Experience Helps Guide ILD Prevention/Management With Trastuzumab Deruxtecan in HER2+ Breast Cancer

Clinical trials evaluating fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated that interstitial lung disease (ILD) was a possible toxicity associated with treatment with the antibody-drug conjugate; however, guidelines and increased experience with the use of the agent in real-world practice have helped inform the management of this possible toxicity for these patients. according to Sneha Phadke, DO, MPH.

“Since we've all grown more familiar as clinicians using the trastuzumab deruxtecan and managing patients who have early-grade or low-grade ILD, the chance that the ILD would progress and become very severe or fatal is lower than it was when we didn't have as much experience with the agent,” said Phadke, who presented on the management of HER2-positive/HER2-low breast cancer at an OncLive^® State of the Science Summit™ on breast cancer.

In an interview with OncLive, Phadke expanded on the investigation of trastuzumab deruxtecan as a possible treatment option for patients with HER2-positive breast cancer who have high-risk residual disease following neoadjuvant systemic therapy, discussed several ongoing studies looking at the escalation or de-escalation of therapy for patients with early-stage HER2-positive breast cancer, and highlighted the findings for the subcutaneous formulation of trastuzumab (Herceptin) plus pertuzumab (Perjeta) and hyaluronidase-zzxf (Phesgo). Phadke is a clinical associate professor of Internal Medicine-Hematology, Oncology, and Blood and Marrow Transplantation in the Carver College of Medicine at the University of Iowa in Iowa City.

OncLive: What were the key findings for research evaluating the subcutaneous formulation of trastuzumab/pertuzumab?

Phadke: Within HER2-positive breast cancer, one study I [highlighted] was regarding a subcutaneous formulation of trastuzumab and pertuzumab [with hyaluronidase]. The phase 3 FeDeriCa study [NCT03493854] showed that [subcutaneous trastuzumab/pertuzumab/hyaluronidase plus chemotherapy] seemed to be equivalent in terms of efficacy [vs intravenous (IV) trastuzumab/pertuzumab plus chemotherapy]. Data showed that the pathologic complete response [pCR] rate was almost identical between the IV and subcutaneous arms [at 60% (95% CI, 53%–66%) and 60% (95% CI, 53%-66%), respectively].¹

Patients actually preferred the subcutaneous version as shown in the [phase 2] PHranceSCa trial [NCT03674112] because of less time in clinic.²

What is the rationale for looking at the escalation or de-escalation of therapy for patients with early-stage HER2-positive disease?

I also reviewed the standard of care for patients who have high-risk HER2-positive disease with residual disease after neoadjuvant therapy. [Data from] the [phase 3] KATHERINE trial [NCT01772472] have been around for several years now, and most [clinicians] are very familiar with using ado-trastuzumab emtansine [Kadcyla; T-DM1] in this situation.

However, I also went over several potential practice-changing studies, where the trials were looking at escalating therapy [by] using more chemotherapy or a different type of chemotherapy, or a different antibody-drug conjugate [ADC] for patients who have higher-risk residual disease.

[Some of these trials] are also looking at de-escalation, where we're using less chemotherapy up front. Then, if a patient achieves a pCR, then we don't need to escalate therapy and can just continue them on their anti-HER2 therapy.

Ongoing trials are looking to bring in trastuzumab deruxtecan as a potential replacement to T-DM1 in the adjuvant. What concerns are there about the risk of ILD in this patient population?

One trial that that specifically looking at trastuzumab deruxtecan vs T-DM1 [for patients with residual invasive HER2-positive breast cancer following neoadjuvant therapy] is the phase 3 DESTINY-Breast05 trial [NCT04622319]. [ILD] is a very legitimate concern. We don't see much pneumonitis or ILD with T-DM1, and we know from prior studies that there were some grade 5 ILD events with trastuzumab deruxtecan. However, the difference is that there are [now] some very specific guidelines to follow as far as surveillance for ILD in patients who are on trastuzumab deruxtecan.

Is there any ongoing or planned research in the HER2-positive breast cancer space at the University of Iowa that you would like to highlight?

We have one study that I went over in my talk is called the phase 3 Astefania trial [NCT04873362]. This is a study looking at escalating therapy for patients who have residual HER2-positive disease by adding the immunotherapy atezolizumab [Tecentriq] to T-DM1, then comparing that to the standard of care of T-DM1 alone. Patients need to have residual disease with involved lymph nodes after completing neoadjuvant systemic therapy.

Patients who have high-risk residual disease after neoadjuvant systemic therapy will be randomized to one of those 2 arms, and we have that study ongoing at the University of Iowa.

References

1. Tan AR, Im SA, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. doi:10.1016/S1470-2045(20)30536-2
2. O'Shaughnessy J, Sousa S, Cruz J, et al. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study. Eur J Cancer. 2021;152:223-232. doi:10.1016/j.ejca.2021.03.047