Hope S. Rugo, MD: That's really interesting, Claudine. Could you talk a little bit about the other data we saw at the San Antonio Breast Cancer Symposium in 2019 about the oral tyrosine kinase inhibitor tucatinib?

Claudine J. Isaacs, MD: That was another exciting presentation. Those were the results from the HER2CLIMB study, which were published recently in The New England Journal of Medicine. Tucatinib is a tyrosine kinase inhibitor. It's irreversible, and it targets HER1 [human epidermal growth factor receptor 1] and HER2. This trial was a randomized phase III study, and the key on this is eligibility. In the United States, this looked at the group of patients that we would be thinking of in the third-line setting. All patients had to have had prior trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine], and the randomization in this trial was that all patients got Xeloda [capecitabine] and trastuzumab.

They either got tucatinib with that, it was placebo controlled, or they received a placebo. What they saw in that study were impressive findings looking at comparing what we achieved with the addition of tucatinib in this setting. Probably the highest level thing, 1 of the 2 things that are the most worthwhile end points to retain from this study, is that there was an overall survival benefit again. It was not negligible. It was about a 4.5-month prolongation overall survival for the group of women who got the tucatinib on top of the capecitabine and the trastuzumab in the setting.

The other thing that was really interesting is this trial specifically allowed patients with brain metastases. It actually required patients to have an MRI [magnetic resonance imaging] prior to going on study. Just under half of the patients had brain metastases, and that group got benefit from the addition of tucatinib. I think what's important to note is it's not just the group of patients who had brain metastases who derived benefit. It was both patients who had brain metastases as well as patients who did not have brain metastases. The progression-free survival [PFS] benefit was very similar in both of those groups.

If you looked at PFS overall there was a benefit. If you looked at PFS in patients who had brain metastases and who didn't, there was a very similar degree of benefit, and the same thing for overall survival. I think this is something that we can consider for our patients who have brain metastases, but I think it's a very definitive type of trial in a group of patients where we would really be considering this agent today in the United States in terms of how we practice.

Hope S. Rugo, MD: It’s a really fascinating study, and of course it was great to have the data published at the same time and see the reduced rate. Although people get diarrhea, the rate is much less than others. We saw data at ASCO [American Society for Clinical Society] this last year, in 2019, about the NALA trial and also a trial done in China with pyrotinib and capecitabine, other oral tyrosine kinase inhibitors. Priyanka, can you tell us a little bit about that?

Priyanka Sharma, MD: The NALA trial was also a third-line trial in patients who had received prior 2 lines of therapy and randomized between capecitabine and lapatinib versus neratinib plus capecitabine. Unlike the HER2CLIMB trial, where 100% of patients had received what we would consider traditional first-line and second-line treatment, pertuzumab in first-line and trastuzumab emtansine second-line, in NALA I think it was about 50% who had received trastuzumab emtansine in second-line and much less first-line pertuzumab. There was no difference in median PFS, but per the trial design, which allowed them to do analysis looking at means, if the separation of curves was a little bit later, which is what was seen in the NALA trial, they noted a difference of 2 months in the mean PFS.

Also it was noted that a smaller proportion of patients needed intervention for CNS [central nervous system] disease on the neratinib arm compared to lapatinib arm. They did not put any data in terms of responses in the brain per se, and actually neratinib plus capecitabine was approved last month by the FDA to be used after failure of 2 prior lines of HER2-targeted therapy. The approval doesn't specify which types of prior lines of HER2 therapy needed to be delivered in the first-line and second-line setting. One of the toxicities of this combination is diarrhea, and we've seen that with other trials, with neratinib, especially when you combine with capecitabine.

In spite of anti-diarrhea prophylaxis, patients had significant grade 3 diarrhea; I think 20% to 25% of patients in the neratinib arm had grade 3 diarrhea. This has been one the limiting factors in terms of utilization of this drug, which has been available to us to use in the adjuvant setting. The other trial with pyrotinib came out of China. During the time this trial was conducted, China did not have approval of pertuzumab and just barely got approval of trastuzumab emtansine.

Even though this was a third-line trial, patients hadn't received pertuzumab and trastuzumab emtansine. The addition of pyrotinib to capecitabine did show improvement in progression-free survival, so from that standpoint the trial met its primary end point. The median PFS was prolonged from 4 months versus 11 months in this trial. Again, the caveat was that the competitor arm wouldn't necessarily be considered standard in regions where we have pertuzumab and trastuzumab emtansine available.

Hope S. Rugo, MD: I think this is really interesting because the pyrotinib trial has this huge PFS benefit, more than what we've seen with other oral tyrosine kinase inhibitors, and also a benefit in patients with brain metastases. The key with that trial is that some of the patients hadn't actually ever received trastuzumab so, they were a relatively treatment naïve group of patients who didn't have access to other therapies. Regardless, having additional agents available to patients who don't have access to other therapies in other countries where the drugs are effective is a great thing.

I don't know that pyrotinib will really have a role in what we are looking at right now.

Transcript Edited for Clarity