Quality of life during treatment with trastuzumab deruxtecan—is quality of life maintained due to high efficacy?

Introduction

As metastatic or recurrent breast cancer is difficult to cure, the goals of treatment are to prolong the survival and maintain the quality of life (QOL) of patients. Trastuzumab deruxtecan (T-DXd) is a new generation anti-HER2 antibody-drug conjugate (ADC) that features a stable linker and a high drug-to-antibody ratio (DAR: 7–8) (1). The payload, the topoisomerase I inhibitor (MAAA-1181a), has high cell membrane permeability and a bystander effect, and this is thought to be one reason why T-DXd shows a high response rate. The DESTINY-Breast01 trial showed a response rate of >60% in patients with advanced or recurrent HER2-positive breast cancer who had undergone a median of six prior regimens (2).

The DESTINY-Breast02 trial was a phase 3 study comparing T-DXd with the physician’s choice therapy in patients with unresectable metastatic HER2-positive breast cancer previously treated with trastuzumab emtansine (T-DM1) (3). A total of 608 patients with HER2-positive advanced breast cancer with a history of T-DM1 treatment were randomized in a 2:1 ratio to receive either T-DXd or the physician’s choice treatment (trastuzumab/capecitabine or lapatinib/capecitabine). The prior treatment history of patients before metastatic recurrence was predominantly 2 or 3 regimens. In the T-DXd group, 47.3% and 30.3% of patients had received 2 and 3 prior regimens, respectively, while in the physician’s choice therapy group, these numbers were 45.5% and 31.2%, respectively (3). The primary endpoint was progression-free survival (PFS) as determined by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), response rate, duration of response, and safety.

The results of the trial showed that T-DXd reduced the risk of disease progression by 64% compared with the physician’s choice therapy. The median PFS was 17.8 months for patients receiving T-DXd, whereas it was 6.9 months for those administered the physician’s choice therapy group. Additionally, OS was significantly improved with T-DXd (39.2 months) compared with that in the physician’s choice therapy group (26.5 months), with a hazard ratio of 0.66 (3).

In the DESTINY-Breast03 trial, compared with T-DM1, T-DXd demonstrated a significant extension in PFS in patients with unresectable or metastatic HER2-positive breast cancer with prior treatments including trastuzumab and taxanes (4) (PFS: T-DXd 28.8 months, T-DM1 6.8 months; hazard ratio 0.33), leading to T-DXd being used earlier than T-DM1. Consequently, T-DXd is currently a highly anticipated drug rapidly transforming treatment paradigms in breast cancer.

Patient-reported outcomes (PRO) in the DESTINY-Breast02 trial

Maintaining QOL is crucial in metastatic disease treatment. The DESTINY-Breast02 trial assessed the QOL of patients using several tools, including the tumor-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the breast cancer-specific EORTC QLQ-BR45, and general health-related QOL assessments like the EQ-5D-5L. The median duration of treatment was 11.3 months (interquartile range, 6.2–20.5 months) for the T-DXd group, compared to approximately 4.5 months for the group receiving the physician’s choice of therapy (5).

The analysis concentrated on changes from baseline and the time to definitive deterioration (TDD), which was defined as a change of 10 points or more from baseline. The EORTC QLQ-C30 global health status (GHS) score revealed that the median TDD was longer for the T-DXd group at 14.1 months [95% confidence interval (CI): 10.4–18.7] compared to 5.9 months (4.3–7.9) for the physician’s choice therapy group [hazard ratio (HR): 0.5573, P<0.0001] (5).

In terms of significant secondary PRO measures from the QLQ-C30, including physical functioning, the T-DXd treatment prolonged the TDD (median TDD of 18.7 vs. 6.8 months; HR: 0.4637, 95% CI: 0.3575–0.6014; P<0.0001) and pain symptoms [18.7 months (14.1–23.8) vs. 5.8 months (5.0–7.0); HR: 0.3779, 95% CI: 0.2941–0.4857; P<0.0001] compared to the physician’s choice therapy group. In the T-DXd group, 170 out of 406 patients (42%) reported definitive worsening of pain symptoms, while 110 out of 202 patients (54%) in the physician’s choice therapy group did. Moreover, in the QLQ-BR45 breast and arm symptom scales, the T-DXd group demonstrated a longer median TDD compared to the physician’s choice group (breast symptoms HR: 0.4164, 95% CI: 0.2928–0.5921, P<0.0001; arm symptoms HR: 0.5737, 95% CI: 0.4415–0.7456, P<0.0001) (5).

Based on the efficacy and safety findings from the DESTINY-Breast02 trial, these results reinforce the overall benefit of T-DXd for patients with unresectable or metastatic HER2-positive breast cancer who have previously received T-DM1 treatment.

Other PRO for T-DXd

In the DESTINY-Breast03 trial, PROs and hospitalization data were compared between patients with metastatic HER2-positive breast cancer receiving either T-DXd or T-DM1. The EORTC QLQ-C30 GHS scores were comparable between the groups, showing no clinically significant changes (with a baseline change of less than 10 points). The median treatment durations were 14.3 months for the T-DXd group and 6.9 months for the T-DM1 group (6). In the QLQ-C30 GHS and other predefined PROs, the T-DXd group was favored over the T-DM1 group, with median time to first hospitalization being 219.5 d for T-DXd, whereas 60.0 d for T-DM1. The EORTC GHS/QoL score was maintained throughout treatment in both groups, and despite the longer treatment duration for T-DXd, the HRQoL score did not deteriorate compared with that for T-DM1 (6).

