DESTINY-Breast03 Could Have Long-Lasting Effects on the Treatment Landscape of HER2+ Breast Cancer

Marcela Mazo Canola, MD

After fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated efficacy over ado-trastuzumab emtansine (T-DM1; Kadcyla) in pretreated patients with metastatic HER2-positive breast cancer in the DESTINY-Breast03 trial (NCT03529110), trastuzumab deruxtecan is being considered the new second-line standard of care for this patient population, according to Marcela Mazo Canola, MD, who added the agent also generated encouraging responses in patients with brain metastases.

The phase 3 DESTINY-Breast03 trial examined the safety, efficacy, and antitumor activity of trastuzumab deruxtecan vs T-DM1 in patients with HER2-positive, unresectable or metastatic breast cancer. Trastuzumab deruxtecan produced an improvement in progression-free survival with a hazard ratio of 0.2840.¹

“I’m using [trastuzumab deruxtecan] more and getting myself more familiar with the medication and safety profile. It is important to mention the rates of interstitial lung disease [ILD] that we saw in the phase 2 DESTINY-Breast01 trial [NCT03248492]. Thankfully, DESTINY-Breast03 didn’t have any grade 4 or grade 5 cases [of ILD]. But we still must be mindful of that potential toxicity,” Mazo Canola said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Mazo Canola, a physician at the University of Texas Health, San Antonio, discussed pivotal trials in early-stage and metastatic HER2-positive breast cancer, plus ongoing trials to watch.

OncLive^®: What was the most important update that you gave during your presentation at the IPC meeting?

Mazo Canola: The most important findings that were discussed came from the updated subgroup analysis of the phase 3 KATHERINE study [NCT01772472], presented by Terry P. Mamounas, MD, [of Orlando Health] and colleagues, at [the European Society for Medical Oncology (ESMO) Congress 2021]. [These findings showed] that those patients that were treated with adjuvant T-DM1 after they had [minimal] residual disease [MRD] did not have increased incidence of central nervous system [CNS] events. [These data] also clarified that the overall survival [OS] in that patient population was similar, and using T-DM1 did not increase the risk of having brain metastasis.

How does this updated data set affect your discussions with patients?

[The findings from KATHERINE] allow us to give patients reassurance. Although we know that in HER2-positive disease there is an increased risk of having brain metastases after the patient is treated for early-[stage] HER2-positive breast cancer, it confirms that benefit that we have seen with the use of adjuvant T-DM1. It reassures the patients that even though there was an increase in the cases that had CNS metastases, the time to develop those CNS metastases was longer in patients who received T-DM1.

How have you found yourself incorporating T-DM1 with extended adjuvant therapy, given that past clinical trials with neratinib (Nerlynx) and pertuzumab (Perjeta) were conducted with trastuzumab (Herceptin)?

If patients have MRD, we discuss [the administration of] T-DM1 for 14 more cycles, and if they have high-risk disease, I also discuss the use of neratinib in the adjuvant setting with them as a way to decrease their risk [of recurrence].

I tend to offer [neratinib] more to patients who have higher-risk disease. It’s hard for patients because they have been through a prolonged treatment regimen with neoadjuvant chemotherapy, surgery, and 14 cycles of T-DM1, and then [you consider] putting them into more extended therapy. Some [patients] are receptive to additional therapy, some are not.

Are there any preventive or early prophylactic strategies that you’ve found helpful in managing the adverse effects (AEs) that are associated with extended therapy?

[Informing patients about] what to expect and education are [helpful]. If you prepare the patients for what to expect, how their treatment could go, how many cycles of treatment are expected, and what the potential benefit of those therapies is, it improves compliance and tolerance because the patients are educated. They know when to reach out if they have any problems. [Patients can] avoid visits to the hospitals. Communication with this patient population is key.

What are the implications of the phase 3 FeDeriCa study (NCT03493854)?

FeDeriCa was a noninferiority study comparing the use of intravenous [IV] pertuzumab and trastuzumab with fixed-dose, subcutaneous pertuzumab and trastuzumab, and [results showed] that in patients who are undergoing neoadjuvant chemotherapy with an anthracycline and a taxane, the use of a fixed-dose, subcutaneous injection was noninferior to the IV formulation.

