★ Trastuzumab deruxtecan demonstrates a median progression-free survival of 13.2 months versus 8.1 with chemotherapy in HER2-low and HER2-ultralow hormone-positive metastatic breast cancer after one or more lines of endocrine therapy

Positive results from the phase 3 DESTINY-Breast06 trial showed that trastuzumab deruxtecan demonstrated a statistically significant and clinically relevant improvement in progression-free survival (PFS) compared to standard chemotherapy in patients with hormone receptor-positive metastatic breast cancer ( RH) and HER2-low (IHC 1+ or IHC 2+/ISH-) and in the total trial population (HR positive, HER2-low and HER2-ultralow [definido como IHC 0 con tinción de membrana]) after one or more lines of endocrine treatment. The results (LBA1000) have been presented at the American Society of Clinical Oncology Annual Meeting (#ASCO24).

This drug is an antibody conjugate specifically targeting HER2 discovered by Daiichi Sankyo and developed and marketed by the Daiichi Sankyo Alliance | AstraZeneca.

In the analysis of the primary objective of patients with HR-positive HER2- metastatic breast cancerlowthis ADC reduced the risk of disease progression or death by 38% versus chemotherapy (hazard ratio: 0.62; confidence interval [IC] 95%: 0.51-0.74; p<0.0001). Median PFS was 13.2 months in this ADC arm versus 8.1 months in the chemotherapy arm, as assessed by a blinded independent central review committee (BICR).

In analysis of the key secondary endpoint of PFS by BICR in the total trial population, this ADC achieved a similar 37% reduction in the risk of disease progression or death versus chemotherapy, with a median PFS of 13.2 months in this ADC arm vs. 8.1 months with chemotherapy (hazard ratio: 0.63; 95% CI: 0.53-0.75; p<0.0001).

Prespecified exploratory analysis showed that clinically relevant improvement in PFS was consistent among HER2 patients-low and HER2-ultralow. In HER2 patients-ultralowthis ADC showed a 22% reduction in the risk of disease progression or death compared to chemotherapy, with a median PFS of 13.2 months with this ADC versus 8.3 months with chemotherapy (hazard ratio 0.78; 95% CI: 0.50-1.21).

In HER2 patients-low, the confirmed objective response rate (ORR) was 56.5% in this ADC arm, with nine confirmed complete responses (CR) and 194 partial responses (PR) versus 32.2% in the chemotherapy arm, with zero RC and 114 RP. In the total trial population, the confirmed ORR in this ADC arm was 57.3% with 13 CR and 237 PR versus 31.2% in the chemotherapy arm, with 0 CR and 134 PR. In HER2 patients-ultralowthe confirmed ORR in the arm of this ADC was 61.8%, with 4 CR and 43 PR, compared to 26.3% in the chemotherapy arm, with 0 CR and 20 PR.

“Endocrine therapies are widely used in the early stages of treatment for HR-positive metastatic breast cancer, but after one or more lines of treatment, patients often have limited efficacy with additional endocrine therapy.”says Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology, University of Milan and Head of the Division of Early Drug Development, European Institute of Oncology, IRCCS, Italy, and Principal Investigator of the trial. “With a median progression-free survival of more than one year, the DESTINY-Breast06 results show that this ADC could become a new standard of treatment for patients with HER2-low and HER2-ultralow tumors after endocrine therapy in the context “metastatic”.

The safety profile of this ADC in DESTINY-Breast06 was consistent with that of previous breast cancer clinical trials, with no new safety concerns identified. The most common grade 3 or higher treatment-related adverse events (TEAEs), which occurred in 5% or more of patients treated with this ADC, were neutropenia (20.7%), leukopenia (6.9% ) and anemia (5.8%). Interstitial lung disease (ILD) or pneumonitis occurred in 11.3% of patients treated with this ADC. Most episodes of PID or pneumonitis were low grade (grade 1 [n=7; 1,6%] or grade 2 [n=36; 8,3%]). There were three grade 3 (0.7%), zero grade 4, and three grade 5 (0.7%) PID episodes, as determined by an independent committee.

“This ADC continues to offer innovative results for a drug targeting HER2 in different types of cancer”states Ken Takeshita, MD, Global Director of R&D at Daiichi Sankyo. “These latest results from DESTINY-Breast06 demonstrate clinically relevant results with this ADC, even in tumors with very low levels of HER2 expression, suggesting that it could have an important role in the treatment of a wide range of metastatic breast cancers with HER2 expression”.

“DESTINY-Breast06 represents another potential paradigm shift in the way we treat patients across the spectrum of HR-positive metastatic breast cancer.”says Susan Galbraith, MBBChir, PhD, Executive Vice President of Oncology R&D at AstraZeneca. “The results reinforce the potential of this ADC to improve outcomes earlier in treatment and in a broader population of patients with HER2 breast cancer who have not been eligible for HER2-targeted therapy.”

Patients in the DESTINY-Breast06 trial received a median of two prior lines of endocrine therapy in each treatment arm. In the total trial population, 14.9% of patients (n=65) in this ADC arm had received one prior line of endocrine therapy and 67.8% (n=295) had received two prior lines of endocrine therapy. endocrine therapy. No patients in the trial had received prior treatment with chemotherapy in the metastatic setting. The median duration of follow-up was 18.2 months. At the data cutoff on March 18, 2024, a total of 119 patients (14.0%) remained on treatment in the study, with 89 patients (20.5%) receiving this ADC and 30 (7.2%) receiving chemotherapy.

I.C.: confidence interval; CR: complete response; DR: duration of response; Hazard ratio; ND: not available; PFS: progression-free survival; ORR: objective response rate; OS: overall survival; PR: partial response; EE: stable disease.

i Descriptive analysis

ii By central laboratory

iii According to BICR evaluation

iv Maturity less than 40% for interim OS analysis (HER2-low)

v No significance test was performed according to the multiple testing procedure

vi A p value of 0.0046 is required for statistical significance in this interim analysis of OS

vii TRO is (RC + RP)

Fountain: Dare