Trastuzumab Deruxtecan Continues to Reshape HER2+ Breast Cancer Treatment Paradigm

Lubna Chaudhary, MD, MS

The phase 3 DESTINY-Breast02 (NCT03523585), DESTINY-Beast03 (NCT03529110), and DESTINY-Beast04 (NCT03734029) trials evaluating fam-trastuzumab deruxtecan-nxki (Enhertu) helped reshape the treatment paradigm for patients with advanced HER2-positive or HER2-low breast cancer, and additional research could help identify other subgroups of patients who could benefit from treatment with the antibody-drug conjugate (ADC), according to Lubna Chaudhary, MD, MS.

“Right now, we are using [trastuzumab deruxtecan] for our patients with advanced HER2-positive or HER2-low [disease]. There are some data [showing] that trastuzumab deruxtecan is effective in patients whose disease would be called HER2–ultra-low, which is essentially immunohistochemistry [IHC] 0. That needs to be teased out a bit,” Chaudhary explained. “If we have efficacy of this drug in any HER2 expression, then these categories of ultra low vs low vs positive would not matter. It would just be used in all comers. I do feel that needs to be teased out a bit more.”

In an interview with OncLive^®, Chaudhary, an associate professor of medicine, hematology, and oncology, at the Medical College of Wisconsin, in Milwaukee, discussed how findings from the various DESTINY-Breast trials affected the treatment landscape in HER2-positive breast cancer and the trials’ impact on the treatment arena, and expanded on the evolving treatment landscape for patients with HER2-positive breast cancer and the importance of staying updated on new drugs and clinical trials.

OncLive: Could you expand on how the findings from DESTINY-Breast03 affected the HER2-positive breast cancer treatment landscape?

Chaudhary: DESTINY-Breast03 was the practice-changing study that looked at randomization between trastuzumab deruxtecan vs ado-trastuzumab emtansine [Kadcyla; T-DM1] in patients with HER2-positive breast cancer, and that [study] set the stage for using trastuzumab deruxtecan as a second-line [treatment].

DESTINY-Breast03 was a randomized phase 3 clinical trial in patients with advanced HER2-positive metastatic breast cancer. At that time, prior to the results of the study and the approval of trastuzumab deruxtecan, T-DM1 was the standard second-line drug of choice for these patients. It's important to note key attributes of trastuzumab deruxtecan vs T-DM1. Both drugs are ADCs, but the payload and the antibody-to-payload ratio are different.

Trastuzumab deruxtecan is much more potent, and the efficacy has been much more significant compared with other drugs. In DESTINY-Breast03, progression-free survival [PFS] was significantly improved with the trastuzumab deruxtecan arm compared with T-DM1. We also had an overall survival [OS] benefit [with trastuzumab deruxtecan]. [Findings from DESTINY-Breast03] then led to the approval of trastuzumab deruxtecan in the second-line setting.1 That became the standard of care [in the second-line setting] and was practice changing.

How has DESTINY-Breast02 affected the treatment armamentarium for this population?

Another study we discussed was DESTINY-Breast02, which was a very important study because even though we now use trastuzumab deruxtecan as our second-line [standard of care], we still have patients with advanced metastatic HER2-positive disease who have been treated with T-DM1 or other drugs in their second-line setting. DESTINY-Breast02 answered the specific question [for] patients with metastatic HER2-positive cancer [who had] prior treatment of T-DM1: What would be their response and PFS with trastuzumab deruxtecan compared with treatment of physician’s choice?

These patients were randomly assigned to trastuzumab deruxtecan vs treatment of physician’s choice. In this trial, we saw a significant improvement in PFS in the trastuzumab deruxtecan arm with a median PFS of [17.8] months compared with 6.9 months with treatment of physician’s choice.2 It was reassuring to see that despite use of a prior ADC with T-DM1, these patients still responded very well to another ADC in trastuzumab deruxtecan because of the difference in the mechanistic details of the drug. In addition to PFS, we also had significant OS data on this trial. This was very reassuring to see, and [findings from this trial] gave us a good option of using trastuzumab deruxtecan in the post–T-DM1 setting.

