The invited discussant of the post hoc analysis of TROPiCS-02 was Shom Goel, MBBS, PhD, Laboratory Group Leader at the University of Melbourne and a consultant oncologist at the Peter MacCallum Cancer Centre in Australia. Dr. Goel noted there remains much to learn about the HER2-low subset of breast cancer patients and how to optimally care for them, but the field is advancing thanks to studies like TROPiCS-02 and DESTINY-Breast04.
“In TROPiCS-02, we saw a significant improvement in progression-free and overall survival in the overall study population. In the analysis presented by Dr. Marmé, the investigators have used HER2 immunohistochemistry results in an attempt to separate these tumors into HER2-low [IHC 1+ and 2+] vs IHC 0 subgroups. HER2 IHC was available on 92% of tumors, and more than half of these (52%) were classified as HER2-low. This proportion is similar to that seen in the DESTINY-Breast04 trial. A significant number (40%) [in the current analysis] were in the HER2 IHC 0 group, and for this population, we have no randomized data for an antibody-drug conjugate vs standard chemotherapy,” Dr. Goel said.
Shom Goel, MBBS, PhD
Caveats and Uncertainties
He said the findings are informative, albeit with some caveats: “The analysis was not prespecified; HER2 testing was performed locally; and while HER2-low and HER2 IHC 0 are generally described as distinct entities, the line between them is very blurry. Indeed, concordance among pathologists when trying to distinguish these groups is quite low.” With those caveats in mind, the progression-free survival hazard ratios suggest that sacituzumab govitecan is active in both the HER2-low and IHC 0 subgroups.”
The outcomes between these groups diverged with respect to response rates, with a greater difference in objective response rate seen in the HER2-low group (26% vs 12%) than in the IHC 0 group (16% vs 15%). “What does that mean? Is sacituzumab govitecan slightly less active in HER2 IHC 0 disease compared to HER2-low? We simply don’t know.”
“As more and more antibody-drug conjugates enter clinical development, targeting a wide array of cell surface proteins, it is possible we will find ourselves in an increasingly complex situation, trying to classify and reclassify breast cancer into groups based on target expression using imperfect tools that do not have a biological basis,” Dr. Goel said.
Clinical Implications
With two key studies now showing benefit for antibody-drug conjugate in HER2-low tumors, how should clinicians use these findings? Patients in TROPiCS-02 were more heavily pretreated than those in DESTINY-Breast04, making direct comparisons difficult. “I think the best we can do right now is to be pragmatic,” he said.
To this end, the overall survival benefit seen with fam-trastuzumab deruxtecan-nxki (T-DXd) in DESTINY Breast04 (in less heavily pretreated patients) suggests that it is the optimal drug for most patients with “HER2-low” tumors, when given at a similar point in a patient’s treatment course as was done in DESTINY Breast04. Furthermore, it is unknown how active sacituzumab govitecan-hziy will be after treatment with T-DXd, given that these agents utilize topoisomerase-1 inhibitors as payloads. But based on signs of benefit for sacituzumab govitecan over chemotherapy in the HER2 IHC 0 population, he offered, “If sacituzumab govitecan were to be approved in that population, I think it would be a very reasonable choice.”
Randomized data in IHC 0 patients are forthcoming for T-DXd, and they will help to “fully contextualize this analysis,” he added.
DISCLOSURE: Dr. Goel has received personal fees from Eli Lilly, Pfizer, and Novartis.
