Trastuzumab Deruxtecan Preserves Quality of Life in Patients With HR+, HER2-Low, Metastatic Breast Cancer

Naoto T. Ueno, MD, PhD, FACP

An analysis of patient-reported outcomes (PROs) suggests that patients who receive fam-trastuzumab deruxtecan-nxki (Enhertu) maintain quality of life (QOL), with longer time to deterioration and manageable nausea, vomiting, and fatigue, compared with patients who receive physician’s choice of treatment (TPC), in the DESTINY-Breast04 trial (NCT03734029). The findings show that the recently approved antibody-drug conjugate offers a viable safety profile for patients with hormone receptor–positive, HER2-low metastatic breast cancer.

“Overall, global health scores [GHS] and QOL in DESTINY-[Breast]04 was maintained for patients in the hormone receptor–positive cohort during the entire treatment period of trastuzumab deruxtecan [8.2 months] and TPC [3.5 months],” Ueno, who is the section chief of Translation Breast Cancer Research, and the Nylene Eckles Distinguished Professor in Breast Cancer, in the Department of Breast Medical Oncology at The University of Texas MD Anderson said in a presentation of the findings during the 2022 European Society of Medical Oncology Annual Meeting.

“The mean change from [baseline] remained stable with trastuzumab deruxtecan up to 27 cycles and with TPC up to 13 cycles,” added Ueno, who is also the executive director of The University of Texas MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Research Program and Clinic.

Time to definitive deterioration (TDD) was similar between the 2 arms among all PRO measures of interest. Specifically, the TDD in GHS and QOL between the experimental and control arms was 11.4 months (95% CI, 8.8-16.3) and 7.5 months (95% CI, 5.9%-9.5%), respectively, with a hazard ratio of 0.69 (95% CI, 0.52-0.92; P = .0096). Pain symptoms were stable with trastuzumab deruxtecan as well, with a median TDD of 16.4 months (95% CI, 13.1-21.5), compared with 6.1 months (95% CI, 4.2-75 months) with TPC (HR, 0.40; 95% CI, 0.3-0.54; P < .0001).

Patients also reported superior physical, emotional, and social functioning scores with trastuzumab deruxtecan compared with TPC, according to responses collected via the European Organization for Research and Treatment of Cancer Quality of Life Core 30 questionnaire (EORTC QLQ-C30). The TDD for physical function was 16.6 months vs 7.5 months, respectively, (HR, 0.53; 95% CI, 0.40-0.70; P < .001); 19.2 months vs 10.5 months for emotional function (HR, 0.69; 95% CI, 0.50-0.96; P = .0266); and 12.8 months vs 6.0 months for social functioning (HR, 0.59; 95% CI, 0.45-0.77; P = .001).

With both drugs, the fatigue scores remained stable for the duration of data collection, investigators noted, with a TDD of 11.1 months vs 4.5 months between the 2 arms, respectively (HR, 0.61; 95% CI, 0.47-0.79; P = .0002), The PRO collection revealed that nausea and vomiting were worse with trastuzumab deruxtecan compared with TPC; however, this increase was only clinically relevant for the first 6 cycles. For cycles 7 through 27, nausea and vomiting scores decreased and remained within 10 points of baseline. The TDD for nausea and vomiting was 5.7 months vs 9.3 months (HR, 1.46; 95% CI, 1.09-1.96; P = .0128).

Ultimately, the changes from baseline in fatigue symptoms were similar between the 2 arms and did not worsen overtime with trastuzumab deruxtecan. Although patients did experience more initial nausea and vomiting with the antibody drug conjugate, these symptoms decreased and stabilized by cycle 7.

Moreover, findings from the breast cancer-specific EORTC QLQ-BR23 assessment showed that trastuzumab deruxtecan helped delay deterioration from breast-specific symptoms. The TDD for arm symptoms was 14.4 months vs 8.7 months (HR, 0.62; 95% CI, 0.45-0.85; P = .0027). Breast symptom TDD was not estimable in either arm (HR, 0.71; 95% CI, 0.50-1.01; P = .1008). However, an analysis of breast specific symptoms showed that patients receiving trastuzumab deruxtecan had a TDD of systemic therapy adverse effects of 13.6 months (95% CI, 8.3-22.3) vs 6.1 months (95% CI, 4.4-7.7) with TPC. The hazard ratio in this analysis was 0.70 (95% CI, 0.53-0.92; P = .0110).

