Brufsky Underscores Practicing-Changing Data in HER2+ Metastatic Breast Cancer

The data that emerged from the phase 3 DESTINY-Breast03 trial (NCT03529110) represent a significant advancement in the field of metastatic HER2-positive breast cancer, said Adam M. Brufsky, MD, PhD, FACP, who added that the tripling of progression-free survival (PFS) seen with fam-trastuzumab deruxtecan-nxki (Enhertu) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) will change the natural history of the disease.

“Clearly the DESTINY-Breast03 trial is the most practice-changing work that I’ve seen in HER2-positive disease,” said Brufsky, a professor of medicine at the University of Pittsburgh School of Medicine and associate division chief for the Division of Hematology/Oncology in the Department of Medicine.

Trastuzumab deruxtecan was initially granted accelerated approval from the FDA in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer who received at least 2 prior anti­–HER2-based regimens in the metastatic setting.¹ The regulatory decision was based on findings from the phase 2 DESTINY-Breast01 trial (NCT03248492), in which trastuzumab deruxtecan induced a median PFS of 19.4 months as a third-line treatment for patients with metastatic HER2-positive breast cancer who received prior T-DM1.²

Findings from the DESTINY-Breast03 trial were presented during the 2021 ESMO Congress and subsequently published in the Annals of Oncology.²

The study randomized patients 1:1 to 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 261) or 3.6 mg/kg of T-DM1 every 3 weeks (n = 263). Eligible patients had unresectable or metastatic HER2-positive breast cancer and were previously treated with trastuzumab (Herceptin) and a taxane in the metastatic setting. Notably, patients with clinically stable, treated brain metastases were eligible for enrollment.

At a median follow-up of 15.5 months, the median PFS by blinded independent central review was not reached with trastuzumab deruxtecan (95% CI, 18.5–not evaluable [NE]) vs 6.8 months with T-DM1 (95% CI, 5.6-8.2; HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10^-22). The 12-month PFS rates were 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%), respectively.

Notably, median PFS was significantly improved across all subgroups evaluated, including for patients with brain metastases (n = 114; HR, 0.38; 95% CI, 0.23-0.64).

The median overall survival (OS) was NE in both arms; the 12-month OS rate was 94.1% with trastuzumab deruxtecan (95% CI, 90.3%-96.4%) vs 85.9% with T-DM1 (95% CI, 80.9%-89.7%; HR, 0.56; HR, 0.36-0.86; P = .0072).

Regarding safety, the median treatment duration was 14.3 months with trastuzumab deruxtecan vs 6.9 months with T-DM1. The most common treatment-emergent adverse effect associated with treatment discontinuation with trastuzumab deruxtecan was interstitial lung disease (ILD)/pneumonitis, which occurred in 8.2% of patients treated. No grade 4 or 5 ILD/pneumonitis was observed.

Ultimately, the investigators concluded that the data from the DESTINY-Breast03 trial support trastuzumab deruxtecan as the standard second-line treatment for patients with HER2-positive metastatic breast cancer.

In an interview with OncLive®, Brufsky, who is also the medical director of the Magee-Women’s Cancer Program of UPMC Hillman Cancer Center, associate director for clinical investigations at UPMC Hillman Cancer Center, and codirector of the Comprehensive Breast Cancer Center, discussed the significance of the data from DESTINY-Breast03 with trastuzumab deruxtecan vs T-DM1 for patients with metastatic HER2-positive breast cancer, as well as how the findings set the field up to improve outcomes for patients with brain metastases.

OncLive®: With all the data that emerged from 2021, what stands out to you as being the most practice changing?

Brufsky: The biggest [development] that happened [in metastatic HER2-positive breast cancer] was the DESTINY-Breast03 trial. Clearly, it is a major advance. Those who are doing this work for, in my case, almost 25 years, we recall when the adjuvant trastuzumab [Herceptin] trials were presented in 2005. There was a separation of the curve of close to a 20% absolute difference in early-stage HER2-positive breast cancer from trastuzumab-based regimens and non–trastuzumab-based regimens.

What key findings were presented from the DESTINY-Breast03 trial?

The interesting thing here with DESTINY-Breast03 is that we now have with trastuzumab deruxtecan over a 25-month [median] PFS in the second-line setting vs 6.8 months with T-DM1. That truly is a tripling of PFS, which is clearly going to change the natural history of disease. That is the one thing that has changed practice for most of us in HER2-positive metastatic breast cancer.

Where do you anticipate research will be focused to further improve outcomes for patients with HER2-positive breast cancer?

We saw some very intriguing data from the 2021 San Antonio Breast Cancer Symposium that both trastuzumab deruxtecan and T-DM1 have some intracranial [efficacy]. In fact, brain metastases respond to these agents. [Brain metastases] are the other major [complication] that we worry about in patients with HER2-positive metastatic breast cancer; 50% or more patients will eventually develop brain metastases. If we have something that can treat [our patients with brain metastases], that will be another major advance that may be coming up.

References

1. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 20, 2019. Accessed January 13, 2021. https://bit.ly/3zUGjQM
2. Cortés J, Kim S, Chung W, 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/annonc/annonc741