Breast Cancer - Episode 5
Hope Rugo, MD, FASCO: Ian, can you tell us a little bit more about the treatment options for this patient?
Ian Krop, MD, PhD: Fortunately, for HER2-positive disease we now have a number of large trials that give us a lot of confidence that we’re treating these patients optimally. As far back as 2005, we had large adjuvant trials demonstrating the benefit of HER2-directed therapy with trastuzumab for those patients, and that became the standard. Next, we had the APHINITY trial, which sought to build on the trastuzumab data by assessing the role of pertuzumab in the adjuvant setting.
This was a study that largely looked at HER2-positive, higher-risk patients, and randomized them to a number of different chemotherapy regimens with trastuzumab with pertuzumab, or with placebo. That study initially reported a statistically significant but really modest benefit overall by adding pertuzumab to chemotherapy and trastuzumab. I think we’re better off now that we have updated data that were recorded at San Antonio in 2019. Now we have 6 years of follow-up that confirmed a statistically significant overall benefit but helped us really distinguish who benefits, at least at this time point. Essentially, all of the benefit, at least so far, has been noted in node-positive patients.
Here, the absolute difference in IDFS [invasive disease-free survival] was 4.5%. I think everybody would agree this is a meaningful benefit. There really has been no benefit seen so far in the node-negative patients. The benefit was irrespective of hormone receptor status. It seemed pretty equal for both hormone receptor–positive and hormone receptor–negative HER2-positive patients. Survival was also looked at. It’s in the right direction, favoring pertuzumab. It’s not statistically significant, but these data are still immature.
Adding pertuzumab does come at a cost, both financially and in terms of toxicity. The major toxicity increase with pertuzumab is diarrhea, as we heard from the patient case that I presented. The overall risk is not that high. It's about 10% with grade 3 or higher diarrhea, compared to about 4% without pertuzumab. And essentially, all of that grade 3 toxicity is while the patients are getting chemotherapy. At least in my experience, for most patients it’s manageable with anti-diarrheals like Imodium [loperamide], but for a few it really becomes a problem. In those patients, I think it makes sense to stop pertuzumab rather than compromise their chemotherapy.
We also have data on the use of a very potent tyrosine kinase inhibitor [TKI] called neratinib. This was a study that actually looked at patients who’d already had a year of adjuvant trastuzumab and randomized them to either a year of this oral TKI, neratinib, or a year of placebo. That study did show a statistically significant and probably clinically meaningful benefit with the addition of neratinib, but it was only in the hormone receptor–positive, HER2-positive patients. And, it came at a real cost of toxicity, with a substantial amount of grade 3 or 4 diarrhea—almost 40%.
Studies have shown that can be mitigated, to some extent, with upfront prophylaxis with antidiarrheals, but it’s still something to keep in mind.
We have these 2 adjuvant trials looking at pertuzumab and neratinib, but I think the real game changer came with the KATHERINE trial that looked at patients who had neoadjuvant HER2-directed therapy and chemotherapy and did not have a pathologic response. These are patients who had residual disease after neoadjuvant therapy.
We’ve all known for some time, based on a number of studies, that patients who don’t achieve a pathologic complete response [pCR] do have a higher risk of recurrence compared with those who do have a [pCR]. I think what was important about KATHERINE is that it asked the question, “Can you do something about that inferior outcome by adding a different therapy?” It randomized these patients to T-DM1 [trastuzumab emtansine] for 14 cycles or standard trastuzumab for 14 cycles, and it showed unequivocally that the use of T-DM1 was associated with a substantial improvement in invasive disease-free survival [IDFS]. We saw a hazard ratio of 0.5, and an absolute difference in 3-year IDFS of 11%. So, really a sizeable difference.
It was seen across all the usual subgroups, and the benefit was even seen in patients with pretty minimal residual disease. Based on those data, it’s pretty clear that we should be treating all our moderate- to higher-risk HER2-positive patients with neoadjuvant therapy. Without that neoadjuvant approach, you can’t determine who is going to have a [pCR] and, therefore, who would benefit from adjuvant T-DM1.
I think the data set from KATHERINE led to these guidelines that are now out from a number of groups that recommend all patients with stage II or stage III HER2-positive disease should receive neoadjuvant HER2-directed therapy, and that’s what informed our decision for the patient that I just presented on.
Hope Rugo, MD, FASCO: This is great. I really appreciate that excellent summary about our current options for treatment. I think it’s really interesting how much we’ve learned in the past year or 2 in an area that we thought we’d already learned most about.
Transcript edited for clarity.