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The Iressa/Tarceva Saga, Part II
Iressa was approved by the US FDA in May of 2003 as a third-line therapy, and for the next 18 months it was the only EGFR inhibitor on the market. At the ASCO conference a year later, Frances Shepherd, from the Princess Margaret Hospital in Toronto and chair of the Lung Cancer Committee for the NCI-Canada, first presented the positive results of the BR.21 trial randomizing patients in a 2:1 fashion to either Tarceva or a placebo as second- or third-line treatment for NSCLC; this was subsequently published in the New England Journal of Medicine (abstract here). I’ve summarized the trial and the demonstrated survival benefit in a prior post. So we came out of that meeting knowing that at least one EGFR inhibitor had a proven significant benefit, and while Iressa was the only EGFR TKI on the market, it continued to be prescribed and generally presumed to have similar benefit, given that the two drugs had the same mechanism of action, very similar side effect profile, and shared characteristics for patient populations who seemed to demonstrate the most impressive responses, such as Asians and patients with adenocarcinomas, especially BAC. I also gave an oral presentation confirming responses, some dramatic and long-lasting, for Iressa in BAC, at that ASCO meeting in 2004 (subsequently published, abstract here).
For a little more than six months, we expected the approval of Tarceva based on the proven benefit, and we saw similar characteristics with Iressa. Most of us in the field considered the two drugs to be like Coke and Pepsi, with some mild distinctions, but more similar than different. We were waiting on a trial of Iressa against placebo, but until November of 2004, Iressa was the only commercially available option, so there wasn’t much of a question of which drug to prescribe. People began to switch with Tarceva’s approval, but the big shocker came in December of 2004, when the first announcement of the ISEL (for Iressa Survival Evalaution in Lung Cancer ) trial was released, indicating that there was no significant survival benefit of Iressa compared to a placebo (abstract here).
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Shortly after that, the FDA no longer allows new prescriptions of Iressa, but patients who aren’t progressing can stay on it, and it’s also in other clinical trials. It continues to be widely used outside of the US, especially in Asia, and we’ll talk about why. Continue reading
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.
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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
Duration of Second-Line Therapy: A Data-Free Zone
In contrast to the guidelines that exist for treating advanced lung cancer in the first-line setting for 4-6 cycles, there are really just practice patterns and good judgment to guide decisions of how long to treat in the second-line therapy. First, this is a relatively new question. As I previously mentioned when describing the history of treatment for advanced lung cancer, ten years ago there was plenty of debate about whether the benefits of treating NSCLC were sufficient to make this a standard of care. Second-line chemo for NSCLC with taxotere was first approved by the US FDA in 2000, and topotecan in 1998 for previously treated (and sensitive disease) ED-SCLC. So these are new issues. Continue reading
Single-Agent Zactima/ZD6474 in Advanced NSCLC
As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I’ll focus on the research that gave it as a single agent and where it has led us in terms of current trials.
As I mentioned in my previous post, an early phase I trial just trying to establish an optimal dose showed some activity zactima as a single-agent, as 4 of 9 patients with NSCLC in a Japanese trial showed significant tumor shrinkage on zactima. From there, Dr. Ron Natale at Cedars-Sinai Medical Center in Los Angeles led a randomized phase II trial (abstract here) that compared zactima as a single agent at the higher dose of 300 mg by mouth per day, pretty close to the maximal feasible dose, to iressa at 250 mg by mouth daily. The trial was designed to allow cross-over to the other drug after patients experienced either progression or problematic side effects. So the design was as shown here:
(click to enlarge) Continue reading
Zactima (ZD6474) in NSCLC: Part I
In prior posts I’ve described the idea of combining targeted agents like Tarceva and Avastin, but there are also some single agents that inhibit multiple targets within cancer cells. I’ve described sorafenib/nexavar in a prior post. Today I’ll focus on another multi-targeted agent, known previously as ZD6474, and with a marketing name of Zactima. Similar to the combination of avastin and tarceva, this single oral drug is anti-angiogenic and also blocks EGFR. Although less well studied, it also blocks a protein called RET and can inhibit cell proliferation that way.
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To be more specific, whether Zactima has anti-EGFR activity depends on the dose: it is primarily an anti-angiogenic drug at lower doses, such as 100 mg per day. At higher doses starting around 300 mg, it inhibits EGFR as well. Continue reading
Single-Agent Erbitux Studies in NSCLC
Yesterday I reviewed a series of studies of the EGFR monoclonal antibody cetixumab, or Erbitux, combined with chemotherapy. Overall, these trials are modestly encouraging, without what I would consider to be a potential antagonistic effect when chemo and EGFR tyrosine kinase inhibitors (TKIs) like Iressa or Tarceva. However, we still don’t have studies big enough to establish any role for erbitux. Today, I’ll cover the very limited experience of single-agent Erbitux in advanced NSCLC. Continue reading
EGFR Monoclonal Antibody Therapy in NSCLC: A Focus on Erbitux
Most of the discussion with about inhibiting the EGFR axis in lung cancer has focused on the orally available tyrosine kinase inhibitors (TKIs) that work inside the cells. However, another way to inhibit the cells is by giving an IV “monoclonal antibody” which is a protein that attaches to the outside of the cell at the EGFR target and can block activity. A figure of the two approaches is shown here, with the antibody circled in red:
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Cetuximab, or erbitux, is by far the most studied in cancer. This agent, you may recall, is the one that Martha Stewart was indicted over:
It’s now approved in colon cancer and also in head and neck cancer, but it’s been the subject of much less research in lung cancer than the EGFR TKIs like Iressa and Tarceva. Continue reading
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
Targeted Therapy for Selected Populations in NSCLC
In my last post, I described the somewhat disappointing results for tarceva compared with chemotherapy in a trial of unselected advanced NSCLC patients with a marginal performance status. However, EGFR tyrosine kinase inhibitors like iressa and tarceva were developed as targeted therapies, so perhaps they might prove to be more effective if used selectively, in a targeted population. That targeting might be based on clinical characteristics like using it in never-smokers or bronchioloalveolar carcinoma (BAC), or it might be based on molecular markers like mutations in the EGFR gene or overexpression of the number of copies of the EGFR gene, as determined by fluorescence in situ hybridization, also known as EGFR FISH testing. All of these methods have been employed in early but very promising studies of iressa or tarceva in selected populations. Continue reading
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