Select Excerpts from the Interview

Tracks 2-5, 7

DR LOVE: Can you discuss the mechanism of action of ZD6474 and the trial you presented at ASCO?

DR NATALE: ZD6474 is one of a growing list of multitargeted kinase inhibitors. This is an oral agent that targets vascular endothelial growth factor receptors (VEGFR) 1 and 2. It ranks among one of the most potent inhibitors of the VEGFR kinases. It is also a moderately potent inhibitor of the EGFR tyrosine kinase.

Our objective was to evaluate the effectiveness of ZD6474 in patients with NSCLC. The question was, if ZD6474 is active in lung cancer, is it active because of its EGFR-targeted properties or because of its VEGFR-targeted properties? To answer that question, we designed a randomized, blinded study to compare ZD6474 head to head with gefitinib (Natale 2006; [3.1]).

Patients with NSCLC who had received one or, in a few cases, two prior chemotherapy regimens were eligible. Patients were evaluated at four-week intervals with follow-up CT scans. If evidence of disease progression was found, treatment was stopped. We allowed a four-week period for washout because both drugs have a long half-life, and then treatment was switched while we maintained the blinding. So patients who were first treated with gefitinib were switched to ZD6474 if their cancer progressed, and patients treated with ZD6474 first were then switched to gefitinib.

In the ZD6474 group, the objective response rate was eight percent and the stable disease rate was around 35 percent — a little better than a 40 percent overall benefit rate.

In terms of progression-free survival, the outcome with gefitinib was exactly the same as has been seen in other studies, with a median of a little more than two months. The progression-free survival with ZD6474 was significantly better statistically, at about 11 weeks (Natale 2006; [3.1]). That was the signal we were looking for to tell us whether it would be worthwhile pursuing more costly, larger and more definitive clinical trials.

The crossover part of the study was also important. More than 35 patients in the gefitinib arm made the crossover to ZD6474, and about 30 patients in the ZD6474 arm made the crossover to gefitinib. Crossing over from gefitinib to ZD6474, we had a disease control rate — meaning confirmed stabilization for eight weeks or longer — of around 35 to 40 percent. We would interpret that as meaning that these patients clearly did not have tumors that were sensitive to EGFR inhibition and that their disease stabilization pointed to the VEGFR-targeted properties of ZD6474.

Track 8

DR LOVE: What other studies are currently being conducted with ZD6474?

DR NATALE: At ASCO 2006, another important study was presented combining ZD6474 with docetaxel in the second-line setting (Heymach 2006; [3.1]). We had concerns because in the past, whenever we’ve combined an EGFR inhibitor with chemotherapy, we’ve observed inhibitory effects. Whatever might have been gained by EGFR inhibition was lost because EGFR inhibition slowed the proliferation of the cancer and probably rendered it less chemotherapy sensitive.

In this Phase II trial, patients were randomly assigned to receive docetaxel, combined with placebo, 100 milligrams of ZD6474 or 300 milligrams of ZD6474. The 100-mg dose was probably taking advantage only of ZD6474’s VEGFR inhibitory properties because that dose is probably too low to have any significant EGFR inhibition. The 300-mg dose, however, probably causes some EGFR inhibition.

It is interesting that the results showed that the 100-mg dose was more effective. It had a higher response rate — 26 percent compared to about 10 or 11 percent with docetaxel alone. The 300-mg dose was intermediate between the 100-mg dose and the placebo in terms of progression-free survival, suggesting that once you get some EGFR inhibitory properties at that 300-mg dose, you begin to lose a little bit of what you gained by combining VEGFR inhibitory properties with chemotherapy.

The second reason we believe the 100-mg dose was better is that it was simply less toxic. When you combine a VEGFR-targeted agent — especially an agent that causes skin rash, mild nausea and mild hypertension — with docetaxel, you begin to see an increase in overall toxicity. You also begin to see increased intolerance, especially with respect to fatigue and asthenia, as we saw in our study.

Track 11

DR LOVE: Can you review what we know about the predictors of response to EGFR small-molecule tyrosine kinase inhibitors?

DR NATALE: Patients who have mutations in exon 19 and 21 of the EGFR gene appear to be the subgroup with the best chance of showing a major radiographic response to an EGFR-targeted agent such as erlotinib. Among patients with those mutations, objective responses to gefitinib occur at a rate of around 70 to 80 percent, and they have a median survival of more than a year (Hirsch 2006).

However, only a minority of patients have those types of specific EGFR mutations. In the population of patients with lung cancer as a whole, 12 percent have any mutations, and about half to two thirds of those have specific mutations of exon 19 or 21. Therefore, we’re talking about selecting less than 10 percent of patients to be treated with these agents on the basis of mutations.

Clearly, many other patients can show major radiographic responses or clinical benefits from these drugs that mutations do not predict. Some can be identified by fluorescence in situ hybridization (FISH) analysis of EGFR gene copy number. Upwards of 30 to 35 percent of patients will be so-called FISH-positive, which is predictive of objective responses or some slowing of progression that results in a survival benefit. However, one of the problems with FISH is that many of these patients will not benefit from these agents. So we still don’t have a test that is highly specific and sensitive.

Smoking status remains one of the best criteria you can use at the bedside to enrich the population of patients you select for treatment with an EGFR-targeted agent. In the first-line setting, 12 to 15 percent of patients in North America are never smokers. They smoked fewer than a hundred cigarettes in their lifetime. Some of us believe that the never smokers group can be extended to include patients who smoked less than a pack per day for less than 20 years and stopped smoking 15 or 20 years ago.

Someone who has a limited history of cigarette smoking — stopped smoking 15 or 20 years ago and now presents with lung cancer — has about a 50-50 chance that the cancer is the result of cigarette smoking.

DR LOVE: What fraction would you estimate this group of smokers represents in the first-line setting, in addition to the 10 or 12 percent nonsmokers?

DR NATALE: Probably another 10 percent or so.

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