Trastuzumab Deruxtecan Sustains Survival Benefits in HER2-Low Metastatic Breast Cancer

Shanu Modi, MD

Treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to sustained improvements in overall survival (OS) and progression-free survival (PFS) vs physician’s choice of treatment in patients with previously treated HER2-low metastatic breast cancer, irrespective of hormone receptor status, according to results from the 32-month follow-up of the phase 3 DESTINY-Breast04 trial (NCT03734029) presented at the 2023 ESMO Congress.¹

For all patients, the median overall survival (OS) at the primary analysis was 23.4 months (95% CI, 20.0-24.8) in the T-DXd arm and 16.8 months (95% CI, 14.5-20.0) in the physician’s choice arm (HR, 0.64; 95% CI, 0.49-0.84). At the updated analysis, OS was 22.9 months (95% CI, 21.2-24.5) vs 16.8 months (95% CI, 14.1-19.5) between both arms, respectively (HR, 0.69; 95% CI, 0.55-0.86).

At 24 months, the OS rate in the T-DXd arm was 47.3% (95% CI, 41.9%-52.4%) vs 32.0% (95% CI, 24.5%-39.3%) in the physician’s choice arm. At 36 months, the OS rate between both arms was 26.2% (95% CI, 20.6%-31.9%) and 16.3% (95% CI, 10.3%-23.6%), respectively.

“These results [from the longer follow-up of DESTINY-Breat04] continue to support the use of T-DXd as the new standard of care after 1 line of chemotherapy in patients with HER2-low metastatic breast cancer,” presenting author Shanu Modi, MD, an attending physician at Memorial Sloan Kettering Cancer Center, stated during the conference.

Patients were randomly assigned 2:1 to receive either T-DXd (n = 373) at 5.4 mg/kg every 3 weeks or physician’s choice therapy with capecitabine, eribulin (Halaven), gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane; n = 184). To be enrolled, patients needed to have HER2-low disease, defined by an immunohistochemistry of 1+ or 2+. Patients must also have had unresectable and/or metastatic breast cancer and been previously treated with 1 to 2 lines of prior therapy in the metastatic setting. Patients with hormone receptor-positive disease needed to be considered endocrine refractory.

The updated data cutoff was March 1, 2023, and the median follow-up was 32.0 months (95% CI, 31.0-32.8).

For patients who were hormone receptor positive, the median OS at the primary analysis was 23.9 months (95% CI, 20.8-24.8) in the T-DXd arm (n = 331) vs 17.5 months (95% CI, 15.2-22.4) in the physician’s choice arm (n = 163; HR, 0.64; 95% CI, 0.48-0.88), and at the updated analysis, median OS was 23.9 months (95% CI, 21.7-25.2) vs 17.6 months (95% CI, 15.1-20.2; HR, 0.69; 95% CI, 0.55-0.87). The 24-month OS rates were 49.0% (95% CI, 43.3%-54.5%) in the T-DXd arm and 35.1% (95% CI, 27.3%-43.0%) in the physicians’ choice arm.

Modi noted that findings were consistent with previously reported results that were seen in the primary analysis, of which there was a 31% reduction in the risk of death for patients being treated with T-DXd vs physician's choice chemotherapy.²

The median PFS in all patients of the primary analysis was 8.8 months (95% CI, 8.3-9.8) in the T-DXd arm vs 4.2 months (95% CI, 3.0-4.5) in the physician’s choice arm (HR, 0.37; 95% CI, 0.30-0.45). In the updated analysis, the median PFS was 8.8 months (95% CI, 8.3-9.8) in the T-DXd arm and 4.2 months (95% CI, 3.0-4.5) in the physician’s choice arm (HR, 0.36; 95% CI, 0.29-0.45). At 24 months, the PFS rate in the T-DXd arm was 14.5% (95% CI, 10.8%-18.7%).

For patients with hormone receptor–positive disease in the primary analysis, the median PFS in the T-DXd arm was 9.6 months (95% CI, 8.4-10.0) vs 4.2 months (95% CI, 3.4-4.9) in the physician’s choice arm (HR, 0.37; 95% CI, 0.30-0.47). The updated analysis showed a median PFS of 9.6 months (95% CI, 8.4-10.0) in the T-DXd arm vs 4.2 months (95% CI, 3.4-4.9) in the physician’s choice arm (HR, 0.37; 95% CI, 0.30-0.46). The 24-month PFS rate was 15.4% (95% CI, 11.3%-20.0%) with T-DXd.

An exploratory analysis assessed patients with hormone receptor-negative disease. OS in the primary analysis was 18.2 months (95% CI, 13.6-not evaluable) with T-DXd compared with 8.3 months (95% CI, 5.6-20.6) in the physician's choice arm (HR, 0.48; 95% CI, 0.24-0.95). The updated analysis showed an OS of 17.1 months (95% CI, 13.6-23.0) compared with 8.3 months (95% CI, 5.6-20.4) between both arms, respectively (HR, 0.58; 95% CI, 0.31-1.08).

The 24-month OS rates were 22.4% (95% CI, 18.5%-47.5%) in the T-DXd arm compared with 11.8% (95% CI, 2.0%-31.2%) in the physician's choice arm.

The median PFS in the primary analysis by blinded independent central review was 8.5 months (95% CI, 4.3-11.7) in the T-DXd arm vs 2.9 months (95% CI, 1.4-5.1) in the physician’s choice arm (HR, 0.46; 95% CI, 0.24-0.89). The updated analysis by investigator review highlighted a median PFS of 6.3 months (95% CI, 4.2-8.5) in the T-DXd arm and 2.9 months (95% CI, 1.4-4.2) in the physician’s choice arm (HR, 0.29; 95% CI, 0.15-0.57).

Modi noted that there was a 42% reduction in the risk of death and a 71% reduction in disease progression in this hormone receptor–negative population receiving T-DXd.

In all patients, the PFS2 was 15.4 months (95% CI, 13.6-16.5) in the T-DXd arm vs 9.7 months (95% CI, 8.3-10.8) in the physician’s choice arm (HR, 0.51; 95% CI, 0.41-0.64). In the hormone receptor-positive cohort, the median PFS2 was 15.5 months (95% CI, 13.8-17.2) in the T-DXd arm and 10.5 months (95% CI, 8.3-11.4) in the physician’s choice arm (HR, 0.51; 95% CI, 0.40-0.64).

Treatment-emergent adverse effects (TEAEs) of grade 3 or higher occurred in 54.4% of patients in the T-DXd arm and 67.4% in the physician’s choice arm, with serious TEAEs occurring in 29.1% vs 25.6%. Due to TEAEs, treatment discontinuation was reported in 16.7% vs 8.1%, dose interruptions in 41.8% vs 42.4%, dose reductions in 24.0% vs 37.8%, and deaths in 4.0% vs 2.9% of the T-DXd and physician’s choice arms, respectively. Deaths that occurred while on treatment were reported in 3.8% vs 4.7%.

The most common drug-related TEAEs that were grade 3 or higher in the T-DXd arm were neutropenia (14%), anemia (9%), and fatigue (8%). For those on the physician’s choice arm, the most common were neutropenia (42%), leukopenia (19%), and transaminases increase (11%).

References

1. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients with HER2-low unresectable and/or metastatic breast cancer: updated survival results of the randomized, phase 3 DESTINY-Breast04 study. Ann Oncol. 2023;34(suppl 2):S334-S335. doi:10.1016/j.annonc.2023.09.553
2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690