Positive results from the phase 3 DESTINY-Breast06 trial showed that trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with standard chemotherapy in patients with hormone receptor (RH)- and HER2-positive metastatic breast cancer.-short (IHC 1+ or IHC 2+/ISH-) and in the entire study population (HR-positive, HER2-short and HER2-ultra-low (defined as IHC 0 with membrane staining)) after one or more lines of endocrine treatment. The results (LBA1000) were presented at the annual meeting of the American Society of Clinical Oncology (#ASCO24).
This drug is an antibody conjugate specifically targeting HER2, discovered by Daiichi Sankyo, developed and marketed by the Daiichi Sankyo Alliance | AstraZeneca.
When analyzing the main task of patients with HR-positive HER2-metastatic breast cancershortthis ADC reduced the risk of disease progression or death by 38% compared with chemotherapy (risk ratio: 0.62; 95% confidence interval (CI): 0.51-0.74; P
When analyzing the key secondary endpoint of PFS by BICR in the overall study population, this ADC achieved a similar 37% reduction in the risk of disease progression or death compared with chemotherapy, with a median PFS of 13.2 months in this ADC group versus 8. 1. months of chemotherapy (hazard factor: 0.63; 95% CI: 0.53-0.75; P
A prespecified exploratory analysis showed that the clinically meaningful improvement in PFS was consistent among patients with HER2.-short and HER2-ultra-low. In patients with HER2-ultra-lowthis ADC showed a 22% reduction in the risk of disease progression or death compared with chemotherapy, with a median PFS of 13.2 months with this ADC compared to 8.3 months with chemotherapy (risk ratio 0.78; 95% CI: 0.50–1.21).
In patients with HER2-shortThe confirmed objective response rate (ORR) was 56.5% in this ADC group with nine confirmed complete responses (CR) and 194 partial responses (PR), compared with 32.2% in the chemotherapy group with zero RC and 114 RP. In the overall study population, the confirmed ORR in this ADC group was 57.3% with 13 CR and 237 PR compared with 31.2% in the chemotherapy group with 0 CR and 134 PR. In patients with HER2-ultra-lowthe confirmed ORR in the ADC group was 61.8% with 4 CR and 43 CR compared with 26.3% in the chemotherapy group with 0 CR and 20 CR.
“Endocrine therapy is widely used in the early stages of treatment for HR-positive metastatic breast cancer, but after one or more lines of treatment, patients often experience limited benefit from additional endocrine therapy.”“says Giuseppe Curigliano, MD, PhD, professor of medical oncology at the University of Milan and head of the early drug development unit at the European Institute of Oncology, IRCCS, Italy, and principal investigator of the study. “With a median progression-free survival of more than one year, the results of the DESTINY-Breast06 trial indicate that this ADC may become the new standard of care for patients with HER2-low and HER2-ultra-low tumors after endocrine therapy in the context of “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. The most common treatment-emergent adverse events (TEAEs) grade 3 or higher, occurring in 5% or more of patients receiving 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 receiving this ADC. Most episodes of PID or pneumonitis were of low severity (grade 1 (n=7; 1.6%) or grade 2 (n=36; 8.3%)). According to the independent committee, there were three episodes of grade 3 PID (0.7%), zero grade 4 and three episodes of grade 5 (0.7%).
“This ADC continues to offer innovative drug results targeting HER2 across multiple cancer types.”– states Ken Takeshita, MD, global director of research and development at Daiichi Sankyo. “The latest results from the DESTINY-Breast06 trial demonstrate clinically meaningful results with this ADC even in tumors with very low levels of HER2 expression, suggesting that it may have an important role in the treatment of a wide range of HER2-expressing metastatic breast cancers.”.
“DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer.”“,” says Susan Galbraith, MBBChir, Ph.D., executive vice president of oncology research and development at AstraZeneca. “The results support the potential of this ADC to improve outcomes early in treatment and in the broader population of patients with HER2 breast cancer who are not eligible for HER2-targeted therapy.”
Patients in the DESTINY-Breast06 study had received an average of two prior lines of endocrine therapy in each treatment arm. Of the overall study population, 14.9% of patients (n=65) in this ADC group had previously received one line of endocrine therapy, and 67.8% (n=295) had previously received two lines of endocrine therapy. None of the patients in the study had previously received chemotherapy for metastatic disease. The average follow-up duration was 18.2 months. At the data cutoff date of 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.
| Measure of effectiveness | HER2 low (IHC 1+ and IHC 2+/ISH-) | General study population (HER2-short and HER2-ultra-low) | HER2 ultra-low (IHC 0 with membrane staining)i, ii | |||
| This ADC (n=359) | Chemotherapy (n=354) | This ADC (n=436) | Chemotherapy (n=430) | This ADC (n=76) | Chemotherapy (n=76) | |
| SLP | ||||||
| Median PFSIII (months) (95% CI) | 13.2 months | 8.1 months | 13.2 months | 8.1 months | 13.2 months | 8.3 months |
| Risk ratio (95% CI) | 0.62 (0.51;0.74) | 0.63 (0.53;0.75) | 0.78 (0.50;1.21) | |||
| p-value | P | P | — | |||
| S.G. | ||||||
| Median OS 12 months (%) (95% CI) | N.D.iv | N.D. | N.D. | N.D. | N.D.iv | N.D.iv |
| OS ratio for 12 months (%) (95% CI) | 87.6% | 81.7% | 87.0%
| 81.1%
| 84.0% | 78.7% |
| Risk ratio (95% CI) | 0.83 (0.66;1.05) | 0.81 (0.65, 1.00)saw | 0.75 (0.43, 1.29) |
| 0.75 (0.43-1.29) |
|
| p-value | p=0.1181V | — | — |
|
|
|
| TRO | ||||||
| Verified ORRi, iii, vi Hey(%) (n) | 56.5% (203) | 32.2% (114) | 57.3% (250) | 31.2% (134) | 61.8% (47) | 26.3% (20) |
| Best general answer | ||||||
| CR % (n) | 2.5% (9) | 0 | 3.0% (13) | 0 | 5.3% (4) | 0 |
| RP% (n) | 54.0% (194) | 32.2% (114) | 54.4% (237) | 31.2% (134) | 56.6% (43) | 26.3% (20) |
| EE% (p) | 34.8% (125) | 48.0% (170) | 33.9% (148) | 49.3% (212) | 28.9% (22) | 55.3% (42) |
| Median DR (months) | 14.1 months | 8.6 months | 14.3 months | 8.6 months | 14.3 months | 14.1 months |
IC.: confidence interval; CR: full answer; DR: duration of response; Hazard factor; ND: no data; PFS: progression-free survival; ORR: objective response rate; OS: overall survival; PR: partial response; EE: stable disease.
descriptive analysis
ii Central Laboratory
iii As assessed by BICR
iv Maturity less than 40% for interim analysis of fixed assets (HER2-short)
v Significance testing was not performed using multiple testing procedures.
vi A p value of 0.0046 was required to ensure statistical significance in this interim analysis of overall survival.
vii TRO is (RC + RP)
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