Trastuzumab Deruxtecan Maintains QOL and Global Health Status in HER2+ Metastatic Breast Cancer

Overall health status and quality of life (QOL) were maintained among patients with HER2-positive metastatic breast cancer (MBC) who were treated with fam-trastuzumab deruxtecan-nxki (Enhertu) compared with those who received ado-trastuzumab emtansine (T-DM1; Kadcyla), according to patient reported outcomes (PROs) from the phase 3 DESTINY-Breast03 trial (NCT03529110) presented at the European Society for Medical Oncology Breast Cancer Congress 2022.¹

Results from the analysis showed that patients treated with trastuzumab deruxtecan (n = 261) had a median time to first hospitalization of 219.5 days (range, 0-723) vs 60.0 days (range, 0-399) in the T-DM1 arm (n = 263). The median treatment duration for those who received trastuzumab deruxtecan was also longer compared with T-DM1, 14.3 months (range, 0.7-29.8) and 6.9 months (range, 0.7-25.1), respectively.

“The evidence of maintained QOL whole on treatment with trastuzumab deruxtecan and delayed definitive deterioration across prespecified scales vs T-DM1 further supports the improved efficacy and the manageable safety profile of trastuzumab deruxtecan vs T-DM1,” Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano and the head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy said. “[This] supports trastuzumab deruxtecan as a standard of care for patients with HER2-positive MBC.”

The PRO and hospitalization end points analysis consisted of data collected from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 questionnaire (QLQ-C30), the EORTC Quality of Life Breast cancer questionnaire (QLQ-BR45), the EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L), and a hospitalization records assessment. Curigliano noted that completion compliance for health related–QOL questionnaires was high in both treatment arms, with a completion rate over 97% at baseline and greater than 82% from cycles 3 to 27.

As of May 21, 2021, 51.4% of patients were still receiving trastuzumab deruxtecan and 18.0% were still receiving T-DM1. The mean change from baseline per EORTC QLQ-C30 was 1.98 (standard deviation [SD], 21.34; range, –50.0-66.7) and 4.07 (SD, 22.05; range, –75.0-58.3), respectively.

Across all prespecified PRO variables of interest, the HR for time to definitive deterioration (TDD) favored trastuzumab deruxtecan vs T-DM1.

Using EORTC QLQ-C30 favored trastuzumab deruxtecan vs T-DM1, the median TTD of global health status was 9.7 months (95% CI, 7.3-12.5) compared with 8.3 months (95% CI, 7.0-10.3; HR, 0.88; 95% CI, 0.70-1.11; P = .2829). The median TTD of pain symptoms was 10.8 months (95% CI, 8.3-14.0) vs 8.3 months (95% CI, 6.6-9.8), respectively (HR, 0.75; 95% CI, 0.59-0.95; P = .0146); median TTD for physical functioning was 16.7 months (95% CI, 14.5–not estimable [NE]) vs 10.3 (95% CI, 8.3-21.0) (HR, 0.77; 95% CI, 0.59-0.89; P = .0529); median TTD for emotional functioning was 16.4 months (95% CI, 14.1-19.9) and 10.5 months (95% CI, 9.0-13.8), respectively (HR, 0.69; 95% CI, 0.53-0.89; P = .0049). Finally, social functioning outcomes also favored trastuzumab deruxtecan with a median TTD of 11.1 months (95% CI, 7.3-13.4) compared with 9.0 (95% CI, 7.1-11.3) with T-DM1 (HR, 0.90; 95% CI, 0.71-1.14; P = .03577).

Arm and breast symptoms were measured via outcomes from EORTC OLO-BR45 with median TTD for trastuzumab deruxtecan vs T-DM1 both favoring the investigational arm: arm symptoms (P = .0033), breast symptoms (P = .1329).

Finally, the median TTD of the visual analog scale assessed by EQ-5D-5L was 13.2 months (95% CI, 10.1-15.3) and 8.5 months (95% CI, 7.3-10.4), respectively (HR, 0.77; 95% CI, 0.61-0.98; P = .0354).

Additional findings related to hospitalization showed that patients in the trastuzumab deruxtecan and T-DM1 arms were hospitalized at similar rates (6.9% vs 7.2%). The median length of hospital stay was 10.5 days (range, 1-181) and 9.0 days (range, 2-25), respectively.

In DESTINY-Breast03 a total of 524 patients who were previously treated with trastuzumab (Herceptin) and a taxane were randomly assigned to receive trastuzumab deruxtecan or T-DM1. trastuzumab deruxtecan was administered at a dose of 5.4 mg/kg every 3 weeks and T-DM1 was given at 3.6 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, overall response rate, duration of response, and health economics outcomes research.

On May 4, 2022, the FDA approved trastuzumab deruxtecan for the treatment of patients with metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting and for those who developed disease recurrence within 6 months of receiving prior therapy in the neoadjuvant or adjuvant setting.²

Baseline patient characteristics were well balanced between the 2 arms; the median age was 54.3 years (range, 27.9-83.1) and 54.2 years (range, 20.2-83.0) in the trastuzumab deruxtecan and T-DM1 arms, respectively. Most patients in both arms had visceral disease (70.5% and 70.3%, respectively) and had previously received treatment for MBC (92.0% and 89.0%, respectively). Number of prior lines of therapy was also balanced, with 49.4% of patients in the trastuzumab deruxtecan arm receiving 2 or more prior lines of therapy compared with 52.1% in the T-DM1 arm.

Updated data presented as part of the analysis showed that the median PFS for patients who received trastuzumab deruxtecan was not reached (95% CI, 18.5–NE) compared with 6.8 months (95% CI, 5.6-8.2) for those who received T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22). The 12-month PFS rates were 75.8% (95% CI, 69.8%-80.7%) and 34.1% (95% CI, 27.7%-40.5%), respectively. The median durations of follow-up were 16.2 months and 15.3 months, respectively.

“Trastuzumab deruxtecan improved PFS [in a way] that is unprecedented,” Curigliano said. “[This benefit] is confirmed in the current analysis and the previous analysis, across all subgroups.”

In terms of safety, patients treated with trastuzumab deruxtecan experienced any grade drug-related treatment-emergent adverse effects (TEAEs) at a rate of 98.1% comparted with 86.6% in the T-DM1 arm. Drug-related TEAEs of grade 3 or higher occurred in 45.1% and 39.8% of patients, respectively. Serious drug-related TEAEs were present in 10.9% and 6.1% of patients, respectively.

References

1. Curigliano G, Dunton K, Rosenlund M, et al. Patient-reported outcomes (PROs) from DESTINY-Breast03, a randomized phase 3 study of trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC). Presented at: European Society for Medical Oncology Breast Cancer Congress 2022. May 3-5, 2022; Berlin, Germany.
2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed May 6, 2022. bit.ly/3M7mgnH