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.

Both Iressa and Tarceva emerged in early clinical trials around 2000-2001. Both showed some activity in a few heavily pre-treated patients with NSCLC in the initial Phase I testing to find a safe dose in humans, leading to a lot of buzz/hype about these agents, not just in the cancer community, but also in the business world (Iressa is pictured on the cover of Forbes):

Unfortunatley, it’s much easier for the mass media to hype (irresponsibly) the promise of magic bullets and miracle pills for cancer than for pharmaceutical companies and oncologists to actually deliver that.

Dr. Roman Perez-Soler from Albert Einstein School of Medicine presented some encouraging results in a single-arm trial of Tarceva at our biggest worldwide oncology meeting (ASCO) back in 2001 (final publication abstract here) with primary side effects of rash and diarrhea. Interestingly, Dr. Perez-Soler and his colleagues were the first to note that patients with a rash seemed to do better than the patients who didn't develop a rash, leading those developing tarceva to favor an approach of moving tarceva forward at the maximum tolerated dose (in general) of 150 mg by mouth daily.

We then didn’t hear much about Tarceva for several years, while the large randomized NCI Canada BR.21 trial of Tarceva vs. placebo (described in a prior post, but we'll get to it again in our chronological story here) was being conducted.

In contrast, a couple of important trials came out with Iressa a year later, known as the IDEAL trials (Iressa Dose Evaluation in Advanced Lung Cancer). The IDEAL-1 and IDEAL-2 trials were identical in design, with each enrolling just over 200 previously treated patients with advanced NSCLC who were randomized to receive Iressa at one of two doses previously found to be safe, 250 mg or 500 mg by mouth per day. The only differences between the trials were that IDEAL-1 was run in Japan and Europe primarily and allowed patients with just one or more prior chemo regimens, while IDEAL-2 was run in the US and required patients to have received at least two prior chemotherapy regimens (since taxotere was approved as a survival-improving second-line treatment after initial first-line chemo). Patients continued on one of the two doses of the extremely desirably new drug until the time of progression, as shown here:

Both trials were presented at ASCO in 2002 and subsequently published in prominent journals (IDEAL-1 abstract here, and IDEAL-2 abstract here). The results demonstrated that there was certainly activity of Iressa in previously treated patients with advanced NSCLC. The IDEAL-1 trial showed a higher response rate of around 20%, vs. about 10% in the US-based IDEAL-2, and it wasn’t clear whether this was because the patients on the US-based trial had been treated more extensively, or perhaps this was related to the finding in IDEAL-1 that Japanese patients seemed to do better than other patients. Interestingly, both trials found that there was not an improvement in response rate or survival with an increase from 250 mg to 500 mg per day, but there was an increase in side effects, primarily rash and other skin-related issues, and diarrhea. The results of the trials are summarized in tables below:

Interestingly, while the response rate in the US trial was around 10% and the trial from outside the US was around 20%, both trials found that symptom improvement was seen in around 40% of patients, and this was also not better at the higher dose:

This suggested that you didn’t have to show a significant response to benefit from Iressa. On the other hand, skeptics suggested that the improvement in symptoms could just be from coming off of chemo and receiving the new hot drug everyone wanted, and that many people would feel better if you took them off chemo and just gave them sugar cubes for a few weeks.

At this point, the two companies developing Iressa and Tarceva, AstraZeneca and OSI Pharmaceuticals, took two different directions with their remarkably similar drugs. Looking at the similar activity of Iressa at 250 mg vs. 500 mg in the IDEAL trials, but higher toxicity at the higher dose, AZ focused on the story of treating with the minimum biological dose, hoping to provide a treatment that had activity and very mild side effects. Conversely, OSI noted that more rash may be associated with better results and pushed to maximal tolerated dose, despite greater side effects. And we waited to see which interpretation would be borne out by the clinical trials.

While it was felt that a placebo-controlled large phase III trial to really prove a survival benefit from Iressa was warranted, in May of 2003, after a meeting that featured several patients who had dramatic benefits from Iressa to provide testimonials, the US FDA approved Iressa at 250 mg per day based on the demonstrated activity in terms of responses and symptom improvement. Although the evidence was weaker than the FDA usually requires, they felt that approval was indicated because of the lack of any other real alternatives and the possibility of dramatic results in a minority of patients. However, they did require additional testing to subsequently confirm a survival benefit, but for the next 18 months Iressa became the standard therapy for third-line treatment of lung cancer in the US.

Don’t miss the next exciting installment, in which we’ll review why Tarceva is now the standard EGFR TKI used in the US for lung cancer, and Iressa is relegated to the status of a historical footnote here…