A New ADC and The TULIP Trial


Our panel of experts review the latest data on the antibody drug conjugate, trastuzumab duocarmazine.

Sara Hurvitz, MD: We have a question from the audience, what is our preferred second- or third-line therapy in a patient with brain metastasis? Would you use tucatinib [Tukysa] or T-DXd [trastuzumab deruxtecan]? And how do you choose between those?

Vijayakrishna Gadi, MD, PhD: It is different based on each patient. The overall survival data with the intentionality of enrolling patients with brain metastases that were active and untreated on HER2CLIMB, for that patient, I favor the HER2CLIMB regimen, which is a combination of tucatinib, trastuzumab and capecitabine [Xeloda]. You could try to use [trastuzumab] deruxtecan, as it has good control, and with more data it could work in patients with active brain metastases, but currently that’s still an unproven hypothesis.

Sara Hurvitz, MD: Dr Mahtani, what do you think?

Reshma Mahtani, DO: You could argue that in the second-line setting, especially in a patient that doesn’t have a huge amount of brain metastases, you could offer a local therapy and consider the T-DXd regimen as we discussed. I would use tucatinib in that setting because when a patient develops brain mets [metastases] in the second line it’s a sign of what’s to come. Many of these patients don’t do well in the CNS [central nervous system] on subsequent follow up and more brain mets appear. When you have a drug that gets into the CNS, has a high response rate, and has an overall survival benefit it’s hard to ignore that data in that setting. As Dr Gadi mentioned, for some patients the regimen may be difficult. There’s an IV [intravenous] and an oral component, so you’re worried about patients compliance or if they’re overwhelmed with all the pills. It’s a conversation that must be individualized for each person.

Sara Hurvitz, MD: Dr Iyengar, what do you think?

Neil Iyengar, MD: Dr Gadi and Dr Mahtani hit all the high points. To elaborate on Dr Mahtani’s point about the onset of brain mets being a signal for the future, I agree. Once that blood-brain barrier has been disrupted the likelihood of recurrence, new brain mets, or progression of existing stable brain mets becomes an issue for these patients, and potentially life-limiting. An interesting unplanned analysis from HER2CLIMB was presented, and it looked at the time to new brain metastases or death. Patients on the tucatinib-containing arm had prolonged time from randomization of new brain metastasis or death compared to the placebo arm. This is reassuring. I would reach for the tucatinib-based regimen in our patients with brain metastasis.

Sara Hurvitz, MD: As we round up the ESMO [European Society for Medical Oncology Annual Meeting]abstracts, we have another question, the TULIP trial. Dr Gadi, can you go through these data? This poster was overshadowed by the DESTINY-Breast03 [NCT03529110], but it did meet its primary end point.

Vijayakrishna Gadi, MD, PhD: This is a late-breaking abstract number 15. It still has a lot of play from Dr Saura. This is a molecule called trastuzumab duocarmazine versus physician’s choice. This is another antibody-drug conjugate. This is an alkylator, a distinction to T-DM1 [trastuzumab emtansine] where you have a tubular inhibitor. With [trastuzumab] deruxtecan you have a triple one inhibitor. This is a new mechanism of action for the chemotherapy component. Once this drug is internalized and the linker is broken down, it is also a molecule [that] I understand is capable of bystander effects. It kills the cell within, but also theoretically might be able to attack some cells around. It’s similar in terms of its abilities to [trastuzumab] deruxtecan. In this randomized phase 3 study, physician’s choice had several options. Three of them were chemotherapy plus trastuzumab, and one of them was lapatinib [Tykerb] plus capecitabine. Some options is hair loss, but it is not a major component. The chemotherapies were vinorelbine [Navelbine], and eribulin [Halaven], and capecitabine. That's something that people may notice. This is a 2:1randomization, the study population was well-balanced. The study population, was about 10% Asian, which is different compared to what we saw on the DESTINY-03 trial, a predominantly white population.

People had seen an average of 4 or 5 prior lines of therapy at randomization, this is another EMF [electromagnetic field] line trials. Some saw pertuzumab [Perjeta] in 61%, and many saw T-DM1, about 85%. Some patients had seen tucatinib, neratinib [Nerlynx], and [trastuzumab] deruxtecan on this trial. A similar Nth line population, but with some interesting things to mention. The PFS [progression-free survival] was the primary end point and we have data for that, but there was also a hint at looking at OS [overall survival] and other things as well. For the topline data, they had many events for the PFS to be read. We’re looking at 7 months favoring the new molecule. The [trastuzumab] duocarmazine molecule versus physician choice of 4.9 months in this Nth line study, the hazard ratio was 0.64, a 36% improvement, a statistically significant P-value. If you look at the curves, you see each one of those landmark points at 12 months. Going onwards, the lines stay apart, they don’t meet, and they stay stably apart. In terms of OS, it’s not mature yet or not statistically significant, but it tilts in favor towards the new molecule at 20.4 months versus 16.3 months. That may emerge as a positive signal in this Nth line. When you look at response to therapy, it’s not a lot different than what you’re seeing with the physician’s choice chemotherapy.

Overall responses were about 28% in the new molecule versus 30% with the physician’s choice, target lesions responded 70% versus 58%, and the clinical benefit rates—this combination of CRs [complete responses], PRs [partial responses], and stable disease—was 38.5% versus 32%. A hint at more activity, patients had maintained their responses longer and PFS was likely different. Based on that, looking positive for an efficacy signal. The other side of the coin is the toxicity, particularly ocular toxicity. What do you think about that and how we’re going to roll that into our practices? Apart from that, it’s not different from the physician’s choice chemotherapy in terms of toxicity. Few greater than a grade 3 toxicities in terms of meaningful numbers, other than the ocular toxicity, which is a special interest here. That’s 30% of folks with events in the physician’s choice arm versus 78% in the new molecule for ocular toxicity, and the grade 3 rate was 21%. A lot of serious dry eye, and the requirement that we’re going to need [an] ocular oncologist involved in this. Pneumonitis is generally low grade, and grade 3 events were 2.5%, not in the ballpark of where we see [trastuzumab] deruxtecan. It looks promising, but I’m not sure how it will fair in terms of toxicity and FDA approvals.

This transcript has been edited for clarity.

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