Dato-DXd Shows Promise as a More Tolerable ADC in HER2-Negative mBC

Igor Makhlin, MD

Assistant Professor of Medicine (Hematology-Oncology)

Hospital of the University of Pennsylvania

Philadelphia, PA

DISCUSSION QUESTIONS

Share your perspectives and offer insights on the trial design and outcomes of TROPION-Breast01 (NCT05104866). ​

• How may datopotamab deruxtecan (Dato-DXd) contribute to addressing current unmet needs in the treatment of metastatic breast cancer (mBC)?​
• Which patient subgroups might obtain the greatest clinical benefit from Dato-DXd?​
• Overall, where do you envision Dato-DXd positioning itself along the future treatment trajectory of patients with hormone receptor–positive, HER2-negative (score 0 by immunohistochemistry) or HER2-low mBC?

IGOR MAKHLIN, MD: We saw Dato-DXd had an improvement in progression-free survival [PFS] from 4.9 months [with chemotherapy] to 6.9 months.¹ It was a modest improvement like we've seen with sacituzumab govitecan [Trodelvy] and an objective response rate increasing from 22.9% [with chemotherapy] to 36.4% [with Dato-DXd], so it had an improved objective response rate as well. It did have less adverse events [AEs] and specifically less high-grade AEs.

I think importantly, what we're seeing is that there was much less neutropenia with Dato-DXd compared with standard chemotherapy. There was 31% grade 3 or higher for standard chemotherapy vs 1% for Dato-DXd. But the unique toxicities they noted were 22% all-grade ocular toxicity vs 8% for chemotherapy, and then also some mucositis and stomatitis. For drug-related interstitial lung disease, we saw the rate was low, mainly grade 1 or 2. There was 3% all-grade pneumonitis and 1% grade 3 or higher, so it's lower than trastuzumab deruxtecan [T-DXd; Enhertu].^1,2

This drug is not yet approved, but I suspect we may see an approval at some point in 2024. How would this impact how you think of it and specifically, would this impact whether you think about sacituzumab vs datopotamab? How do you think about this in terms of the toolbox with antibody-drug conjugates [ADCs]?

ALEXANDER BARSOUK, MD: It looks like comparable activity to sacituzumab, but fewer AEs in terms of bone marrow suppression and cytopenias^.1,3 So it could be a better, tolerable drug. It’s difficult to say if it's more effective or not, but it's targeting approximately the same patient population and could be better tolerated.

MALEK SAFA, MD: I think the data are great and it gives our patients another option. The question, will be when somebody progresses on 1 ADC, what is the mechanism of that resistance and how we sequence these different combinations of targets and cytotoxic drugs?

MAKHLIN: I think that's the million-dollar question. Has anybody had experience sequencing in the present? Have you sequenced sacituzumab after T-DXd or vice versa, and have you noted responses?

I've inherited a couple of patients from a colleague who had tried it and unfortunately did not see responses. That was mostly sacituzumab after T-DXd.

We had a poster spotlight on sequencing ADCs, 1 after the other or with some intervening chemotherapy at San Antonio [Breast Cancer Symposium in 2023], which showed regardless of what you start out with, the first ADC being sacituzumab or T-DXd, the second ADC for most patients was not very effective.⁴ I think the median PFS was 70 days. Before you even get to your next scan, the patients are progressing.

To the point just made, we don't know why [resistance occurs]. We don't know if it's the payload being resisted or if it's the target being downregulated. There's a Translational Breast Cancer Research Consortium study currently being designed to try to answer this question. It's a crossover study where you start with one or the other, and then you cross over…and there are going to be some biopsies to try to figure out the mechanisms. But this is a tough situation.

For Dato-DXd, we don't have survival data just yet. It's not mature yet. Would mature overall survival [OS] data impact your decision, given that we have OS data for sacituzumab but not yet for Dato-DXd? Even if Dato-DXd gets approved on the basis of PFS alone? Would anybody wait for the OS data, or would you just start using it?

SHYAMAL BASTOLA, MD: I think we would probably start using it. Sacituzumab is a good drug, but there are a lot of toxicity issues, especially in a third-line or fourth-line setting with challenging [patient fitness]. If there are preliminary data that there is better tolerance and it is approved, I think it would be used.

MAKHLIN: There are so many different ADCs that are being tested. For those who are local in Pennsylvania, at Penn Medicine we are opening up a trial [ACE-Breast-03 (NCT04829604)]…of a new ADC called ARX788. It's a HER2-targeted ADC, but it's a different payload compared with T-DXd, a tubulin inhibitor. This is for patients who are progressing on T-DXd and have had up to 5 lines of prior therapies for HER2-positive mBC. If anybody has patients who they need to put on after T-DXd…we can screen your patients, but there are plenty of new ADCs that are being tested and hopefully we'll be getting more approvals in the coming few years.

REFERENCES:

1. Bardia A, Jhaveri K, Im S-A, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl_2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015

2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

3. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003

4. Huppert L, Mahtani R, Fisch S, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC). Cancer Res. 2024;84(9_supplement): PS08-04. doi:10.1158/1538-7445.SABCS23-PS08-04