T-DXd Improves PFS Irrespective of Time to Progression, Type of Endocrine Resistance in HER2-Low/-Ultralow Metastatic Breast Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) improved progression-free survival (PFS) vs treatment of physician’s choice (TPC) regardless of time to progression (TTP) on frontline endocrine therapy plus CDK4/6 inhibition and type of endocrine resistance in patients with hormone receptor–positive, HER2-low/-ultralow metastatic breast cancer, according to data from the phase 3 DESTINY-Breast06 trial (NCT04494425) presented during the 2024 San Antonio Breast Cancer Symposium.1

In the population of patients who had 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).

Moreover, the 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).

“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,” Aditya Bardia, MD, MPH, FASCO, lead study author and professor in the Department of Medicine, Division of Hematology/Oncology at UCLA Health’s Jonsson Comprehensive Cancer Center in Los Angeles, California, said in a presentation of the data.

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.

Patients were randomly assigned 1:1 to 5.4 mg/kg of T-DXd every 3 weeks (n = 436) or TPC (n = 430), which consisted of capecitabine (Xeloda; 59.8%), nab-paclitaxel (Abraxane; 24.4%), or paclitaxel (15.8%).

The study had previously met its primary end point, demonstrating an improvement in PFS in the HER2-low (HR, 0.62; P < .0001) population.2 A key secondary end point of PFS in the HER2-low/-ultralow population was also met (HR, 0.64; P < .0001).

“The objectives of this analysis were to investigate the benefit of T-DXd in patients with different responses to endocrine therapy, assess the efficacy of subsequent therapies post progression on T-DXd/TPC, and understand the benefit of T-DXd in patients with varying disease burdens,” Bardia said.1

Investigators also found that T-DXd 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 (PFS2), which served as a secondary end point of the trial, was also presented in the intention-to-treat population (n = 866). Findings showed that 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). Bardia stated that 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,” Bardia said. 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.

With respect to safety Bardia explained that the safety profiles for T-DXd and TPC in the TTP and disease burden subgroups were consistent with the overall population.

“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,” Bardia concluded.

Disclosures: Dr Bardia disclosed receiving funding from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, Menarini, Merck, Novartis, Pfizer, and Sanofi; and consulting fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, Menarini, Merck, Novartis, Pfizer, and Sanofi.

References

1. Bardia A, Hu X, Dent R, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) by pace of disease progression on prior endocrine-based therapy: additional analysis from DESTINY-Breast06. Presented at: San Antonio Breast Cancer Conference; December 10-13, 2024; San Antonio, TX. Abstract LB1-04.
2. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000