Trastuzumab-deruxtecan significantly delays disease progression in chemotherapy-naïve patients with HER2-low and -ultralow, HR+ metastatic breast cancer
Results of the phase III DESTINY-Breast 06 study, presented at ASCO 2024, demonstrate that trastuzumab deruxtecan (T-DXd) significantly delays the disease progression compared to single agent chemotherapy in patients with chemotherapy-naïve, hormone-receptor positive (HR+), HER2-low metastatic breast cancer who received at least one line of prior endocrine therapy (ET). Importantly, similar results were obtained in the subgroup of patients with ultralow HER2 expression, further increasing the proportion of breast cancer patients that could benefit from T-DXd.
Background
Based on the results of the DESTINY-Breast04 study, T-DXd was granted EMA approval for the treatment of patients with HER2-low metastatic breast cancer who received at least one prior line of chemotherapy. In this, HER2-low was defined as a level of HER2-expression on immunohistochemistry (IHC) of 1+, or 2+ in combination with a negative in situ hybridisation (ISH) test. Building on the positive results of this trial, DESTINY-Breast06 evaluated T-DXd in an earlier treatment line for HR+ metastatic breast cancer (i.e., endocrine pretreated, but chemotherapy-naïve) and further broadened the patient population to also include patients with an ultralow level of HER2 expression. This ultralow HER2 expression was defined as IHC 0 according to the ASCO/CAP criteria with a faint or incomplete membrane staining in ≤10% of the tumour cells.
Study design
In total 866 patients with HER2-low or -ultralow, HR+ metastatic breast cancer were randomised (1:1) to receive T-DXd (5.4 mg/kg) or treatment of physicians choice (TPC), which could consist of either capecitabine, nab-paclitaxel, or paclitaxel. In order to be eligible for the study, patients were not allowed to have received prior chemotherapy in the metastatic setting and had to be pretreated with two or more lines of endocrine therapy (ET) for metastatic disease. Patients who received one line of ET in the advanced setting were also allowed to participate if they had experienced disease progression within 24 months of adjuvant therapy, or within 6 months after the start of ET in combination with a CDK4/6 inhibitor in the metastatic setting. The primary endpoint of the trial was PFS by blinded independent central review (BICR) in the subgroup of patients with HER2-low disease. Key secondary objectives included PFS in intent-to-treat population (ITT= HER2-low and -ultralow) and overall survival (OS). PFS and OS were also evaluated in the HER2-ultralow population in a prespecified exploratory analysis.
Results
Of the 866 patients enrolled in the study, 713 had HER2-low disease while the remaining 153 were scored as HER2-ultralow. Baseline patient and disease characteristics were well-balanced between the two treatment arms both in the HER2-low and ITT population. In the ITT population, the median number of treatment lines was two, with about 90% of patients being pretreated with a CDK4/6 inhibitor. About 9% of patients in the study consisted of patients who received just one prior line of ET in the metastatic setting and progressed within 6 months of ET + CDK4/6 inhibition. The most common chemotherapy that was used in the TPC arm was capecitabine (59.8%), followed by nab-paclitaxel (24.4%) and paclitaxel (15.8%).
T-DXd significantly improved the PFS of patients with HER2-low disease compared to TPC, with a median PFS of 13.2 and 8.1 months, respectively (HR[95%CI]: 0.62[0.51-0.74]; p< 0.0001). Results in the ITT population were very consistent with this finding, with a median PFS of 13.2 and 8.1 months for T-DXd and TPC, respectively. In an exploratory analysis, the PFS improvement obtained with T-DXd over TPC in HER2-ultralow patients was consistent with what was seen in the HER2-low and ITT population (median PFS: 13.2 vs. 8.3 months; HR[95%CI]: 0.78[0.50-1.21]).
Results for OS were still immature at the time of the analysis (~40% maturity) but already indicated a trend for a better OS with T-DXd. In the HER2-low population, the 12-month OS rate was reported at 87.6% for T-DXd as compared to 81.7% with TPC (HR[95%CI]: 0.83[0.66-1.05]). Corresponding rates in the ITT population were 87% and 81.1%, respectively (HR[95%CI]: 0.81[0.65-1.00]). Of note, 17.9% of TPC treated patients in the ITT population received T-DXd after discontinuation of the study drug. T-DXd also outperformed TPC in terms of objective response rate (ORR), both in the HER2-low (56.5% vs. 32.2%) and ITT (57.3% vs. 31.2%) population. In the HER2-ultralow cohort, this difference in ORR was even more pronounced at 61.8% for T-DXd vs. 26.3% for TPC.
The safety profile of T-DXd was in line with previous reports without new safety signals. Interstitial lung disease (ILD) continues to be a concern with T-DXd with an incidence of treatment-related ILD of 11.3% as compared to 0.2% with TPC. While this ILD was mainly grade 1-2 (9.9%), there were still 3 ILD-related deaths in the T-DXd arm.
Conclusions
T-DXd induces a statistically significant and clinically relevant PFS benefit over TPC in ET-pretreated, but chemotherapy-naïve patients with HR+, HER2-low and -ultralow metastatic breast cancer. No new safety signals were identified. As such, DESTINY-Breast06 establishes T-DXd as an effective new treatment option for patients with HR+, HER2-low and -ultralow metastatic breast cancer following ET. As such, this study further broadens the population of breast cancer patients that could benefit from T-DXd. Taken together, the HER2-low and -ultralow population included in this trial represents about 85% of all the HR+/HER2- metastatic breast cancer patients.
Reference
Curigliano G, et al. Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) of chemotherapy in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2 immunohistochemistry (IHC) >0<1+ metastatic breast cancer (mBC): Primary results from DESTINY-Breast06. Presented at ASCO 2024; Abstract LBA1000.
