Clinical Utility of the Data from ESMO 2021 in HER2+ Breast Cancer
The panel analyzes the data from DESTINY-Breast03 and DESTINY-Breast01 and how these data will further impact practice.
Sara Hurvitz, MD: Neil, when you have a patient in the second-line setting, what are the end points in clinical trials that compel you to change practice? T-DM1 [trastuzumab emtansine] is supported by overall survival data from the EMILIA trial, but the DESTINY-Breast03 overall survival is not mature. It has a strong trend, but we don’t know if patients receiving crossover therapy as standard of care will have a substantial overall survival benefit. Does that sway you away from using it in the second-line setting, or are these efficacy outcomes acceptable for you to switch?
Neil Iyengar, MD: I look at the overall survival data. As we begin to see our patients with HER2 [human epidermal growth factor receptor 2]–positive disease living longer, we will wait longer for that data. Most of our patients will receive these treatments at some point. I’m looking at the progression-free survival and objective response rate, particularly if someone needs more rapid disease control. The response rate was impressive in the DESTINY-Breast01 and the DESTINY-Breast03 trials, which is important. Quality of life and the safety profile of the drug are important as well, because our patients are living longer and will likely be exposed to all these drugs at some point. Patient selection factors will matter in how we select our agents. Patients may have preferences for regimens that fit better in their lifestyle; it may not just be the data. We’re fortunate to have enough available treatments that we can have these nuanced conversations with our patients.
Sara Hurvitz, MD: Quality of life, the payload of setting—it’s important to keep track of that in these studies where we see results released. It’s not a win if patients aren’t enjoying their lives while their disease is being controlled.
We have an audience question about the drug looked at in DESTINY-Breast01 trials. As a review, T-DXd [trastuzumab deruxtecan] is an antibody-drug conjugate [ADC]. It’s basically trastuzumab, the HER2-targeted monoclonal antibody linked to a chemotherapy payload that targets topoisomerase 1. We’re discussing an ADC. In DESTINY-Breast03, this was compared with a different ADC, T-DM1 [trastuzumab emtansine]. One question arose about hormone receptor coexpressing breast cancers, and in the forest plot of DESTINY-Breast03, none of the subgroups shown had less benefit from T-DXd [trastuzumab deruxtecan]. It’s rare to see a forest plot where every subgroup had benefits from the treatment. The subsets of patients with hormone receptor–positive or hormone receptor–negative breast cancer both seem to benefit. How do you feel about these data, based on the subgroup analysis? Reshma, can you speak about this?
Reshma Mahtani, DO: I share your comments on that forest plot, where you don’t see a differential benefit in ER [estrogen receptor]–positive vs ER-negative HER2+ patients. In the earlier setting, when we used the CLEOPATRA regimen, which many of us after that induction period of chemotherapy dropped the taxane and started hormonal therapy as a maintenance with that HP [trastuzumab, pertuzumab] backbone. There are ongoing trials looking at the benefit of CDK inhibitors on top of that. The PATINA study looked at that approach plus or minus a CDK inhibitor. There’s rationale in considering that approach, but in the setting of the data we looked at, I’d feel comfortable giving an ER+ HER2+ patient trastuzumab deruxtecan, knowing that the ER expression will not differentially affect their benefit.
Sara Hurvitz, MD: V.K., we have a question about early ILD [interstitial lung disease] and whether you suspect ILD to be appropriate to continue T-DXd [trastuzumab deruxtecan] and start steroids, and use the same dose or a reduced dose? Can you address this critical question?
Vijayakrishna Gadi, MD, PhD: This is a toxicity that we don’t have a lot of leeway with; the label and guidance from the company are very clear. If you suspect that, the recommendation is to hold the drug if it’s grade 1. If it’s grade 2, 3, or 4, the recommendation is to discontinue the drug. You’ll have a patient in front of you, and you’ll make the right choice, but for those grade 1 toxicities you may or may not need to start steroids. Hold the drug, let it resolve, and revisit the issue. If the risk-benefit ratio is in favor of restarting, then restart the same dose or lower dose, whichever the guidance is based on what you’re observing. It’s not worth crossing that line with this drug.
Sara Hurvitz, MD: To reiterate, grade 1 is asymptomatic, with just some ground-glass opacities on scan; you must hold even for that. The strict guidance you’re speaking to may underlie why we’re seeing better toxicity in the DESTINY-Breast03, because that was implemented.
This transcript has been edited for clarity.
