Mary Anne Fenton, MD, clinical director, Breast Medical Oncology, Rhode Island Hospital, director, Quality, Lifespan Cancer Institute, associate clinical professor, medicine, Warren Alpert Medical School, Brown University, discusses findings from the phase 3 DESTINY-Breast02 trial (NCT03523585) in patients with HER2-positive metastatic breast cancer.

The trial evaluated fam-trastuzumab deruxtecan-nxki (Enhertu) vs treatment of physician's choice in patients with HER2-positive unresectable and/or metastatic breast cancer who received prior treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla). Key eligibility criteria for the study included centrally confirmed HER2-positive disease by immunohistochemistry or in situ hybridization. Physician’s choice of treatment included a combination of capecitabine with either trastuzumab (Herceptin) or lapatinib (Tykerb).

Findings from the primary analysis of the randomized, open-label, multicenter trial presented at the 

 showed that the median progression-free survival (PFS) for patients who received trastuzumab deruxtecan (n = 406) was 17.8 months (95% CI, 14.3-20.8) vs 6.9 months (95% CI, 5.5-8.4) for those given physician’s choice of treatment (n = 202), translating to a 64% reduction in the risk of disease progression or death (HR, 0.3589; 95% CI, 0.2840-0.4535; 

The PFS benefit was observed across all patient subgroups, Fenton says, including patients older or younger than 65 years of age, patients with hormone receptor–positive or ­–negative disease, prior treatment with pertuzumab (Perjeta), visceral disease, and baseline treated brain metastases. There was an early separation in the Kaplan-Meier curves for PFS, indicating that trastuzumab deruxtecan overcame early drug resistance. Additionally, investigators observed a significant change in tumor size. Although no new safety signals were reported with a longer follow-up, early recognition and management of pneumonitis remains important for patients treated with trastuzumab deruxtecan, Fenton concludes.

Videos

Mary Anne Fenton, MD, discusses findings from the phase 3 DESTINY-Breast02 trial in patients with HER2-positive metastatic breast cancer.

Dr Fenton on Findings from the DESTINY-Breast02 Trial in HER2+ Breast Cancer

Mary Anne Fenton, MD, clinical director, Breast Medical Oncology, Rhode Island Hospital, director, Quality, Lifespan Cancer Institute, associate clinical professor, medicine, Warren Alpert Medical School, Brown University, discusses findings from the phase 3 DESTINY-Breast03 trial (NCT03529110) in patients with metastatic, HER2-positive breast cancer.

Updated findings from DESTINY-Breast03 were presented by Sara A. Hurvitz, MD, of the University of California, Los Angeles, at the 2022 San Antonio Breast Cancer Symposium. This trial enrolled patients with centrally confirmed, HER2-positive, locally advanced or metastatic breast cancer who had previously received trastuzumab (Herceptin) and a taxane. Accordig to Fenton, this patient population was similar to that of the phase 3 DESTINY-Breast02 trial (NCT03523585), which evaluated the efficacy and safety of fam-trastuzumab deruxtecan-nxki (Enhertu) vs physician’s choice of treatment in patients with HER2-positive metastatic breast cancer previously treated with ado-trastuzumab emtansine (Kadcyla). DESTINY-Breast03 randomized patients to receive either trastuzumab deruxtecan or trastuzumab emtansine in the second-line setting

Trastuzumab emtansine is a HER2-targeted, microtubule-stabilizing antibody-drug conjugate (ADC) with about 3 chemotherapy molecules per antibody, Fenton explains. Trastuzumab deruxtecan, another ADC, has a higher payload than trastuzumab emtansine, as well as a cleavable linker with a bystander effect.

In DESTINY-Breast03, patients who received trastuzumab deruxtecan achieved a longer progression-free survival (PFS) and overall survival (OS) than those who received trastuzumab emtansine. An early separation of the curves was observed between the 2 arms, indicating that trastuzumab deruxtecan can overcome early drug resistance and induce durable responses, Fenton emphasizes. The median PFS was 28.8 months in the trastuzumab deruxtecan arm vs 6.8 months in the trastuzumab emtansine arm. The median OS was not yet reached (NR) with 72 OS events vs NR with 97 OS events in the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively.

Additionally, similarly to the findings from DESTINY-Breast02, trastuzumab deruxtecan provided a consistent survival benefit across all prespecified patient subgroups in DESTINY-Breast03, including patients with hormone receptor (HR)–positive disease, those with HR-negative disease, those with prior pertuzumab (Perjeta) exposure, and those with visceral disease or brain metastases at baseline, Fenton notes.

Furthermore, as in DESTINY-Breast02, the most common treatment-related adverse effects experienced by patients who received trastuzumab deruxtecan in DESTINY-Breast03 included nausea, vomiting, alopecia, constipation, and anemia, Fenton explains. Careful monitoring of patients receiving trastuzumab deruxtecan is crucial, as this agent is associated with high rates of pneumonitis, Fenton says.

Many guidelines now recommend trastuzumab deruxtecan as second-line therapy in patients with HER2-positive locally advanced or metastatic breast cancer, Fenton adds. Ongoing trials are investigating the efficacy of this agent in the frontline setting for patients with newly metastatic HER2-positive breast cancer, Fenton concludes.

Mary Anne Fenton, MD, discusses findings from the phase 3 DESTINY-Breast03 trial in patients with metastatic, HER2-positive breast cancer.

Mary Anne Fenton, MD

Articles

Dr Fenton on Findings from the DESTINY-Breast02 Trial in HER2+ Breast Cancer

Dr Fenton on Trastuzumab Deruxtecan Vs Trastuzumab Emtansine in HER2+ Breast Cancer