Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 1

Perioperative Treatment of Early Stage HER2+ Breast Cancer

December 24, 2019

Ian E. Krop, MD, PhD:We’ve been fortunate in the treatment of early phase II—positive breast cancer in that there have been 3 large trials that have helped inform our best management practices. In one of them, the APHINITY trial—which was an adjuvant trial of patients with mostly high-risk HER2-positive early stage disease—they randomized patients to a standard chemotherapy, either anthracycline-based or nonanthracycline-based treatment, with either trastuzumab and pertuzumab or trastuzumab and placebo. This was testing whether the addition of pertuzumab added to the benefits of chemotherapy and trastuzumab.

We just got updated data from this study at the San Antonio Breast Cancer Symposium in 2019. The overall trial showed a small but statistically significant benefit to the addition of pertuzumab in terms of invasive disease-free survival, which was the primary end point of the study. In these updated data, we have more clarity about which patient actually benefits from the addition of pertuzumab. It’s very clear from these data that essentially all the benefit of pertuzumab is in patients with higher-risk disease, specifically those with node-positive cancers. There the added benefit of pertuzumab is becoming quite substantial. In contrast, in patients with lower-risk disease, defined by node-negativity, there essentially was no benefit. Fortunately, those patients do very well, and I think it’s very clear that pertuzumab really does not add in that situation.

We also learned in these updated data that the benefit of pertuzumab was really irrespective of hormone receptor status. The initial trial seemed to suggest that most of the benefit was in ER [estrogen receptor]—negative HER2-positive cancers. But with further follow-up and more estrogen receptor–positive cancers recurring, it’s clear that the benefit is relatively equal between both subtypes. In summary, the addition of pertuzumab is beneficial in patients with node-positive, HER2-positive breast cancer, irrespective of hormone receptor status.

Another trial that we have data for in the adjuvant setting is a trial called ExteNET. This was also looking at a high-risk population. But it was an interesting design in that it looked at patients who had already completed a year of chemotherapy and HER2-directed therapy, essentially a year of trastuzumab. In that population they then randomized patients with a second year of therapy—either neratinib, which is the oral kinase inhibitor, both HER2 and EGFR, or a placebo. What was found in that study was that there was benefit that was statistically significant and clinically meaningful in those patients who received neratinib compared with placebo. In that study the subgroup analysis clearly showed that essentially all the benefit was in estrogen receptor—positive HER2-positive cancers. Neratinib had really no effect in ER-negative HER2 positive cancers.

Neratinib is associated with significant adverse effects, most prominently grade 3 diarrhea, which in that study was approaching 40%. That’s definitely something that needs to be managed. Prophylactic Imodium is recommended basically at the start of therapy. Waiting for patients to develop diarrhea leads to more problems, so Imodium should be started at the same time patients start the neratinib.

Lastly, the other large trial for which we have data was perhaps the most impactful, and that’s the KATHERINE trial. This was a trial that looked at patients with HER2-positive early stage disease who received neoadjuvant therapy. The type of neoadjuvant therapy really wasn’t specified other than it had to contain a taxane and that it included trastuzumab. Most of the patients on that study received some type of standard neoadjuvant therapy, often with an anthracycline, a taxane, and trastuzumab. Only a small percentage of patients had pertuzumab because of when that trial was conducted.

In the patient population that had neoadjuvant therapy, those with residual disease were then randomized in the KATHERINE trial to either a standard of care of 14 cycles of trastuzumab or 14 cycles of T-DM1 [ado-trastuzumab emtansine]. What was found was that those patients who received T-DM1 [ado-trastuzumab emtansine] had essentially 50% less recurrences than those patients who received trastuzumab. That benefit was irrespective of hormone receptor status and irrespective of nodal status. It was really across the board. The benefits were quite consistent.

The only thing that was worth pointing out in terms of population was the type of recurrences that happened. The reduction of recurrences with T-DM1 [ado-trastuzumab emtansine] was seen in both distant recurrences, essentially all types of recurrence, except for those patients with CNS [central nervous system] disease. That was not modified at all with the use of T-DM1 [ado-trastuzumab emtansine]. The rate of recurrence was similar in CNS disease for both, the trastuzumab and T-DM1 [ado-trastuzumab emtansine] arm. So that’s clearly an unmet medical need that we need to think about.

Transcript edited for clarity.