[The results from FeDeriCa] opened the opportunity for those patients to spend less time in the chair [receiving treatment] and decrease the time that they’re investing in an infusion center. That was likely the biggest win of all. I want to note that there was no difference in the safety between the IV presentation and the subcutaneous presentation. [AEs] were equal, [although] there may have been more skin or local irritation with the injection. But [this is] a good option for a certain patient population.

Could you expand on what patient populations will most benefit from fixed-dose, subcutaneous pertuzumab and trastuzumab?

[These are] patients who don’t want to invest a long time in an infusion chair. For example, at [Mays Cancer Center], we serve a population that sometimes needs to travel and drive for a long time. If those patients can leave the infusion clinic quickly, that means that they will get home at an earlier time. Those are the populations that might benefit from having this option, instead of sitting for another 2 or 3 hours in an infusion chair.

Regarding the DESTINY-Breast03 trial, what was impressive about the updated results?

DESTINY-Breast03 investigated the use of trastuzumab deruxtecan in previously treated patients with metastatic [HER2-positive breast cancer]. We’re currently anxiously waiting for the results of the phase 3 DESTINY-Breast05 trial [NCT04622319], which is set to publish in 2027. [DESTINY-Breast05] will compare the use of trastuzumab deruxtecan vs T-DM1 in patients who have residual breast cancer after chemotherapy.

DESTINY-Breast03was first presented at ESMO 2021. We were fortunate enough to hear an update from Sara A. Hurvitz, MD, FACP, [of UCLA], at the 2021 San Antonio Breast Cancer Symposium [SABCS]. Trastuzumab deruxtecan, [an antibody-drug conjugate consisting of a humanized] monoclonal antibody [trastuzumab] payload [covalently linked] to the topoisomerase inhibitor [deruxtecan], has been proven to be very efficacious in patients who have been pretreated for metastatic HER2-positive breast cancer. The trial [examined] whether there was any effectiveness or any improvement in median OS in patients who were pretreated with a taxane or trastuzumab.

[The results] were quite impressive. Those patients [treated with trastuzumab deruxtecan] improved their median OS even more so than what we had seen in the phase 3 CLEOPATRA trial [NCT00567190]. With the data presented at SABCS, we have also seen responses in the brain, which is very important in this patient population, since they have an increased risk of having metastatic disease in the brain.

What is the importance of the phase 2 HER2CLIMB trial (NCT02614794)?

HER2CLIMB initially investigated patients who had metastatic [HER2-positive breast cancer] using trastuzumab and capecitabine [Xeloda] in combination with tucatinib [Tukysa] or placebo. We received the updated results [at SABCS 2020] on patients who had brain metastases, and [this was] impressive information. Even in patients who had active metastatic brain disease, meaning patients who did not have any radiation or surgery, [trastuzumab and capecitabine plus tucatinib showed] quite remarkable activity.

There was a big improvement in median OS in all patient populations with treated and untreated brain metastases. [Notably], half of those patients were alive and well after 2 years of treatment. [These are] impressive results with durable response rates in the brain in this patient population.

There is also a smaller phase 2 trial (NCT03501979) investigating trastuzumab and capecitabine plus tucatinib in patients with leptomeningeal metastases in HER2-positive breast cancer. What is known so far about this study?

We need to get more information about that specific study, but [it is] encouraging information and [offers another potential] therapeutic option for this difficult-to-treat patient population.

Have any of these updated analyses changed how you think about treatment sequencing in the metastatic setting?

The biggest change is that I think of trastuzumab deruxtecan as my next line of therapy in patients who have progressed [on prior therapy]. We’re doing studies to see whether trastuzumab deruxtecan will be our new standard of care for second-line metastatic HER2-positive breast cancer. But based on the results that we have seen in DESTINY-Breast03, that is going to be the case.

Are there any forward-looking studies that you want to mention?

The ones that I’m really looking forward to are the phase 3 DESTINY-Breast02 trial [NCT03523585] and DESTINY-Breast05. [These trials] are going to make a big difference in the survival of our patients who present with early-[stage] HER2-postive breast cancer.

Reference

1. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/j.annonc.2021.08.2087