Data from the phase 3 DESTINY-Breast06 trial, presented at the 2024 San Antonio Breast Cancer Symposium, reveal that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) significantly improves progression-free survival (PFS) compared to physician’s choice of chemotherapy (TPC) in patients with hormone receptor–positive, HER2-low/ultralow metastatic breast cancer, irrespective of the time to progression (TTP) on frontline endocrine therapy plus CDK4/6 inhibition and type of endocrine resistance.
The multi-center, open-label DESTINY-Breast06 trial enrolled patients with hormone receptor–positive metastatic breast cancer with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–negative) or HER2-ultralow (IHC 0 with membrane staining) expression. Patients could not have received prior chemotherapy and must have had at least 2 prior lines of endocrine therapy with or without targeted therapy for metastatic disease; or received 1 line of therapy for metastatic disease and developed progression within 6 months of starting frontline endocrine therapy with a CDK4/6 inhibitor or developed recurrence within 24 months of starting adjuvant endocrine therapy.
Progression-Free Survival
In patients with a TTP of less than 6 months, the median PFS was 14.0 months with T-DXd vs 6.5 months with TPC (HR, 0.38; 95% CI, 0.25-0.59). Patients with a TTP between 6 and 12 months had a median PFS of 13.2 months with T-DXd vs 6.9 months with TPC (HR, 0.69; 95% CI, 0.43-1.12). Patients who went more than 12 months before progressing on frontline therapy experienced a median PFS of 12.9 months with T-DXd vs 8.2 months with TPC (HR, 0.67; 95% CI, 0.51-0.88).
Endocrine Resistance
Median PFS was 12.4 months (95% CI, 10.3-15.2) with T-DXd vs 6.6 months (95% CI, 5.4-7.4) with TPC in patients with primary endocrine resistance (HR, 0.57; 95% CI, 0.42-0.77). Patients with secondary endocrine resistance achieved a median PFS of 13.2 months (95% CI, 12.0-15.5) with T-DXd vs 9.5 months (95% CI, 8.0-11.1) with TPC (HR, 0.68; 95% CI, 0.55-0.84).
Aditya Bardia, MD, MPH, FASCO, lead study author and professor at UCLA Health’s Jonsson Comprehensive Cancer Center, stated, “T-DXd demonstrated a clinically meaningful efficacy benefit vs TPC regardless of time to progression on frontline endocrine therapy plus CDK4/6 inhibition, as well as efficacy regardless of disease burden.”
Objective Response Rate and Duration of Response
T-DXd also improved the objective response rate (ORR) and duration of response (DOR) vs TPC across all TTP subgroups and in patients with primary and secondary endocrine resistance. The confirmed ORRs with T-DXd and TPC, respectively, were 67.7% and 25.4% in patients with a TTP of less than 6 months; 60.0% and 28.8% in patients with a TTP between 6 and 12 months; and 59.5% and 33.1% in patients with a TTP greater than 12 months.
The confirmed ORRs were 57.8% and 25.7% with T-DXd and TPC, respectively, in patients with primary endocrine resistance; and 57.1% and 34.0%, respectively, in those with secondary endocrine resistance.
The median DOR with T-DXd and TPC, respectively, in patients with a TTP of less than 6 months, between 6 and 12 months, and greater than 12 months were as follows: 11.1 months vs 7.3 months; 13.7 months vs 11.5 months; and 15.7 months vs 11.1 months. The median DOR was 11.1 months with T-DXd vs 7.3 months with TPC in patients with primary endocrine resistance and 15.4 months vs 10.1 months in those with secondary endocrine resistance.
Time to Second Progression
Time to second progression (PFS2) was also presented in the intention-to-treat population (n = 866). The median PFS2 was 20.3 months with T-DXd vs 14.7 months with TPC (HR, 0.62; 95% CI, 0.52-0.74; P < .0001). According to Bardia, PFS2 was clinically meaningful in favor of T-DXd across all TTP subgroups. Patients with a TTP of less than 6 months had a median PFS2 of 18.9 months (95% CI, 14.4-24.0) with T-DXd vs 15.2 months (95% CI, 10.9-17.5) with TPC (HR, 0.73; 95% CI, 0.46-1.14). Patients with a TTP between 6 and 12 months had a median PFS2 of 17.1 months (95% CI, 13.9-31.8) with T-DXd vs 13.7 months (95% CI, 10.3-17.1) with TPC (HR, 0.59; 95% CI, 0.37-0.94). Patients with a TTP greater than 12 months had a median PFS2 of 20.0 months (95% CI, 18.6-25.3) with T-DXd vs 14.3 months (95% CI, 12.6-15.9) with TPC (HR, 0.57; 95% CI, 0.43-0.75).
PFS benefit with T-DXd was also observed regardless of disease burden, with notable efficacy in patients with lower disease burden. In patients with less than 3 local or metastatic sites at baseline the median PFS was 15.3 months with T-DXd vs 8.4 months with TPC (HR, 0.55; 95% CI, 0.42-0.72). Among patients with at least 3 local or metastatic sites at baseline the median PFS was 11.4 months with T-DXd vs 7.2 months with TPC (HR, 0.71; 95% CI, 0.57-0.89).
Of note, T-DXd also improved PFS vs TPC in patients with (HR, 0.59; 95% CI, 0.48-0.72) and without (HR, 0.70; 95% CI, 0.51-0.96) liver metastases, a baseline tumor size greater (HR, 0.57; 95% CI, 0.45-0.72) and lower (HR, 0.71; 95% CI, 0.55-0.96) than the median, and those with (HR, 0.65; 95% CI, 0.55-0.78) and without (HR, 0.51; 95% CI, 0.30-0.85) visceral disease.
According to Bardia, the safety profiles for T-DXd and TPC in the TTP and disease burden subgroups were consistent with the overall population.
Bardia concluded that T-DXd is an effective treatment option in patients with hormone receptor–positive, HER2-low/-ultralow metastatic breast cancer following at least 1 endocrine-based therapy.
