You are here: Home: LCU 2 | 2006 : Interview - Herbst, Roy S. Herbst, MD, PhD

Tracks 1-16

Track 1 Introduction Track 2 Incorporation of bevacizumab into adjuvant clinical trials of lung cancer Track 3 ZD6474: A novel dual-receptor tyrosine kinase inhibitor against VEGF and EGFR Track 4 Side-effect profile of ZD6474 Track 5 Development of novel targeted therapies in lung cancer Track 6 Research strategies to identify predictive markers Track 7 Importance of obtaining tissue in current lung cancer clinical trials Track 8 Use of neoadjuvant studies to evaluate therapeutic agents in lung cancer Track 9 Treatment of EGFR inhibitor-associated rash Track 10 Tumor histology and location and risk of bleeding associated with bevacizumab Track 11 Use of bevacizumab in patients with CNS metastases Track 12 Potential rationale for bleeding events associated with bevacizumab Track 13 Potential antitumor effects of bevacizumab on primary and distant metastatic disease Track 14 Use of erlotinib with or without chemotherapy in nonsmokers Track 15 Use of bevacizumab and erlotinib combination Track 16 Ongoing and future research strategies to develop targeted therapies in lung cancer

Select Excerpts from the Interview

Track 3-4

DR LOVE: What are some of the anti-angiogenic agents in development right now that you believe are promising?

DR HERBST: So many different agents are emerging that I liken this period to when the taxanes were first introduced in lung cancer therapy. One of the agents that I think is most promising, or at least will make it to the more advanced stages sooner than others, is a drug called ZD6474. It’s an oral agent, and it shows dual-receptor TKI activity against both the VEGF receptor 2 and the EGFR receptor.

It’s somewhat like a combination bevacizumab and erlotinib in one molecule. It’s reasonably well tolerated, and several trials have already shown promising results (5.1). One trial has evaluated this drug versus gefitinib in a blinded fashion (Natale 2005) and showed a time to progression benefit in favor of ZD6474.

A second trial, which I led with John Haymack, showed that docetaxel with ZD6474 produced an improvement in time to progression versus docetaxel alone (Herbst 2005a). In the second-line lung cancer setting, that combination is about to be evaluated in Phase III trials.

DR LOVE: You said ZD6474 is like a combination of bevacizumab and erlotinib, yet its VEGF mechanism works from the inside rather than the outside of tumor cells, correct?

DR HERBST: It is a different mechanism than bevacizumab. Instead of trapping the ligand, VEGF, thereby preventing activation of the receptor on endothelial cells, these agents are working inside the cell at the level of the tyrosine kinase. If active, these types of agents have the potential for being more convenient, perhaps less expensive, and more active.

The downside would be that any combination molecule might not exhibit the optimal activity against both receptors. So you run the risk that perhaps this becomes a good inhibitor of angiogenesis, but maybe at the doses that are being used it’s a weaker inhibitor of EGFR compared to the scenario in which you use two drugs that each show activity independently for one receptor or the other.

DR LOVE: What are the major toxicities associated with ZD6474?

DR HERBST: The toxicities are mostly related to EGFR inhibition, meaning some rash and mild diarrhea. However, the rash is a bit different than the rash one sees with a pure EGFR inhibitor.

The other issue is that many of these small molecules — and this agent is no exception — produce some asymptomatic prolongation of the cardiac QT interval, which has not been an issue in clinical trials, although followed closely. To my knowledge, no significant toxicity has been associated with that.

Track 10

DR LOVE: What questions do you commonly receive from medical oncologists about the use of bevacizumab?

DR HERBST: Oncologists want to use bevacizumab, but bleeding is of some concern. Right now, oncologists would probably not treat outside of the indications studied during the clinical trial because of the concern for bleeding. But the question often comes up, “Would you treat a patient with a centrally located adenocarcinoma?” We clearly need more data on that subject.

My approach is to discuss it with the patient. You need to follow these patients closely. What is a central lesion? Which lesions are most likely to bleed? I have treated some patients who have large tumors in the chest and I have gotten away with it, but a risk does exist that is probably somewhere in the range of one to two percent.

Track 14

DR LOVE: Would you discuss your approach for NSCLC patients who have never smoked?

DR HERBST: I often receive questions from medical oncologists about the never-smokers and if they should use erlotinib with chemotherapy. I believe that’s a reasonable approach; I’ve used it several times myself. For patients who have never smoked, our collaborative group showed a median survival of approximately 22 months versus 10 months for never-smokers who received carboplatin/paclitaxel/erlotinib versus carboplatin/paclitaxel, respectively (Herbst 2005b; [5.2]). The number of never-smokers in the trial was around 110 patients.

Vince Miller is leading a CALGB trial that will include larger numbers of patients to try to confirm this finding. But in a never-smoker with a good performance status — usually zero to one — it’s reasonable to consider administering chemotherapy with erlotinib. Now, if the patient is a never-smoker with marginal performance status, you might not want to administer chemotherapy. This is a group for whom I’ve recommended erlotinib alone.

Track 15

DR LOVE: Can you discuss the combination of bevacizumab and erlotinib for NSCLC?

DR HERBST: I often receive calls from physicians about this combination, not only from clinicians, but also from investigators. It seems as if the combination is being used frequently. When we set out to do these trials, our goal was to pilot the combination of two targeted agents so we could then add chemotherapy in the future.

It always bothered me a little that we were using targeted therapy to reduce side effects with the ultimate goal of adding back all the chemotherapy. Of course, adding chemotherapy became less interesting when the gefitinib studies, including the INTACT studies (Herbst 2004; Giaccone 2004), and the erlotinib studies, including TRIBUTE (Gatzemeier 2004; Miller 2004; Herbst 2005b), didn’t show a benefit when chemotherapy was added to EGFR inhibitors.

In our two-center study (MD Anderson and Vanderbilt), the combination of bevacizumab and erlotinib looked good, with a median survival of 12.6 months in patients who failed at least one platinum-based chemotherapy regimen for recurrent or metastatic disease: All patients had nonsquamous tumors, and all patients were without brain metastases (Herbst 2005c).

Those data made people take note, and now one agent is approved in lung cancer, and survival data for the other are looking good in randomized studies (Sandler 2005). This is a combination that has really taken off.

There is currently a Phase III trial being conducted in the United States that takes patients in the second-line setting and randomly assigns them to bevacizumab with erlotinib versus erlotinib alone (5.3). This combination is also being evaluated in clinical trials as neoadjuvant therapy, adjuvant therapy and maintenance therapy.

I often get calls from physicians in the community to ask how to use this combination. Should they add bevacizumab to erlotinib for someone whose disease might be progressing? Should they use the combination as standard second-line therapy? I try to encourage them to enter the patient on a clinical trial because the only way we’re going to make progress is to test these combinations in a clinical study.

Occasionally, if someone is not a candidate for a study or has had too many prior therapies, then I’ll advise the physician about how we’ve done it and refer them to our paper.

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