Updates in the Treatment of HER2+ and HER2-Low Breast Cancer - Episode 5

Establishing the Role of Neratinib Therapy in Early-Stage HER2+ Breast Cancer

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Expert oncologists share their perspectives on when it would be appropriate to consider neratinib therapy in early-stage HER2+ breast cancer.


Andrew Seidman, MD: In terms of other HER-2 [human epidermal growth factor receptor 2] directed agents in the adjuvant setting, we have just 1 right now, an oral tyrosine kinase inhibitor, neratinib. VK, maybe you can remind us how neratinib is the first drug that was ever approved for early breast cancer before it was approved for metastatic disease. How did that happen, and how is it relevant for today’s practice?

Vijayakrishna Gadi, MD, PhD: Just to overview what that molecule is, it’s a poly kinase inhibitor, but mostly the HER2 family and the EGFR family. It hits those molecules quite well, nanomolar efficiency. In the ExteNET study, patients who were previously treated with a trastuzumab-containing adjuvant therapy regimen, upon completion of that, were invited to be randomized within a 2-year time frame to have ExteNET be delivered for a year, and then they came off it.All the conventional endpoints were monitored. The 2-year data showed a small difference, the 5-year data showed a slightly bigger difference, and that has held up nicely. In that trial, a lot of the benefit that was driving those curves apart was really in the hormone positive subset. What do we do in the hormone positive patients? We also give them estrogen therapy. So this dual targeting concept is starting to emerge, and dual targeting of estrogen in HER2 positive cancers at the same time is showing a benefit. There’s now been a lot of data analysis teasing out more findings from that trial. We do see a delayed onset of brain metastases when patients do emerge with brain metastases. We know also that when patients are starting that therapy within a few months of completing the trastuzumab, that’s when they’re most likely to benefit. And there’s now even a smaller subset showing that patients who don’t achieve a pathologic complete response also seem to derive a lot of benefits. So there’s a lot of interesting pearls. Obviously, these are all exploratory analyses, but that’s the [INAUDIBLE].

Andrew Seidman, MD: We could think of the overall trial results, and then we can look for the less than 1 year, greater than 1 year subset, the node positive, the hormone receptor positive, and there’s some value to that for your higher risk patients. I also was struck by the fact that ExteNET was conducted in the pre-pertuzumab era, and in the era where we didn’t have T-DM1 [trastuzumab emtansine] to consider for the post-neoadjuvant patients. So for me, I’m very highly selective on when I might consider it. I don’t know. Have any of you used it much, and in what context?

Stephanie Graff, MD: I reserve neratinib for sort of stage 3.8, if that’s a thing. I’m pretty selective, and I also pretty exclusively deal with the hormone receptor positive patient population, the co-positive, if you will.

William Gradishar, MD: I would echo that, and in addition, the patient has to be highly motivated. I wanted to make one other comment about the T-DM1 [trastuzumab emtansine] question that you posed, and that is, there was a subset of patients who became HER2 negative after therapy. In that population—and granted it wasn’t a big group, I think it was 70 or 80 patients—the addition of T-DM1 [trastuzumab emtansine] in that group, even though they became HER2 negatives, still conferred a benefit. It does raise the question, were they all HER2 negative or HER2 low?

Andrew Seidman, MD: Right. I think that’s a very good point. I’ve heard physicians say, at the time of definitive surgery, it looks like we got rid of all the HER2 positive cells so I don’t really need to target HER2 anymore. But we’re not on safe ground in doing that at all.

Stephanie Graff, MD: Breast cancer is just very heterogeneous, and it’s important to remember that as we’re deciding our treatment.

Transcript edited for clarity.