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CD 2, Tracks 20-25

DR LOVE: Chuck, can you review the results from the lapatinib trial you presented at ASCO 2006?

DR GEYER: This was a Phase III trial comparing the approved dose of capecitabine as the control arm to the Phase I combination dose of 2,000 mg/m² of capecitabine per day on days one to 14 of 21 days with 1,250 mg of lapatinib per day continuously. The patient population included women with breast cancer who had received prior anthracycline, taxane and trastuzumab therapy. They were not allowed, however, to have received prior capecitabine (Geyer 2006).

When the Independent Data Monitoring Committee (IDMC) reviewed the data, they recommended early closure of the trial because the boundary had been crossed for superiority. The median time to progression was improved from about 4.5 to 8.5 months. The response rate was also increased from 14 to 22 percent, but it did not meet statistical significance (Geyer 2006).

An interest with lapatinib is the potential impact it might have in reducing CNS events, and this was tracked. Numerically fewer — four versus 11 — CNS relapses were recorded in the lapatinib arm. But too few total events occurred to make any definitive statement (Geyer 2006).

Toxicity was a concern because we saw overlapping toxicity. With the combination, we saw overall increases in diarrhea, hand-foot syndrome and skin rashes but virtually no Grade IV toxicities. The Grade III toxicities weren’t appreciably different. So the concern about additive toxicity with lapatinib and capecitabine wasn’t borne out (Geyer 2006).

Because of the cardiotoxicity issue with HER2 blockade, careful cardiac monitoring was provided. Patients underwent scans every six weeks for the first six months and then every 12 weeks. Conservative criteria were used to define a cardiac event (Geyer 2006).

Patients who had symptomatic heart failure, obviously, would have been considered as having an event. Also patients who had asymptomatic declines with a relative decrease of more than 20 percent from baseline to below normal were considered to have had an event. On the study, four cardiac events occurred with lapatinib/capecitabine and one with capecitabine alone, and all were asymptomatic (Geyer 2006).

DR LOVE: Debu, what is your opinion of lapatinib and where it’s heading?

DR TRIPATHY: It was interesting that this study showed almost a doubling of time to disease progression without a concomitant increase in response rate that was significantly different (Geyer 2006). I believe this is going to be a very important drug in this population of patients.

One can extend this even further and ask whether it will delay time to disease progression in patients with HER2-positive disease as up-front or adjuvant therapy.

DR WOLFF: One question posed after the presentation was whether this study could indirectly be addressing a question we have been unable to answer: Is the continuation of anti-HER2 therapy truly important for the patient whose disease is progressing on first-line anti-HER2 therapy?

The study that could never be done was for patients who were receiving paclitaxel and trastuzumab, and at progression they were randomly assigned to vinorelbine with trastuzumab or vinorelbine alone.

This study essentially asks, for the patient whose disease is progressing on trastuzumab, is switching to another chemotherapy drug but continuing an anti-HER2 therapy — in this case, lapatinib — better than not continuing the targeted therapy?

The answer in this case is yes. How much of this is an effect of lapatinib itself, as a drug that is active in patients whose disease has progressed on trastuzumab, and how much of it is simply a continuation of anti-HER2 therapy?

DR LOVE: Joyce, for a patient who experiences progression after receiving adjuvant trastuzumab, would you reinstitute trastuzumab? How would you factor in lapatinib if it were available?

DR O’SHAUGHNESSY: I haven’t had to cross that bridge yet, but I believe it would depend on the disease-free interval. If it was very brief, I’d be inclined to use lapatinib, but it’s important to find out whether we need trastuzumab to maximize the effectiveness of lapatinib.

If patients have had a decent disease-free interval, they obviously are somewhat resistant to trastuzumab but they still may retain some sensitivity. I believe the randomized trial being conducted of lapatinib alone versus lapatinib with trastuzumab is very important.

DR RUGO: That trial that Dr Geyer presented is interesting because it requires that patients receive two prior chemotherapy regimens and trastuzumab for metastatic disease. It’s not testing what to do if a patient has relapsed within a year of adjuvant therapy.

Another trial is testing the combination of trastuzumab and lapatinib with paclitaxel, but the patients are not allowed to have relapsed on adjuvant trastuzumab. They have to be off it. They are randomly assigned to paclitaxel/trastuzumab with or without lapatinib as first-line therapy.

All these trials are going on now, and we’re not going to have results for a while. Right now we have to finalize the neoadjuvant and adjuvant trial designs, which are incredibly controversial. Opinions vary tremendously.

DR LOVE: Cliff, can you comment on some of the options that are being discussed for the next generation of adjuvant trials for patients with HER2- positive disease?

DR HUDIS: The Aphrodite trial is currently written as one year of trastuzumab, one year of lapatinib, one year of trastuzumab with lapatinib or a sequence of trastuzumab for six months followed by lapatinib for six months. The neo-Aphrodite trial tries to investigate the biology by administering trastuzumab or lapatinib alone or the combination before surgery, following with the remainder of a year of treatment.

In the cooperative groups, the North Central proposal that is currently being worked on is built on the same themes of single-agent lapatinib versus single-agent trastuzumab versus the combination. We have a preoperative proposal matching that, which uses preoperative trastuzumab, lapatinib or the combination along with weekly paclitaxel for a fixed period of time. It provides a chance to observe the pathway markers and markers of resistance.

The big controversy is whether people are brave enough, as those planning the Aphrodite trial appear to be, to commit to a year of lapatinib without any trastuzumab for a patient with HER2-positive, early-stage disease. That’s either brilliant or a leap of faith.

DR GEYER: The NSABP and the CIRG have agreed to work together on our B-31 replacement and their BCIRG 006 replacement study, with the idea of testing chemotherapy/trastuzumab with or without bevacizumab as the question. We are waiting for more information from the pilot data to reach consensus on some of the chemotherapy backbone issues, and we hope to have the study out by the end of the year.

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