Lapatinib Clinical Trial

DR HUDIS: I’m comfortable with a randomized clinical trial that has one arm containing lapatinib as the only anti-HER2 therapy. The responses to this scenario don’t surprise me. We have an evidence-based practice and we have one of the largest and most consistent experiences ever with trastuzumab as adjuvant treatment, so I think deviating from that in a setting where a patient has a curable disease is a pretty big challenge.

Breast Cancer Update 2006 (8)

DR LISA CAREY: I consider HER2-driven breast cancer, in a biologic sense, as being at least two different groups. The HER2-positive, hormone receptor-negative group is different from the HER2-positive, hormone receptor-positive group. They both benefit from HER2-targeted treatments, but they are different.

In terms of how HER2 functions, we’re obtaining a lot of information from the emerging studies of trastuzumab resistance and the pathways that are important in trastuzumab resistance. The first issue — and I believe lapatinib speaks to this — is whether HER1 is important in acquired HER2 resistance.

The fact that lapatinib shows efficacy in patients with acquired trastuzumab resistance I believe provides a strong suggestion that the HER1 pathway may be implicated in getting around HER2 signaling. Tumor cells are smart, and they figure out ways to go around our therapeutic interventions.

DR JENNY C CHANG: We have a lot of preclinical data about the synergism between lapatinib and trastuzumab. Our group evaluated MCF-7 HER2-overexpressing xenografts and found that with the combination of lapatinib, trastuzumab and endocrine therapy, in ER-positive disease, the tumors all went away. We had almost a 100 percent response rate with the combination of these targeted molecules. That is strong evidence of cross talk between these different pathways and that pan-HER inhibition is probably necessary.

Breast Cancer Update 2007 (4)

DR MARTINE J PICCART-GEBHART: The ALTTO trial will accrue approximately 8,000 women. We wanted to investigate several possible approaches using chemotherapy and several anti-HER2 treatments, including lapatinib or trastuzumab and the sequencing or combination of trastuzumab and lapatinib. The combination of trastuzumab and lapatinib everyone understands because you can achieve maximal inhibition by attacking the receptors on both sides. That should be the better arm, presumably, but the sequential strategy is also important in case the toxicities associated with the combination are problematic.

The sequential arm will use trastuzumab first followed by a rest period and then lapatinib. We have more data with this type of sequence. For practical reasons, we also felt it would be difficult for the patients to start with an oral drug and then after a few months go back to the hospital to receive an intravenous treatment.

This is a worldwide effort, and no standard chemotherapy regimen is accepted throughout the world. Also, we wanted to offer this trial in countries where taxanes are still problematic. So we are not requiring taxanes, but we believe the vast majority of women will receive anthracyclines and taxanes.

At the beginning of the trial, the taxanes will be limited to weekly paclitaxel administered concomitantly with the anti-HER2 treatment for safety reasons. We have safety data for paclitaxel in combination with lapatinib, trastuzumab and the combination. We do not have those data for docetaxel or nab paclitaxel, but we hope to obtain the safety data. If they look good, we will amend the protocol and these other taxanes will also be allowed.

The trial will have two strata. For physicians and patients who choose the strategy of chemotherapy combined with the anti-HER2 therapy, anthracycline-based chemotherapy will be administered first. The selection of a chemotherapy regimen will be open and flexible. For example, it may be four cycles of AC or three cycles of FEC. That is followed by weekly paclitaxel combined with the anti-HER2 treatment.

In the second group, physicians will be able to choose from a list of candidate regimens. They will have to administer the chemotherapy according to the HERA philosophy, by which the chemotherapy is administered first and then patients are randomly assigned to receive biologic therapy, which is not administered in combination with chemotherapy.

In terms of eligibility, the trial is for women up to age 70 with a tumor that is one centimeter or greater in size. A difference in comparison to the previous adjuvant trastuzumab trials is that we will define HER2 positivity according to the recently published ASCO guidelines. Positivity means IHC staining of 3+, but you now need more than 30 percent of the cells stained for the tumor to be considered 3+. FISH positivity is also defined slightly differently than before in that the FISH ratio has to be greater than 2.2.

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