Trastuzumab Deruxtecan Preserves QOL in HER2-Low Breast Cancer

Naoto T. Ueno, MD, PhD, FACP

Patient-reported outcomes (PROs) from the DESTINY-Breast04 trial (NCT03734029) showed a quality-of-life (QOL) benefit from treatment with trastuzumab deruxtecan (Enhertu) compared with physician’s choice of therapy (TPC) in patients with hormone receptor–positive, HER2-low metastatic breast cancer.

The findings suggest that antibody-drug conjugate may be a more tolerable agent than TPC , according to Naoto T. Ueno, MD, PhD, FACP, who presented the findings during the European Society of Medical Oncology Congress 2022.

“These results suggest trastuzumab deruxtecan treatment delays the deterioration of global health score [GHS] and QOL and shows a QOL benefit of trastuzumab deruxtecan vs TPC in patients with hormone receptor–positive, HER2-low metastatic breast cancer,” said Ueno, who is section chief of Translation Breast Cancer Research, the Nylene Eckles Distinguished Professor in Breast Cancer in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, and executive director of the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic.

The patient-reported outcomes endpoints were assessed via 3 measurement tools: the European Organization for Research and Treatment of Cancer Quality of Life Core 30 questionnaire (EORTC QLQ-C30), the EORTC QLQ-BR23, and the EuroQol 5-dimension scale questionnaire (EQ-5D-5L). These measurement tools were oncology-specific, breast cancer specific, and general health-specific, respectively. Together, these assessments measure global health status, functioning and symptoms scales, and self-rated health status, as well as identify any changes from baseline and the time-to-definitive deterioration.

Using the EORTC QLQ-C30 assessment, the time to definitive deterioration (TDD) in GHS and QOL was 11.4 months (95% CI, 8.8-16.3) with trastuzumab deruxtecan compared with 7.5 months (95% CI, 5.9%-9.5%) with TPC. The hazard ratio for GHS/QOL TDD was 0.69 (95% CI, 0.52-0.92; P = .0096). For pain symptoms, the TDD between the experimental and control arms were 16.4 months (95% CI, 13.1-21.5) and 6.1 months (95% CI, 4.2-7.5), respectively. The hazard ratio for pain symptom TDD was 0.40 (95% CI, 0.30-0.54; P < .0001).

The TDD for other functioning status of interest between patients receiving trastuzumab deruxtecan or TPC were as follows: physical functioning TDD was 16.6 months vs 7.5 months (HR, 0.53; 95% CI, 0.40-0.70; P < .0001); emotional functioning TDD was 19.2 months vs 10.5 months (HR, 0.69; 95% CI, 0.50-0.96; P = .0266), and social functioning TDD was 12.8 months vs 6.0 months (HR, 0.59; 95% CI, 0.45-0.77; P = .0001).

Using the EORTC QLQ-BR23 assessment, arm symptom TDD was 14.4 months vs 8.7 months (HR, 0.62; 95% CI, 0.45-0.85; P = .0027); breast symptoms TTD was not estimable in either arm (HR, 0.71; 95% CI, 0.50-1.01; P = .1008). Lastly, the TDD in the visual analog scale was assessed using the EQ-5D-5L and was 12.0 months vs 6.8 months (HR, 0.73; 95% CI, 0.54-0.97; P = .0288).

“Similar TDD results were observed among the all-patient cohort in PRO measures of interest,” Ueno noted.

DESTINY-Breast04 is an open-label, multicenter phase 3 study designed to assess the survival benefit of trastuzumab deruxtecan in patients with pretreated, endocrine refractory, HER2-low disease. Eligible participants needed to have received 1 or 2 prior lines of chemotherapy to enroll. The trial randomly assigned patients 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). The PRO analysis was conducted in the primary efficacy end point population of patients with hormone receptor–positive disease per the statistical analysis plan.

In the trastuzumab deruxtecan arm (n = 331), the median patient age was 56.8 years (range 31.5-80.2). Metastatic sites included 5.4% of patients with brain metastases, 74.6% with liver metastases, and 29.6% with lung metastases. Overall, 90.0% had visceral metastases. Most patients had received previous therapy with a targeted therapy (78.2%) and 70.4% had previously received a CDK4/6 inhibitor.

At a median data cutoff of 18.4 months, 15.6% of patients (n = 58) were still receiving trastuzumab deruxtecan vs 1.7% with TPC (n = 3). The median duration of treatment was 8.2 months (range, 0.2-33.3) vs 3.5 months (range, 0.3-17.6), respectively.

In the hormone receptor–positive cohort, the median progression-free survival with the antibody-drug conjugate vs TPC was 10.1 months and 5.4 months, respectively (HR, 0.51; P < .0001). The median OS was 23.9 months vs 17.5 months (HR, 0.64; P = .0028).

In terms of safety, grade 3 or greater treatment-emergent adverse events (TEAS) occurred in 52.6% of patients (n = 195) who received trastuzumab deruxtecan compared with 67.4% who received TPC (n = 116). However, the antibody-drug conjugate required dose discontinuation in 16.2% of patients (n = 60) compared with 8.1% (n = 14) in the control group.

The most common TEAEs with trastuzumab deruxtecan compared with TPC, were nausea, fatigue, and neutropenia. The rates of each of these TEAEs between the 2 groups were 73% vs 24%; 48% vs 42%; and 33% vs 51%.

Patients were asked to complete these assessments at baseline (cycle 1), and after cycle 2, and cycle 3. Following cycle 3, they were asked to complete them every 2 cycles (cycles 5, 7, etc), at the end of treatment, and at a 40-day follow-up visit, and a 3-month follow-up visit. The rate of questionnaire compliance was 92% at baseline and approximately 80% for cycles 2 to 27.

GHS and QOL were maintained with both trastuzumab deruxtecan and TPC. 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.

Similarly, investigators noted that fatigue scores remained stable over time with both drugs, until change from baseline data fell below 10% in each arm. Although symptoms of nausea and vomiting were worse with trastuzumab deruxtecan than with TPC, this increase was only clinically relevant in the early cycles, Ueno said, after which the scores decreased and remained stable. Between cycles 7 and 27, nausea and vomiting remained within 10 points of baseline. The TDD for fatigue between the 2 arms was 11.1 months vs 4.5 months (HR, 0.61; 95% CI, 0.47-0.79; P = .002), and 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). Both assessments were made using the EORTC QLQ-C30 assessment.

Ultimately, the HRs for TDD favored trastuzumab deruxtecan over TPC for almost all PRO variables of interest (range, 0.40-0.73), investigators stated. The change from baseline in fatigue symptoms were similar between the 2 agents and did not worse over time with the antibody-drug conjugate; and the effect of trastuzumab deruxtecan on nausea and vomiting was only clinically relevant in the first 6 cycles.

“Overall, GHS [and] QOL in DESTINY-Breast04 was maintained for patients in the hormone receptor–positive cohort during the entire treatment period of trastuzumab deruxtecan or TPC,” Ueno concluded. “The QOL benefit observed from the patient’s perspective confirm the efficacy and safety results of DESTINY-Breast04.”

_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.}