Select Excerpts from the Interview

Track 1

DR LOVE: Can you provide an overview of the tumor mutations that are associated with increased response to EGFR TKIs in non-small cell carcinoma?

DR JOHNSON: We were involved in the discovery of a correlation between genetic changes in the epidermal growth factor receptor (EGFR) and the likelihood of response to treatment with either gefitinib or erlotinib (Lynch 2004; Jackman 2006).

We observed a subgroup of patients who had dramatic, long-lived responses (1.1), and that was unusual in NSCLC. Subsequently, my colleagues Dr Tom Lynch and Dr Lecia Sequist led a trial that prospectively identified EGFR mutations in patients with newly diagnosed, previously untreated NSCLC.

Patients with EGFR mutations were treated with gefitinib. We reported the results for 31 patients, with a response rate of approximately 60 percent and a time to progression of about one year (Sequist 2007). Whether those patients with mutations would have done just as well with chemotherapy remains unknown.

Track 9

DR LOVE: Would you comment on the nonprotocol management of patients with EGFR mutations and phenotypic predictors of response, such as nonsmoking status?

DR JOHNSON: We believe the place to begin to answer that question is in first-line treatment of metastatic disease for patients with previously untreated NSCLC. Trials to answer that question — how patients fare with the EGFR TKIs versus those treated with conventional chemotherapy — will be available within the next two years.

That question may be more difficult to answer in the adjuvant setting.

DR LOVE: What about in the first-line metastatic setting, off protocol?

DR JOHNSON: The agents aren’t approved for first-line therapy, but we have had trials with first-line erlotinib and gefitinib for the past five years in our institution. We’ve considered it when a patient tests mutation-positive and wouldn’t otherwise qualify for a trial.

Tracks 10-12

DR LOVE: What’s your algorithm for the management of metastatic disease in the clinical setting for patients who are not in the EGFR-enriched populations — an average patient, a smoker, et cetera?

DR JOHNSON: We follow the Eastern Cooperative Oncology Group (ECOG) algorithm. For patients with adenocarcinoma without brain metastasis, serious cardiovascular or cerebrovascular problems or clotting, we recommend paclitaxel, carboplatin and bevacizumab.

For patients with SCC, brain metastasis or hemoptysis, we administer paclitaxel and carboplatin. We try to utilize the same drugs off study as we do on study. For patients with a number of serious medical issues, we’ll use a single agent such as vinorelbine.

DR LOVE: What’s been your experience with the regimen of carboplatin/ paclitaxel with bevacizumab, particularly in terms of the side effects and toxicity?

DR JOHNSON: Side effects include hypertension and an increased risk of clotting, bleeding and proteinuria, which are all manageable. We also see an increased risk of deep venous thrombosis and pulmonary emboli.

DR LOVE: How do you approach second-line therapy for patients with NSCLC?

DR JOHNSON: For patients in second-line therapy off study who have been treated with two agents — most commonly carboplatin/paclitaxel in our setting — and have a good response and go off therapy for an extended period, we’ll commonly go back to docetaxel as second-line therapy.

For a patient who shows a mediocre response, we will commonly use erlotinib as the second agent. We often use pemetrexed as the third-line agent for the patients who don’t quite fit into classic clinical response categories.

For almost everybody off study, we use one of the three approved agents for second-line treatment — pemetrexed, docetaxel or erlotinib.

Tracks 18-19

DR LOVE: Which of the new biologic agents show promise and may be coming into the clinic in the near future?

DR JOHNSON: One of the classes of agents I believe will likely find a place is the targeted kinases, such as those that include a VEGF receptor blockade. Sunitinib and sorafenib have been approved for kidney cancer, and a response rate of 10 to 12 percent has been recorded with sunitinib among previously treated patients with NSCLC (Socinski 2006).

The other agent I work with is vandetanib, which when combined with docetaxel reached its primary endpoint of prolonging progression-free survival (Heymach 2006). It is now being tested in a large trial to find out if it increases response rates.

We have also found that a number of patients can be maintained on vandetanib from six months up to two years. We believe that represents a particularly sensitive subset, and we hope to identify what conveys such sensitivity in those particular tumors.

DR LOVE: What is the proposed mechanism of action of vandetanib?

DR JOHNSON: Vandetanib is an inhibitor of the VEGF receptor and the EGFR. It inhibits the VEGF receptor II at a level about five times lower than the EGFR.

When you use a higher dose of vandetanib, 300 milligrams a day, the patients don’t do as well as when you administer a lower dose, 100 milligrams a day, within a randomized Phase II trial. Does that have to do with toxicity, in that if you use a lower dose you can administer it for a longer period of time, or is it that with the lower dose you block the VEGF II without blocking the EGFR? That’s currently under investigation.

DR LOVE: What are the side effects and toxicities of vandetanib?

DR JOHNSON: Rash, diarrhea and, as with many of these agents, prolongation in the QTc interval — the length of time it takes for the heart to repolarize. Thus far, no clinical increased risk of arrhythmia has been recorded. Another effect that can occur is increased sensitivity to the sun. We also see elevation of blood pressure but less proteinuria than with bevacizumab.

In terms of bleeding, randomized Phase II studies have evaluated vandetanib at two different doses with docetaxel versus docetaxel alone (Heymach 2006), and an up-front study has been conducted of vandetanib alone versus vandetanib and paclitaxel/carboplatin or paclitaxel/carboplatin alone (Heymach 2007).

No increased risk of bleeding has been found among those patients, and that includes the subsets of patients with brain metastasis and SCC excluded from the trials with bevacizumab.

Track 22

DR LOVE: Can you discuss the ASCO presentation evaluating prophylactic cranial radiation in small cell lung cancer (Slotman 2007)?

DR JOHNSON: That study observed 286 patients who had extensive-stage small cell lung cancer.

Patients were randomly assigned to one of several different doses of prophylactic cranial radiation. Results showed a threefold reduction in the primary endpoint of cumulative incidence of symptomatic brain metastasis.

Even more impressive was that the risk of dying was reduced by more than 30 percent (1.2).

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