Sara A. Hurvitz, MD, reflects on key pivotal trials and recent regulatory decisions that have propelled progress forward in metastatic HER2-positive breast cancer.
The year 2020 saw a myriad of promising studies that resulted in several FDA-approved options for patients with metastatic HER2-positive breast cancer, according to Sara A. Hurvitz, MD, who added that among the most exciting highlights were the data that read out from the phase 2 DESTINY-Breast01 trial (NCT03248492) with fam-trastuzumab deruxtecan-nxki (Enhertu).
Earlier data from the trial, led to the FDA approval of the antibody-drug conjugate in December 2019 in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting.1
Updated results from the study presented during the 2020 San Antonio Breast Cancer Symposium indicated that trastuzumab deruxtecan elicited prolonged, durable responses and overall survival (OS) rates in this patient population.2
With an additional 9.4 months of follow-up, patients who received trastuzumab deruxtecan experienced a median duration of response of 20.8 months. Additionally, the estimated 12-month overall survival (OS) rate was 85% (95% CI, 79-90), while the 18-month estimated OS rate was 74% (95% CI, 67-80). Although the data are still immature, the preliminary median OS was 24.6 months (95% CI, 23.1–not estimable [NE]). Patients experienced a median progression-free survival (PFS) of 19.4 months (95% CI, 14.1 months–NE).
“It's interesting to reflect on the fact that 20 years ago, Dennis J. Slamon, MD, PhD, of the UCLA Jonsson Comprehensive Cancer Center, and his colleagues, published the first-line data with trastuzumab in the metastatic setting; this was the first HER2-targeted agent,” Hurvitz explained. “In the trial, the median OS was about 2 years. It's interesting that we're seeing that in [DESTINY-Breast01] that patients had been treated with a median of 6 prior lines of therapy and achieved an OS of at least 2 years. These are very encouraging data.”
In an interview with OncLive®, Hurvitz, director of the Breast Cancer Clinical Research Program and co-director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, reflected on key pivotal trials and recent regulatory decisions that have propelled progress forward in metastatic HER2-positive breast cancer.
Hurvitz: 2020 was an active year for [drug development in] HER2-positive, metastatic breast cancer. We had  approvals beginning with February 2020 where neratinib [Nerlynx] plus capecitabine was approved by the FDA for HER2-positive metastatic disease in the third-line setting and beyond. We had fam-trastuzumab deruxtecan-nxki approved as a single agent for patients who had been treated with 2 or more prior therapies in the metastatic setting based on the DESTINY-Breast01 study. We also had the FDA approval of tucatinib [Tukysa] in combination with capecitabine and trastuzumab [Herceptin] in April 2020 for use in the second-line setting and beyond, including patients with brain metastases. Most recently, in December 2020, we had the FDA approval of margetuximab-cmkb (Margenza), the fourth agent in the past year.
It really is an exciting time for patients who are diagnosed with metastatic HER2-positive breast cancer [with all of these options].
Sequencing is a trickier question because we don't have a lot of data to inform that type of decision. Right now, we still use taxane trastuzumab/pertuzumab [Perjeta] in the first-line setting based on the CLEOPATRA study. Until a new agent goes head-to-head against this regimen, it will remain the frontline standard.
The second-line standard, based on level 1 evidence, is trastuzumab emtansine (T-DM1; Kadcyla) based on the EMILIA and TH3RESA studies. We do have combination of tucatinib, capecitabine, and trastuzumab available for use in the second-line setting, but it wasn't tested against T-DM1 in the HER2CLIMB trial. As such, I would reserve the use of that regimen for patients who have central nervous system metastases.
One of my colleagues William J. Gradishar, MD, of the Northwestern University Feinberg School of Medicine, once called the third-line setting and beyond the Wild West. I love that analogy because it's very true. We have so many regimens we can use, and sequencing [of these options] hasn't been tested in a randomized clinical trial. [Right now], we sequence based on tolerability, the toxicity profile, and the data that we have relating to the agents. Many of us would use trastuzumab deruxtecan as our third-line agent of choice, but that may be moving up into earlier-line settings as new data accumulate from the phase 3 trials that are ongoing.
Updated results from the DESTINY-Breast01 trial were presented at the 2020 San Antonio Breast Cancer Symposium; we now have around 20 months of follow-up. We do see an even better objective response rate of around 61% and a median PFS that is getting close to around 20 months. If anything, the results have gotten better with longer follow-up. A median OS of around 24 months was reached, but there weren't a lot of events yet recorded. As such, I believe that the OS [data are] going to continue to evolve as more events accumulate.