Additionally, findings from the EuroQol 5-dimension scale questionnaire (EQ-5D-5L) demonstrated that TDD in the visual analog scale was 12.0 months with trastuzumab vs 6.8 with TPC months in DESTINY-Breast04 (HR, 0.73; 95% CI, 0.54-0.97; P = .0288).

The open-label, multicenter, phase 3 DESTINY-Breast04 was designed to compare trastuzumab deruxtecan against TPC in patients with hormone receptor–positive, HER2-low metastatic breast cancer. Eligible patients were pretreated and refractory to endocrine therapy. Patients needed to have received 1 to 2 prior lines of chemotherapy to qualify for enrollment. Enrolled patients were randomly assigned 2:1 to receive either trastuzumab deruxtecan at the recommended dose of 5.4 mg/kg every 3 weeks, or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

This was an international study; among patients receiving trastuzumab deruxtecan, 45.0% were from Europe or Israel, 38.7% were from Asia, and 16.3% were from North America. The percentage of patients with visceral metastasis at baseline was 90%. Liver metastases was a prominent baseline characteristic: 74.6% of patients in the experimental arm had liver metastases. Lung metastases and brain metastases were reported in 29.6% and 5.4% of patients at baseline, respectively.

In terms of efficacy, trastuzumab deruxtecan elicited a superior median progression-free survival at 10.1 months vs 5.4 months with TPC (HR, 0.51; P < .001). Similarly, median OS was significantly longer in the experimental group at 23.9 months vs 17.5 months, respectively (HR, 0.64; P = .0028).

Notably, trastuzumab deruxtecan was associated with fewer grade 3 or greater treatment emergent adverse events (TEAEs) than physician’s choice of treatment. The percentage of patients receiving trastuzumab deruxtecan who experienced a grade 3 or higher TEAE was 52.6% (n = 195) vs 67.4% in the control group (n = 116).

Conversely, more patients receiving the antibody-drug conjugate required a dose discontinuation compared with TCP; 16.2% (n = 60) vs 8.1% (n = 14), respectively. The most common TEAEs which emerged during trastuzumab deruxtecan treatment were nausea (73%), fatigue (48%), and neutropenia (33%). The rates of nausea and fatigue were greater in the experimental arms than control arms; 24% of patients receiving TPC experienced nausea and 42% experienced fatigue. However, less patients receiving trastuzumab deruxtecan experienced neutropenia than their control counterparts (51%).

Investigators used 3 key PRO measures to better understand patient experiences with the study treatments. They leveraged the oncology-specific EORTC QLQ-C30 to measure GHS and QOL, as well as functioning and symptom scales, this assessment analyzed changes from baseline and TDD. The breast cancer-specific EORTC QLQ-BR23 provided insight as to how the treatments influenced patients’ breast cancer-specific symptoms—specifically arm and breast symptoms. The EQ-5D-5L queried patients with generic questions to get a self-rated health status.

The rate of questionnaire compliance was high; 92% of patients filled out the questionnaires at baseline (cycle 1) and 80% of patients filed questionnaires between cycles 2 and 27. Patients were asked to complete these assessments at each of the first 3 cycles. Following cycle 3, they were asked to complete them at every other cycle (cycles 5, 7, 9, etc) for the duration of treatment, as well as to complete them posttreatment at a 40-day follow-up visit, and again at a 3-month follow-up visit.

GHS ranged from 0 to 100. The mean standard deviation at baseline for trastuzumab deruxtecan and TPC were 36.3 ± 21.8 and 37.8± 22.5 at baseline. The mean change from baseline for overall GHS/QOL were within ± 10 and investigators noted they remained stable over the course of treatment with trastuzumab deruxtecan up to 27 cycles and with TPC up to 13 cycles.

“The hazard ratio for time to definitive deterioration favored trastuzumab deruxtecan over TPC for almost all PRO variables of interest, including pain symptoms,” Ueno concluded. “These results suggest trastuzumab deruxtecan treatment delays the deterioration of GHS/QOL and shows a QOL benefit of trastuzumab deruxtecan in patients with hormone receptor–positive, HER2-low metastatic breast cancer.”

Reference

Ueno NT, Jacot W, Yamashita T, et al. Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase 3 study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract 217O.