William J. Gradishar, MD: Now with respect to other drugs, we’ve already talked about trastuzumab deruxtecan and the significant activity demonstrated in the phase II trial and other trials that are ongoing. There are other antibody-drug conjugates [ADCs] in development. They have different compounds that are linked to the antibody, and the strategy is much the same: to target HER2 [human epidermal growth factor receptor 2] tumor cells and, by the mechanism of how ADCs work, to internalize the cytotoxic drug. There’s also some sense that there may be a bystander effect as well. Even tumors that have relatively low expression of HER2 may be affected by the bystander effect of using these drugs.

Tucatinib we talked about, which in an oral TKI [tyrosine kinase inhibitor], and the HER2CLIMB trial was very impressive. There are other TKIs in development, including pyrotinib, and that was a drug that was talked about in the last year from a trial in Asia. The downside to that drug is that it’s active. It looks in some ways like lapatinib, like neratinib, but it also looks that way with respect to diarrhea, so that’s going to be 1 of the issues with that. My guess is that drug, certainly in the United States, probably isn’t going to go very far.

Neratinib is an interesting drug. It was approved somewhat unusually in the adjuvant setting. Typically, when we see drug approvals, we start in the metastatic disease setting and work our way back to the advanced disease setting. But this drug has a long history and changed hands a few times before it finally settled where it is right now. After the adjuvant data were generated, there was an existing metastatic disease trial called the NALA trial, which had been underway. There are other trials looking in the preoperative setting and a smaller phase II trial that showed truth of principle that neratinib, which is an oral TKI, was active. It was effective even after prior HER2-directed therapy. In the NALA trial, it was patients who had already been exposed to trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine], and the randomization was between capecitabine and lapatinib or capecitabine and neratinib.

These were patients who had gotten what we would view as the best anti-HER2 therapy prior to going on this trial. And capecitabine and lapatinib might have been viewed when this trial was first designed as the next line of therapy based on data. So the comparison was reasonable. It was truly all oral options, because everybody was getting capecitabine. Everybody was getting an oral TKI. And what it demonstrated was that the combination of neratinib and capecitabine was modestly but statistically better than capecitabine and lapatinib. There was an advantage of a couple of months favoring the combination of neratinib and capecitabine. So that is something that the FDA will be considering as it looks for approval of that drug in the third-line setting.

The big issue with neratinib that’s been known since the drug first came on the scene is that it induces diarrhea in a high fraction of patients. Some of the early trials suggested that the fraction of patients experiencing even grade 3 diarrheas was exceedingly high. This was, of course, very worrisome. When you think about the pivotal trial, it was comparing capecitabine with capecitabine and lapatinib, another combination that is not exactly diarrhea-free. There was a lot of concern about how well this would be adopted, how patient-friendly it would be. They recognized this, and they’ve actually developed strategies right from the get-go, as patients go on to neratinib, to start Imodium as well as other potential agents.

In the NALA trial they were able to demonstrate that very few patients, and equal in both arms—only a low percentage—had actually discontinued therapy because of diarrhea. And the fraction of patients who were experiencing grade 3 diarrhea had markedly been reduced. And the number of days where patients were experiencing serious diarrhea had been diminished to the order of about 7. So I think there is a strategy that has been developed that results in markedly less diarrhea than had been seen early on. Nonetheless, it remains a concern among not only patients but also physicians that you have to be on top of this, because if patients start to experience significant diarrhea, they’re not going to want to stay on the drug.

There are other strategies where there have been less data. Bispecific antibodies are targeting more than 1 antigen simultaneously. And those compounds are just starting in clinical trials. But it’s a unique way of approaching the problem, and I think we’ll see more data from those compounds in the next couple of years.

Sara A. Hurvitz, MD: I’m also interested in seeing more data emerge relating to the use of other targeted therapies, including PI3 kinase inhibitors like alpelisib and CDK4/6 inhibitors. There was a study called monarcHER that was presented at ESMO [European Society for Medical Oncology Congress 2019] by Sara Tolaney, showing really exciting efficacy in HER2-positive, hormone receptor—positive metastatic breast cancer with abemaciclib, fulvestrant, and trastuzumab that actually beat chemotherapy and trastuzumab in terms of objective response rate and PFS [progression-free survival]. So I think hitting other pathways is going to be an important way for us to go.

Transcript Edited for Clarity