HER2+ BC: A Year in Review and Updates from SABCS - Episode 8

Ongoing Role of TDM-1 in Metastatic Breast Cancer

January 29, 2021
Targeted Oncology

Experts in breast oncology discuss their real-world experience with trastuzumab emtansine (T-DM1) for patients with advanced HER2-positive breast cancer.

Hatem Soliman, MD: Let’s discuss the role of some of the ADCs [antibody-drug conjugates] that are evolving in the space of the treatment of metastatic HER2 breast cancer when it refers, particularly with trastuzumab emtansine in advanced disease. What has been your experience with using T-DM1 [trastuzumab emtansine] in terms of the responses that you’ve seen in subsequent lines of therapy for your practice. Maybe you can comment on the resistant patients that you’ve seen, who have come off therapy with shorter DFIs [disease-free intervals].

Andrew Seidman, MD: The drug has been around long enough that we’ve seen the spectrum of possible results. Patients progress directly through the first couple of cycles, and then patients have very durable remissions beyond a year. The patients who are benefiting durably from ado-trastuzumab emtansine who get beyond 6 months, there is an option for dose reductions, primarily either for fatigue or neuropathy. There’s room to make 2 dose reductions.

The KATHERINE data suggested that when you compared CNS [central nervous system] events, there was a signal that CNS events occurred with greater frequency in the trastuzumab emtansine group. That is often the first place where there’s a problem. Not always exclusively, patients can progress simultaneously in the CNS and non-CNS sites, but this raises the issue about whether 1 should be thinking about doing routine screening brain imaging for asymptomatic patients. It is against current ASCO [American Society of Clinical Oncology] guidelines but is still being studied prospectively.

Hatem Soliman, MD: Ian [Krop] had presented data previously looking at outcomes of patients on EMILIA with brain metastases, or that at least had CNS disease on therapy. There was a suggestion that in that setting, where the blood-brain barrier is disrupted with parenchymal metastases in the brain. T-DM1 [trastuzumab emtansine] may still be able to play a role in controlling the disease. Some of these bulkier ADCs may get in there, contrary to what we’ve been told or thought to expect.

Andrew Seidman, MD: There is the potential confounding issue of those patients who may already have had brain metastasis, oligometastasis, where they’ve had stereotactic radiation as their primary modality. There have been a number of reports that trastuzumab emtansine can cause radiation necrosis that can be clinically harmful. You’re not sure whether the lesion is progressing on an MRI. The patient may go back to the OR [operating room] for craniotomy, and sometimes you don’t find a viable disease at the site of SRS [stereotactic radiosurgery], but you find radiation necrosis that’s expansive. That’s something that has been reported with T-DM1 [trastuzumab emtansine] in that setting. But when you think about the history of this drug, the comparator in EMILIA was capecitabine and lapatinib. That was the EMILIA trial. T-DM1, or trastuzumab emtansine, was superior to capecitabine-lapatinib.

You could say that the control arm of EMILIA was a straw man, because it was compared with a regimen that nobody would be thinking about today. Those patients progressing on first line taxane trastuzumab got capecitabine or capecitabine-lapatinib. Not surprisingly, capecitabine-lapatinib was better. However, trastuzumab emtansine is a go-to in the second line.

Hatem Soliman, MD: That plays into the other issue, and we wanted to touch briefly on the studies that may be ongoing with T-DM1 [trastuzumab emtansine], that may impact the prior lines of therapy. This is germane with the adaption of KATHERINE over time for some of these patients, which may have an effect on decision-making around using T-DM1 [trastuzumab emtansine] in the metastatic setting.

Andrew Seidman, MD: Let’s discuss an abstract from ASCO from a Japanese group. This group in Japan did a real-world look at outcomes with trastuzumab emtansine and 325 patients who were getting their T-DM1 [trastuzumab emtansine] as either first, or up to 11th, therapy for their HER2+ metastatic disease. The median was the third regimen, but there were patients getting it as their fourth, fifth, sixth, or up to the 11th line of therapy. The overall response rate in this heterogeneous group was about 23%. The median progression-free survival [PFS] was 5 months; the median overall survival was about 2 years. There is efficacy, even in heavily treated patients. This is not the same population as DESTINY-Breast01, but we might compare this with all the caveats of comparing a collection of patients off-study with a formal study. The response rate and the PFS in DESTINY-Breast01, with trastuzumab deruxtecan, compares favorably with this collection series from a Japanese group.

Hatem Soliman, MD: In looking at our options, we talk about what our potential options are for recurrent metastatic disease that have been treated heavily with our better agents up front. We’re using TH [paclitaxel, trastuzumab], and the adjuvants are using T-DM1 [trastuzumab emtansine] in the adjuvant setting. Disease that’s breaking through, or potentially relapsing after that, does require a way to think about how we incorporate some of our better agents, potentially more active agents, up front. It will be interesting to see how the upcoming DESTINY trial in second line that looks at T-DM1 [trastuzumab emtansine] vs trastuzumab deruxtecan. It could be interesting, not that it’s directly talking to this population, but it’s still something that could really set the stage for some shuffling of the deck chairs in figuring out what we do.

Andrew Seidman, MD: The point is well taken that with KATHERINE we see some trastuzumab emtansine being given in the adjuvant setting for those patients who have residual disease. One hopes we’re getting close to the testicular cancer paradigm where we’re not going to have patients relapsing. We’re going to be so good that our adjuvant and neoadjuvant regimens, that hopefully your question will be moot. Trials like DESTINY-Breast02 and studies moving tucatinib earlier in the HER2CLIMB setting are going to be essential to inform what to do in those circumstances. We’re getting closer for patients with stage I disease, but even stage II breast cancer is going to look more like early-stage germ cell tumor.

Hatem Soliman, MD: The point that was important about what trastuzumab deruxtecan was and what the drug actually is delivering in terms of a payload, is very important. Even though they’re both HER2-targeting agents, the difference is in the payload, the SN-38 vs the emtansine and the mechanism of action.

Andrew Seidman, MD: Intuitively, the fact that SN-38 is a topoisomerase interactive drug and emtansine is an antimicrotubule drug, 1 thinks that not using serial antimicrotubule agents might be better. So taxanes disrupt microtubules in a different manner from vinca alkaloids. Emtansine is more vinca-like in terms of its microtubule effects. Microtubule agents used serially, often lead to adding insult to injury, in terms of neuropathy as well, so we know that some patients coming off neoadjuvant TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] or AC-THP [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab], may end up having prohibitive neuropathy when they get trastuzumab emtansine in the adjuvant setting, causing them to stop treatment early. There are a lot of reasons to think about changing your payload as you go along.

Hatem Soliman, MD: That’s critical, because some of these, particularly the neuropathy, can be dose-limiting toxicities over time that we have to manage to be able to get the most of our treatment options.

Transcript edited for clarity.