What has the emergence of the HER2-low classification meant for the breast cancer space?

We also talked about a very important study in the HER2-low space, which is a relatively new subtype. [HER2-low] is not an IHC 3+ by routine assays; rather, HER2-low is defined as IHC 1+ or 2+ [without] fluorescence in situ hybridization [FISH] amplification. Within that group of patients [with advanced HER2-low breast cancer], DESTINY-Breast04 was a very important landmark and practice-changing study where patients who received 1 to 2 prior lines of chemotherapy were randomly assigned to trastuzumab deruxtecan vs treatment of physician's choice of chemotherapy [consisting of] capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel [Abraxane].

In this study, we saw a significant improvement in PFS in the overall cohort, which included patients with hormone receptor [HR]–positive and HR-negative [disease]. We looked at the HR-positive group because this trial primarily had HR-positive patients. Overall, there was a significant improvement in PFS and OS in the trastuzumab deruxtecan arm.

We also touched on an important point regarding what we call triple-negative disease, meaning HR-negative and HER2-low patients. Although the number of [these] patients in the study was small, the exploratory analysis in this particular study group still showed a significant improvement in PFS and OS.

How do HER2-low breast cancer treatment strategies differ based on disease stage, such as early stage vs metastatic?

Currently, the HER2-low subtype is more important in the metastatic setting because of drug approvals. However, in the early-phase setting, the practice and the choice of medications is driven by HR status. Patients [with early-stage] HR-positive and HER2-negative/HER2-low [disease] would be treated similar to patients with estrogen receptor–positive disease. Patients who are HR-negative, regardless of whether they're HER2-zero or HER2-low, the field has not yet moved to a point where HER2-low in early-phase setting is an important point to consider when making treatment decisions. However, in the metastatic setting, that's certainly an important thing to consider at this point because of the approval of trastuzumab deruxtecan [for previously treated patients with advanced HER2-low breast cancer].

Are there any challenges of accurately classifying patients with HER2-low disease?

I don't think it's a big challenge because it is an IHC-based test; however, I would acknowledge that there is a possibility of some variability when it comes to pathologists because it is an IHC-based test, so some potential differences can exist.

Overall, there are clear guidelines that if there's less than 10% protein expression on IHC, that is considered IHC 0. If there is some expression, then it's IHC 1+, and if there is around 50% expression, then it's IHC 2+ and gets stratified by FISH testing. If it's greater than 10%, that should be considered 2+, but that's where some variability can exist. However, because this testing is IHC-based, most of our pathologists have good experience in assessing these tumors.

What unmet needs still need to be addressed for patients with HER2-positive or HER2-low breast cancer?

An important question is the efficacy of trastuzumab deruxtecan in patients with any HER2 expression. It is a good drug, and as long as we have an insight of managing the potential gastrointestinal and lung adverse effects, it is a very effective drug that has shown good outcomes.

In our patients with advanced HER2-positive breast cancer, the landscape has definitely changed in the last year or 2. After first-line treatment with trastuzumab [Herceptin], pertuzumab [Perjeta], and taxane-based chemotherapy, our second-line drug of choice at this time is trastuzumab deruxtecan. Our third-line [treatment] can vary depending on [a patient’s] disease burden and central nervous system concerns, and that's when we can go to either T-DM1 or a tucatinib [Tukysa], trastuzumab, and capecitabine combination.

The other important point to discuss is the concerns around ILD and some of the AEs associated with trastuzumab deruxtecan. As long as those patients are being monitored and we have good guidelines for managing ILD and other AEs, which we do at this point, the comfort [for using trastuzumab deruxtecan] will improve, and this drug will be used when it's indicated.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed October 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer
2. André F, Hee Park Y, Kim SB, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;401(10390):1773-1785. doi:10.1016/S0140-6736(23)00725-0