Use of ADCs in the Second-Line Treatment of HER2+ mBC


Experts introduce the antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) and discuss clinical trial findings and potential use in special patient populations, such as those with brain metastases.


Sara Hurvitz, MD: Melinda, can you take us through [treatment in the] second-line setting? What is the standard treatment at this point for second line? It has recently become a little clearer I think.

Melinda L. Telli, MD: Yes, it has. [The] data from the DESTINY-Breast03 study [was] updated within the last year, and this was a phase 3 trial to really look at second-line therapy. [The study included] patients who’ve had a taxane and trastuzumab in the metastatic setting. Notably, it did include those patients with early relapse, so a disease-free interval less than 6 months from their curative intent treatment.

Patients were randomized to receive T-DXd [trastuzumab deruxtecan] or T-DM1 [trastuzumab emtansine], which had been for many years our standard second-line treatment. I think what we saw there was just a truly remarkable result. T-DXd is incredibly active in the second-line setting [with] response rates of nearly 80%. The updated median progression-free survival [was] nearly 4 times what was seen with T-DM1, around 7 [months] vs about 28 months. And overall survival at this point looks really good in both arms. [The] median has not yet been reached, but a 2-year landmark, we’re seeing already over 7% improvement in overall survival with T-DXd.

So this has been really a great advance. Patients are certainly living longer because of T-DXd. We have to, of course, worry about the toxicity. In that study, initially it was reported ILD [interstitial lung disease] rate of about 10%. It was updated with the most recent analysis showing that it’s up in any grade a little bit more to 15%. Fortunately, no grade 4 or 5 events, which is great. [It’s] certainly something that we are all becoming more familiar with, trying to monitor patients and keep it safe as we give this new treatment.

Sara Hurvitz, MD: So it’s fairly clear right now, first line is THP [docetaxel, trastuzumab, pertuzumab], second line is T-DXd, but there is this little blur about whether or not we should be using T-DXd in patients with brain metastases. Traditionally, we think of ADCs [antibody-drug conjugates] as being big, bulky molecules that can’t get into the brain. There’s some data emerging that suggests perhaps that preconceived notion [is] not correct. What do you think and what do we know, Debu?

Debu Tripathy, MD: Well, when you look at brain metastases in its entirety, it clearly is a problem for HER2+ metastatic breast cancer patients. [It appears in] 30%, 40%, maybe even more, depending on the circumstances and the details will, at some point, develop brain metastases. I think that in early-stage patients, the brain may be a sanctuary site. We see that, independent of pCR [pathological complete response], brain metastases develop at the same rate, in contrast to systemic metastases. So that is an issue.

We’ve seen that smaller molecules like capecitabine and tyrosine kinase inhibitors do penetrate the blood-brain barrier. There’s early data with capecitabine/lapatinib and capecitabine/neratinib responses, and we have traditionally thought that antibodies don’t, but they do cross the blood-brain barrier, especially if they’re already disrupted. And this was evident in the DESTINY-Breast03 study that enrolled patients, not with active brain metastases, but with treated brain metastases. They did see some actual responses, and also lowering of CNS [central nervous system] events. So I think there is evidence that there’s crossing of the blood-brain barrier.

The HER2CLIMB study was actually designed to enroll patients with brain metastases, and more than half of the patients with brain metastases actually had untreated brain metastases that were asymptomatic. [They saw] an improvement in progression-free and overall survival in that group specifically and also that in the untreated group, there was a response rate of better than 45%. So that was important. And going back to the DESTINY-Breast03, there actually were some responses there too. So maybe some of them could have been active. It’s hard to say with evolutionary changes that brain metastases can undergo.

Finally, there’s the TUXEDO study, which is a small study that looked at T-DXd in untreated brain metastases. Of the numbers analyzed so far, 5 out of 6 of patients who’ve completed treatment and were valuable, so a response rate of 83%. So that’s astounding if it holds up. And of course, those trials are going to be expanded, so we’ll get more information about those.

Sara Hurvitz, MD: Heather, you have a patient who has experienced disease progression on THP, [and also] has systemic metastases and cranial CNS metastases. What’s your go-to second-line regimen? If I can put you on the spot.

Heather McArthur, MD: You can put me on the spot. [For] second-line setting with progression, systemic progression, and CNS progression, for all the reasons that Debu just pointed out and all the available data, I would be comfortable using trastuzumab deruxtecan in that space. That is the standard second-line approach, and it does seem to have some benefits in the CNS and whether it’s the antibody drug conjugate or the release of payload that’s penetrating the CNS. We don’t really know, but certainly there’s activity there. I would be comfortable with that approach. I would also be just as comfortable probably using a HER2CLIMB regimen with tucatinib based on patient preference [and] clinical circumstances. I think it’s really exciting that we can actually have these conversations about different regimens to treat what historically was untreatable disease. So we have a wealth of options at the moment.

Transcript edited for clarity.

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