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DR HERBST: Clearly, this patient is one of the 10 percent or so of patients who demonstrate response to these TKIs. I would bet, if we looked at her tumor, we would see either an EGFR mutation or FISH overexpression. The concern is how long this response will last.

People develop resistance to these agents, and she needs to be watched closely. I would probably order a scan for her every three or four months and think about adding something else at the first sign of progression.

DR KIM: I am extremely puzzled by this case. The liver toxicity humbles us. Erlotinib was branded, originally, as a more toxic version of gefitinib. Although we know of other inherent differences, it is puzzling to see similarly structured drugs with the lower-dosed drug causing the profound transaminitis and the higher-dosed drug being exceptionally tolerable.

That makes this a very interesting case. It teaches us a lesson that, indeed, these are different drugs, and even though the structural differences are minor, the distinction is not all dose related.

DR LOVE: Roy, what if she progressed objectively on erlotinib and was still clinically stable?

DR HERBST: She’s received the EGFR inhibitors as second-line therapy, so one option if she were to progress would be to use another chemotherapeutic agent.

The agents one would consider would be pemetrexed or docetaxel (Hanna 2004), although I’m partial to the combination of bevacizumab and erlotinib (Herbst 2005a).

We recently published our Phase II experience at MD Anderson and Vanderbilt, in which that combination in second- or later-line therapy had a time to progression close to seven months, with a median survival of more than a year (Herbst 2005a; [1.1]). Those data are currently being confirmed.

At ASCO this year we’ll hear about a large multicenter Phase II randomized trial that was conducted throughout the United States.

An ongoing trial is evaluating bevacizumab with erlotinib versus erlotinib alone in the second-line metastatic setting: the BETA-2 lung trial.

Based on my experience, if no contraindications were present — for example, disease in the brain — I probably would consider adding bevacizumab to the erlotinib if the tumor progresses.

DR LOVE: Are you more inclined to do this because she’s had such a great response to erlotinib?

DR HERBST: Yes, I probably wouldn’t recommend it off study for someone “cold.” If a patient comes in to whom you want to administer the combination of an EGFR inhibitor and an angiogenesis inhibitor, I’m a great proponent of clinical studies. But in this case, when you already have a patient who is responding to erlotinib, I think it would be reasonable to consider adding the angiogenesis inhibitor.

DR SEIGEL: If we didn’t use bevacizumab and we were going to start chemotherapy with a taxane, would you still continue the erlotinib, even if she objectively progressed on it?

DR HERBST: That is a big question that we all grapple with as we see patients who benefit from the EGFR inhibitors. This is a group for which adding chemotherapy might provide a benefit. Certainly, we know that the never-smokers treated with chemotherapy and erlotinib had a wonderful outcome, a median survival of longer than 20 months, but it was a small group of patients (Herbst 2005b).

The problem here is that we might have missed our window. At the point when she’s starting to progress, you have to assume that something has changed in her EGFR axis. The drug might still provide a benefit, but it’s not a benefit in terms of apoptosis. I probably wouldn’t mix the two. I would either add an anti-angiogenic agent or look for clinical trials.

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