Evolving Role of Trastuzumab Deruxtecan in HER2+/HER2-Low mBC


Sarah A. Hurvitz, MD: Currently, DS-8201 [trastuzumab deruxtecan] is not available anywhere in any country. However, it is undergoing regulatory evaluation in the United States, and the word is that we might have it available in early 2020 for our patients. In terms of where it will be approved, in what disease setting, clearly only HER2-positive metastatic breast cancer. And it’s not totally clear what line of therapy. I don’t think it would be approved in the frontline setting. I don’t think we have data to support its use yet in the second-line setting in place of T-DM1 [trastuzumab emtansine]. There is an ongoing phase III trial that will evaluate whether it is going to be able to replace T-DM1. But I do think people are probably going to move it up and use it in the third-line setting and beyond. The activity level that was seen with this drug in the DESTINY-Breast01 study was pretty extraordinary, so I don’t think we’re going to wait till sixth, seventh, or eighth line. I think third line is probably where people are going to have a good comfort level.

William J. Gradishar, MD: There are other trials evaluating the effect of trastuzumab deruxtecan in breast cancer. One of them is looking at a direct comparison to treatment of physician’s choice. So there’s some license for physicians to choose alternative chemotherapy-trastuzumab regimens that could be considered. That will be an important comparison, not unlike when T-DM1 was being developed; it was compared with treatment of physician’s choice.

The other trial is looking at trastuzumab deruxtecan compared with T-DM1 directly, and this would be an obvious effort to move this drug up in the algorithm for how we treat metastatic disease. And very interestingly, we have early data from a smaller trial suggesting that this drug may be effective in individuals who have tumors expressing low levels of HER2. So in that population, which may ultimately create another slice of the pie—not HER2-postive but HER2-low expressing, where we wouldn’t have considered any HER2-directed therapy—this drug is also being evaluated.

It’s interesting too. There’s some speculation that given the interstitial lung disease, possibly because HER2 is expressed on lung tissue, if you have very low levels and you use this drug, maybe it’s affecting the lung tissue in some sort of adverse way. That’s certainly completely speculative at this point. But if it is effectively treating tumor cells with low levels of HER2 expression, it’s conceivable that it may have some bystander effects on other tissues as well.

Traditionally we’ve evaluated the ER [estrogen receptor], PR [progesterone receptor], and HER2 in making decisions regarding what the best treatment options are for metastatic disease. If a patient was HER2-positive, either by IHC [immunohistochemistry] or FISH [fluorescence in situ hybridization], then they’re a candidate for HER2-directed therapy. However, we now have a drug that potentially is working in HER2-low tumors. And this would have been a category not considered in the past, and as such, the sweep of breast cancers that may be potential candidates for this drug is much broader. What we have to think about when we’re evaluating new patients is testing them for HER2, even low expressors, because there may be a new therapeutic option for them.

Transcript Edited for Clarity

Editor’s Note: This interview took place prior to the FDA approval on December 20, 2019 of fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

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