately in the near future. Since it’s not something you know about before you start treatment, unlike patient sex race or subtype of lung cancer, it’s a different issue.
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