ONCAlert | Upfront Therapy for mRCC

Practical Advice on Using Neratinib for R/R HER2+ mBC

Targeted Oncology
Published Online:12:43 PM, Fri July 19, 2019

Adam M. Brufsky, MD, PhD: How does this fit in with the treatment of brain metastasis? Neratinib has a number of trials that are actually consistent with the CNS [central nervous system] prevention effect. In the NEfERT-T trial, which is a trial of first-line therapy of neratinib and paclitaxel versus trastuzumab and paclitaxel, the progression-free survival was 12 and a half months in both arms. But the interesting thing is that CNS disease as a site of recurrence, was only 8.3% in the neratinib arm—I think the median follow-up was about 2 years or something like that—versus around 18% to 20% in the trastuzumab arm. So it clearly halved the incidence of CNS metastases, so I think it was very strong. In the NALA trial, as we said, we had a reduction in absolute terms of probably 7% or 8% compared to lapatinib. So that also is consistent.

And finally there was a very nice TBCRC trial, TBCRC 22, where neratinib and capecitabine were given in women with obvious brain metastases, and the response rate was almost 50%. It was around 49%, which was very high. And because of that the NCCN [National Comprehensive Cancer Network] considers that level 2 evidence and does have a recommendation for this combination for the treatment of women with obvious CNS brain metastases. And they could be symptomatic or asymptomatic. So I think that there is a body of evidence that clearly suggests very powerfully that this drug does influence the course of brain metastases a little with advanced HER2-positive breast cancer.

What I generally consider when a woman comes with advanced HER2-positive breast cancer and has been through say THP [docetaxel/trastuzumab/pertuzumab] and then TDM1 [trastuzumab emtansine] is do they have brain metastases or not; the extent of the visceral disease; whether they’re hormone-positive disease or not; and what prior therapies they’ve had. And really, I think the bottom line here is determining what at the end of the day is going to bother the patient the most right now. Is it brain metastases? Is it symptomatic disease? You tailor things one way or the other.

Now drugs like the tyrosine kinase inhibitors like neratinib do have activity with systemic disease, so they are a reasonable option. I think that the way to look at this is, we’ve had lapatinib and capecitabine forever, and this is now an advance over that in that we have an irreversible binder that works to suppress the receptor more. It just goes to the disease and stays there. It goes to the tumor and doesn’t come out. And I think that those are the things that are important to know. When people have brain metastases and I’m thinking about what to do, I think going forward, especially if this does get approved by the FDA as a registrational trial, this will be one of my regimens that I use.

The question is, would I combine neratinib with other agents? It’s a good question. I think that I don’t know the answer to that. I think it’s possible that I would combine it with paclitaxel, there’s evidence in NEfERT-T that it’s a good regimen to be used. But a lot of these women have already had paclitaxel or a taxane, docetaxel, then a particle paclitaxel, whatever before.

So I’m not sure. I think that right now I will stick to neratinib and capecitabine, instead of using say trastuzumab and capecitabine. I think a lot of us would consider using the combo of neratinib, trastuzumab, capecitabine. There’s no evidence for that right now. But again, it really depends on the ratio of systemic versus CNS disease, or non-CNS versus CNS disease.

Transcript edited for clarity.

Adam M. Brufsky, MD, PhD: How does this fit in with the treatment of brain metastasis? Neratinib has a number of trials that are actually consistent with the CNS [central nervous system] prevention effect. In the NEfERT-T trial, which is a trial of first-line therapy of neratinib and paclitaxel versus trastuzumab and paclitaxel, the progression-free survival was 12 and a half months in both arms. But the interesting thing is that CNS disease as a site of recurrence, was only 8.3% in the neratinib arm—I think the median follow-up was about 2 years or something like that—versus around 18% to 20% in the trastuzumab arm. So it clearly halved the incidence of CNS metastases, so I think it was very strong. In the NALA trial, as we said, we had a reduction in absolute terms of probably 7% or 8% compared to lapatinib. So that also is consistent.

And finally there was a very nice TBCRC trial, TBCRC 22, where neratinib and capecitabine were given in women with obvious brain metastases, and the response rate was almost 50%. It was around 49%, which was very high. And because of that the NCCN [National Comprehensive Cancer Network] considers that level 2 evidence and does have a recommendation for this combination for the treatment of women with obvious CNS brain metastases. And they could be symptomatic or asymptomatic. So I think that there is a body of evidence that clearly suggests very powerfully that this drug does influence the course of brain metastases a little with advanced HER2-positive breast cancer.

What I generally consider when a woman comes with advanced HER2-positive breast cancer and has been through say THP [docetaxel/trastuzumab/pertuzumab] and then TDM1 [trastuzumab emtansine] is do they have brain metastases or not; the extent of the visceral disease; whether they’re hormone-positive disease or not; and what prior therapies they’ve had. And really, I think the bottom line here is determining what at the end of the day is going to bother the patient the most right now. Is it brain metastases? Is it symptomatic disease? You tailor things one way or the other.

Now drugs like the tyrosine kinase inhibitors like neratinib do have activity with systemic disease, so they are a reasonable option. I think that the way to look at this is, we’ve had lapatinib and capecitabine forever, and this is now an advance over that in that we have an irreversible binder that works to suppress the receptor more. It just goes to the disease and stays there. It goes to the tumor and doesn’t come out. And I think that those are the things that are important to know. When people have brain metastases and I’m thinking about what to do, I think going forward, especially if this does get approved by the FDA as a registrational trial, this will be one of my regimens that I use.

The question is, would I combine neratinib with other agents? It’s a good question. I think that I don’t know the answer to that. I think it’s possible that I would combine it with paclitaxel, there’s evidence in NEfERT-T that it’s a good regimen to be used. But a lot of these women have already had paclitaxel or a taxane, docetaxel, then a particle paclitaxel, whatever before.

So I’m not sure. I think that right now I will stick to neratinib and capecitabine, instead of using say trastuzumab and capecitabine. I think a lot of us would consider using the combo of neratinib, trastuzumab, capecitabine. There’s no evidence for that right now. But again, it really depends on the ratio of systemic versus CNS disease, or non-CNS versus CNS disease.

Transcript edited for clarity.
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