Additionally, in the DESTINY-Breast04 trial targeting patients with unresectable or metastatic HER2-low expressing (IHC1+ and IHC2+ with ISH-negative) breast cancer, 557 patients (with prior lines of chemotherapy and centrally confirmed HER2-low expression) were randomized to receive either T-DXd or the physician’s choice therapy (TPC: gemcitabine, eribulin, capecitabine, paclitaxel, or nab-paclitaxel) in a 2:1 ratio (7). The primary endpoint was PFS in HR-positive patients as determined by BICR, with major secondary endpoints including PFS for all randomized patients, OS for HR-positive patients, OS for all randomized patients, and other evaluations including overall response rate, duration of response, PFS, and safety. A total of 373 patients (88.7% HR-positive) were randomized to the T-DXd group, whereas 184 patients (88.6%) were classified into the TPC group. In the TPC group, 51.1% received eribulin, 20.1% capecitabine, 10.3% nab-paclitaxel, 10.3% gemcitabine, and 8.2% paclitaxel. The median PFS for HR-positive patients was 10.1 months in the T-DXd group, whereas 5.4 months in the TPC group, with a hazard ratio of 0.51 (95% CI: 0.40–0.64, P<0.0001) (7).

PRO data from the DESTINY-Breast04 trial were reported at the ESMO Congress 2022 (8). PROs were measured using EORTC and EuroQol (EQ) group QLQs, including EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L, assessed every cycle up to the third cycle, then every two cycles, and at 40 d and 3 months after treatment cessation. The median TDD for GHS/QOL was 11.4 months in the T-DXd group, whereas 7.5 months in the physician’s choice therapy group (HR: 0.69, 95% CI: 0.52–0.92, P=0.0096). The TDD for all QLQ-C30 subscales except nausea was longer in the T-DXd group, with median TDD for pain being 16.4 months in the T-DXd group, whereas 6.1 months in the physician’s choice therapy group (HR: 0.40, 95% CI: 0.30–0.54, P<0.0001).

A subanalysis comparing QOL in the DESTINY-Breast04 trial, in which 61 patients were randomized to receive T-DXd, whereas 34 were administered capecitabine, was presented at ESMO-BC 2024 (9). The main difference between the subanalysis of the DESTINY-Breast04 study and the DESTINY-Breast02 study is that the DESTINY-Breast02 study compared the T-DXd regimen with the anti-HER2 agent (trastuzumab or lapatinib) plus capecitabine regimen in HER2-positive breast cancer. Other differences were that around 77% of patients in the DESTINY-Breast04 study had received prior treatment with a CDK4/6 inhibitor, and that the DESTINY-Breast02 study included more patients with more prior treatments. In DESTINY-Breast04 study subanalysis, the median PFS was 10.1 months for patients receiving T-DXd, whereas 5.4 months for those administered capecitabine. The median TDD (95% CI) of the QOL/GHS was 16.7 months (10.9–not estimable) in the T-DXd subgroup, whereas 7.0 months (1.5–10.5) in the capecitabine subgroup, with a hazard ratio of 0.42 (0.23–0.78). Notably, the TDD hazard ratios for most PRO indicators, including pain (HR: 0.42; 95% CI: 0.23–0.78) and arm symptoms (HR: 0.55; 95% CI: 0.30–0.99), favored T-DXd over capecitabine (9). The clinical trials we have discussed are summarized in Table 1.

Fewer adverse events do not necessarily correlate with maintaining QOL

Subjective adverse events are associated with a decrease in QOL, but this is offset by the improvement and maintenance of QOL due to the therapeutic/antitumor effect. In the DESTINY-Breast03 study, the frequency and Grade 3 or higher of subjective adverse events such as nausea, vomiting, diarrhoea, fatigue, headache, loss of appetite, and hair loss were higher with T-DXd than with T-DM1 (4). Nevertheless, in terms of the EORTC QLQ-C30 QOL assessment, T-DXd tended to be better in most categories.

In the paper, it is argued that T-DXd is less toxic than T-DM1 because the exposure-adjusted incidence rate (EAIR) is lower in the T-DXd group than in the T-DM1 group (10). However, adverse events that patients are aware of occur more frequently with T-DXd in most categories, and many of these occur early in treatment (10), so it is unlikely that QOL was maintained because T-DXd was less toxic. From this, it is thought that the antitumor effect of T-DXd plays an important role in improving and maintaining QOL.

In addition, the results of the DESTINY-Breast06 study, which compared T-DXd with TPC as first-line treatment for advanced or recurrent breast cancer with low HER2 expression, have been reported. In first-line treatment for cases with low HER2 expression, the T-DXd group had a longer PFS than the TPC group (11). As approximately 60% of the TPC group received capecitabine, the QOL data for the T-DXd and TPC groups will be of particular interest in the future.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-177/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-177/coif). T.Y. reports receiving payments from Chugai, Taiho, Nippon Kayaku, Eli Lilly, Daiichi Sankyo, Pfizer, Astrazeneca, Seagen, MSD, Kyowa Kirin, Ono, Gilead Sciences, and Eisai; and honoraria for lectures from Chugai, Eisai, Daiichi Sankyo, Taiho, Nippon Kayaku, Astrazeneca, Kyowa kirin, Pfizer, Eli Lilly, Novartis Pharma, and MSD. The other author has no conflicts of interest to declare.

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