Treatments for Relapsed/Refractory HER2+ Breast Cancer

Ian Krop, MD, PhD:For patients with metastatic HER2+ breast cancer, we have clear standards of care now based on good clinical trial data for the first- and second-line therapy. For patients with first-line disease—patients who have not received therapy for their metastatic HER2+ disease—we have data from the CLEOPATRA trial, which randomized patients to docetaxel and trastuzumab with either pertuzumab or placebo. That study clearly showed that the dual-blockade approach, the addition of pertuzumab to trastuzumab and chemotherapy, was associated with substantial increases in progression-free survival and a market increase in overall survival—16 months’ improvement in overall survival.

Adding pertuzumab to that regimen does increase toxicity. It’s mostly increased diarrhea and rash, but these were generally manageable toxicities. So in the face of a very large improvement in outcome and a modest increase in toxicity, I think it’s very clear that this taxane—trastuzumab-pertuzumab—regimen should be the standard of care.

In the trial they used docetaxel. I think there are other phase II trials that have shown good benefit using either paclitaxel weekly or even vinorelbine as a backbone with trastuzumab and pertuzumab. I think those are worth considering as well if you are concerned about the potential toxicities of the docetaxel.

For patients who have second-line disease who progress on a trastuzumab-pertuzumab regimen, we have data from the EMILIA trial that looked at patients who had progressed on the trastuzumab regimen and these patients were randomized to either T-DM1 [ado-trastuzumab emtansine] as a single agent or the combination of capecitabine or lapatinib, which was a standard of care at that time for second-line disease.

In that trial also there was a clear difference. T-DM1 [ado-trastuzumab emtansine] was superior, again, both in terms of progression-free survival and overall survival. In this case the investigational arm, the T-DM1 [ado-trastuzumab emtansine] arm, was also less toxic than capecitabine-lapatinib. Again, there was very clear improvement in benefit, and in this case there was actually a reduction in toxicity with use of T-DM1 [ado-trastuzumab emtansine], so I think it’s a no-brainer that this regimen of T-DM1 [ado-trastuzumab emtansine] should be the standard of care second-line therapy.

In the third and later lines of therapy, we actually don’t have a clear standard of care. There has not been a randomized trial in this setting until recently that showed a clear superiority. Basically, I think the recommendations based on the available data are that it’s important to continue the HER2-directed therapy. Either trastuzumab or lapatinib can be used and vary the chemotherapy. So chemotherapy options for patients in third and later line depend a little on what you gave tor the patient in their first line of therapy, but they include agents like vinorelbine, gemcitabine, eribulin. Those are options that are all worth considering. And then capecitabine, which is an oral agent, also has good phase II data combining with trastuzumab.

Using 1 of these agents along with trastuzumab, or the capecitabine-lapatinib regimen, are all good options. There’s probably no clear difference in terms of sequencing, or at least we don’t have good data saying that 1 sequence of drug is better than the other. In practice you’re going to end up using all the different drugs at 1 point or another for most patients. I usually sequence based on patient preference in terms of adverse-effect profile and how often they have to come to the clinic. Drugs like capecitabine and trastuzumab require only every-3-week visits. Capecitabine-lapatinib is oral, so you’re not locked into a given infusion schedule. So those are things to consider. Capecitabine- and vinorelbine-based treatments also don’t cause alopecia, which obviously is something that’s important to some patients.

In select patients, those who are estrogen receptor—positive, you can also consider giving HER2-directed therapy, such as trastuzumab, with endocrine therapy; an aromatase inhibitor and fulvestrant are good options for some patients.

Transcript edited for clarity.