Adam Brufsky, MD, PhD, University of Pittsburgh Comprehensive Breast Cancer Center, Pennsylvania, discusses results from the NALA study in which neratinib combined with capecitabine improved PFS in HER2-positive breast cancer.
My name is Adam Brufsky. I’m a professor of medicine at the University of Pittsburgh. I’m co‑director of a comprehensive breast cancer center and associate chief of the Division of Hematology‑Oncology.
The most important thing here is that we’re looking for drugs that work in third line HER2‑positive breast cancer and beyond. We have Paclitaxel, trastuzumab, pertuzumab first line, and TDM‑1 second line.
Basically, after that, it would have been chemo plus trastuzumab for multiple cycles, maybe lapatinib occasionally. There really wasn’t a lot of other data. Neratinib is an irreversible binder of the HER2 tyrosine kinase that had been tried in a number of clinical trials.
It was definitely equivalent to trastuzumab plus Paclitaxel in an early phase trial, but the important thing is that reduced the incidence of brain metsas a first occurrence in this trial called NEfERT‑T. There was a lot of data, actually, on the combination of neratinib and capecitabine that had been developed over the years so we knew the dose.
That was a development of the NALA trial. NALA basically was a third line HER2 trial comparing neratinib and capecitabine to lapatinib and capecitabine, which was a standard of care for third line therapy and beyond.
Dr. Brufsky: The NALA trial, we took 621 women with HER2‑positive metastatic breast cancer that had been at least through 2 regimens for metastatic disease. About a third of them had had trastuzumab, pertuzumab, as well as TDM‑1.
We randomized them to neratinib and capecitabine or lapatinib and capecitabine, and treated them until progression. What we found in the trial was that the curves tended to separate after about six months. After about the fourth analysis, the fourth set of scans, so that was kind of late.
So, what we call is something called proportional hazards. When we do proportional hazard assumption, we automatically assume that the proportional hazards are the same throughout the trial, but that’s not true.
They really became quite separated after six months. What we did is, we did mean, we didn’t do median survival for progression‑free survival. We did mean progression‑free survival. It was a pre‑specified endpoint.
Basically, the mean progression‑free survival was 8.8 months in the neratinib arms of the trial, versus 6.6. in the lapatinib arms of the trial. That hazard ratio was 0.76, which was statistically significant. The primary endpoint of the trial was that it either had to meet a hazard ratio of significance either in the mean progression‑free survival or in the overall survival.
In the overall survival, there was a mean benefit of about 1.7 months, favoring the neratinib arm, but it was not statistically significant. However, it met its primary endpoint, as required by the FDA, of the hazard ratio of .76 for progression‑free survival.
So, it did meet its primary endpoint, as requested, and will likely get approved by the FDA for this indication based on that. There were other things that happened. The time to symptomatic brain metastasis was reduced, in relative terms, by about probably 30 percent. In absolute terms, by about seven percent.
That meant that it reduced the incidence of progressive brain mets by about seven percent, which was actually quite nice in the trial. The duration of response, if you had neratinib compared to lapatinib, was about 8.5 months, versus about 5.5 months with lapatinib [alone]. Those were all really good in terms of efficacy.
What was nice, and a little bit surprising ‑‑ in a good way, in the toxicity ‑‑ was that while the neratinib had more diarrhea ‑‑ it had about 20 percent grade three diarrhea, which is seven or more stools a day ‑‑ because there was prophylaxis with loperamide, and there was very intensive treatment once the patients developed diarrhea, the median time that women had grade three diarrhea was only four days.
Most of the diarrhea was limited, and really, only in the first cycle. One thing we did do that was commented on in the discussion when someone got up and actually asked questions was that the quality of life for the women, even though they had diarrhea, did not decrease at all.
So that was actually good during the life of the trial. Basically, we’re pleased by these results, and I think that this will actually become a standard of care for the treatment of third line metastatic breast cancer and beyond.
Dr. Brufsky: We’re doing some biomarker analysis of the trial, and getting a sense of subsets, some of these pre‑planned subsets, what their benefit was. We’ll present that at San Antonio. I think that clearly, this is going to become a standard of care at this point.
We also have some studies looking at various ways of mitigating the diarrhea. We have a trial called CONTROL, where people are getting various interventions, such as loperamide, colestipol, or budesonide, which is a steroid. All of these are trying to prevent the diarrhea. Those are a few things that are currently ongoing.
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