Dato-DXd Reveals Promise as a Extra Tolerable ADC in HER2-Destructive mBC

DISCUSSION QUESTIONS

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

• How might datopotamab deruxtecan (Dato-DXd) contribute to addressing present unmet wants within the remedy of metastatic breast most cancers (mBC)?​
• Which affected person subgroups may get hold of the best medical profit from Dato-DXd?​
• General, the place do you envision Dato-DXd positioning itself alongside the longer term remedy trajectory of sufferers with hormone receptor–constructive, HER2-negative (rating 0 by immunohistochemistry) or HER2-low mBC?

IGOR MAKHLIN, MD: We noticed Dato-DXd had an enchancment in progression-free survival [PFS] from 4.9 months [with chemotherapy] to six.9 months.¹ It was a modest enchancment like we have seen with sacituzumab govitecan [Trodelvy] and an goal response price growing from 22.9% [with chemotherapy] to 36.4% [with Dato-DXd], so it had an improved goal response price as effectively. It did have much less opposed occasions [AEs] and particularly much less high-grade AEs.

I believe importantly, what we’re seeing is that there was a lot much less neutropenia with Dato-DXd in contrast with normal chemotherapy. There was 31% grade 3 or increased for normal chemotherapy vs 1% for Dato-DXd. However the distinctive toxicities they famous had been 22% all-grade ocular toxicity vs 8% for chemotherapy, after which additionally some mucositis and stomatitis. For drug-related interstitial lung illness, we noticed the speed was low, primarily grade 1 or 2. There was 3% all-grade pneumonitis and 1% grade 3 or increased, so it is decrease than trastuzumab deruxtecan [T-DXd; Enhertu].^1,2

This drug is just not but authorised, however I think we might even see an approval in some unspecified time in the future in 2024. How would this impression the way you consider it and particularly, would this impression whether or not you concentrate on sacituzumab vs datopotamab? How do you concentrate on this when it comes to the toolbox with antibody-drug conjugates [ADCs]?

ALEXANDER BARSOUK, MD: It seems like comparable exercise to sacituzumab, however fewer AEs when it comes to bone marrow suppression and cytopenias^.1,3 So it might be a greater, tolerable drug. It’s troublesome to say if it is more practical or not, however it’s focusing on roughly the identical affected person inhabitants and might be higher tolerated.

MALEK SAFA, MD: I believe the info are nice and it provides our sufferers an alternative choice. The query, shall be when someone progresses on 1 ADC, what’s the mechanism of that resistance and the way we sequence these completely different combos of targets and cytotoxic medication?

MAKHLIN: I believe that is the million-dollar query. Has anyone had expertise sequencing within the current? Have you ever sequenced sacituzumab after T-DXd or vice versa, and have you ever famous responses?

I’ve inherited a few sufferers from a colleague who had tried it and sadly didn’t see responses. That was largely sacituzumab after T-DXd.

We had a poster highlight on sequencing ADCs, 1 after the opposite or with some intervening chemotherapy at San Antonio [Breast Cancer Symposium in 2023], which confirmed no matter what you begin out with, the primary ADC being sacituzumab or T-DXd, the second ADC for many sufferers was not very efficient.⁴ I believe the median PFS was 70 days. Earlier than you even get to your subsequent scan, the sufferers are progressing.

To the purpose simply made, we do not know why [resistance occurs]. We do not know if it is the payload being resisted or if it is the goal being downregulated. There is a Translational Breast Most cancers Analysis Consortium examine at present being designed to attempt to reply this query. It is a crossover examine the place you begin with one or the opposite, and then you definately cross over…and there are going to be some biopsies to strive to determine the mechanisms. However this can be a robust state of affairs.

For Dato-DXd, we do not have survival information simply but. It isn’t mature but. Would mature total survival [OS] information impression your choice, on condition that we’ve got OS information for sacituzumab however not but for Dato-DXd? Even when Dato-DXd will get authorised on the idea of PFS alone? Would anyone look ahead to the OS information, or would you simply begin utilizing it?

SHYAMAL BASTOLA, MD: I believe we’d most likely begin utilizing it. Sacituzumab is an effective drug, however there are a variety of toxicity points, particularly in a third-line or fourth-line setting with difficult [patient fitness]. If there are preliminary information that there’s higher tolerance and it’s authorised, I believe it will be used.

MAKHLIN: There are such a lot of completely different ADCs which can be being examined. For many who are native in Pennsylvania, at Penn Drugs we’re opening up a trial [ACE-Breast-03 (NCT04829604)]…of a brand new ADC referred to as ARX788. It is a HER2-targeted ADC, however it’s a distinct payload in contrast with T-DXd, a tubulin inhibitor. That is for sufferers who’re progressing on T-DXd and have had as much as 5 traces of prior therapies for HER2-positive mBC. If anyone has sufferers who they should placed on after T-DXd…we are able to display screen your sufferers, however there are many new ADCs which can be being examined and hopefully we’ll be getting extra approvals within the coming few years.

_References:

_{1. Bardia A, Jhaveri Ok, 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 most cancers (BC): Main outcomes from the randomised part 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 beforehand handled HER2-low superior breast most cancers. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{3. Tolaney SM, Bardia A, Marmé F, et al. Last total survival (OS) evaluation from the part 3 TROPiCS-02 examine of sacituzumab govitecan (SG) in sufferers (pts) with hormone receptor–constructive/HER2-negative (HR+/HER2–) metastatic breast most cancers (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 examine of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in sufferers with HER2-low metastatic breast most cancers (MBC). Most cancers Res. 2024;84(9_supplement): PS08-04. doi:10.1158/1538-7445.SABCS23-PS08-04}