New analysis of the DESTINY-Breast06 trial demonstrated that trastuzumab deruxtecan (T-DXd) provides meaningful clinical benefit regardless of time to progression on prior endocrine therapy, offering a promising option for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2) low or ultra-low metastatic breast cancer.
The findings, presented at San Antonio Breast Cancer Symposium (SABCS) 2024 by Aditya Bardia, MD, director of the Breast Oncology Program at UCLA Health Jonsson Comprehensive Cancer Center Cancer Center in Los Angeles, build upon the previously reported primary analysis showing superior progression-free survival (PFS) with T-DXd compared with physician’s choice of chemotherapy (TPC).
“T-DXd demonstrated a clinically meaningful benefit vs standard chemotherapy regardless of time to progression on first-line endocrine-based treatment,” Bardia stated during his presentation. “This included patients with rapid disease progression on first-line endocrine-based treatment.”
Study Design and Methodology
The phase 3 DESTINY-Breast06 trial enrolled patients with HR+, HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization negative) or HER2-ultra-low (IHC 0 with membrane staining) metastatic breast cancer who had progressed on at least one endocrine-based therapy but had not received chemotherapy for metastatic disease. In his presentation, Bardia emphasized that “this trial was the first to include patients with HER2-ultra-low disease.”
“When the T-DXd indication gets expanded, pathologists may benefit from training to clarify HER2-ultra-low from HER2-0,” noted Lisa Carey, MD, deputy director of Clinical Sciences at UNC Lineberger Comprehensive Cancer Center, who was not involved in the study. “However, many are simply adopting the trial description of immunostaining characteristics, and others have not yet started down this path. With the addition of HER2-ultra-low,
The new analysis from the DESTINY-Breast06 trial focused on three key areas: Outcomes based on time to progression on first-line endocrine-based therapy, time from randomization to second progression or death (PFS2), and efficacy by extent of disease and tumor location.
T-DXd Improves PFS in Patients With Rapid Progression on Endocrine Therapy
Among patients with rapid progression (
Similar benefits were observed in patients with intermediate (6-12 months) and longer (> 12 months) time to progression. In patients with progression within 6-12 months, T-DXd provided a median PFS of 13.2 months compared with 6.9 months with TPC (HR, 0.69; 95% CI, 0.43-1.12), whereas in those with progression > 12 months, the median PFS was 12.9 and 8.2 months, respectively (HR, 0.67; 95% CI, 0.51-0.88).
In an interview, Carey commented on these findings, noting that “in relatively more endocrine-resistant tumors, the benefit of more effective chemotherapy is highlighted.”
In the control group, treatment choices included capecitabine (59.8%), nab-paclitaxel (24.4%), and paclitaxel (15.8%). “My guess is that in the real world, most choose capecitabine, as they did in this trial,” Carey said in an interview.
T-DXd Improves Response Rates and PFS2
The objective response rates strongly favored T-DXd across all subgroups, with approximately 60% of patients responding to T-DXd compared with about 25% with standard chemotherapy. In patients with rapid progression, the objective response rate was 67.7% with T-DXd vs 25.4% with TPC. Similar advantages were seen in patients with progression at 6-12 months (60.0% vs 28.8%) and those with progression at > 12 months (59.5% vs 33.1%).
“The response rate of 60% is more than double of what we have seen with other therapies in this setting, which highlights the robust clinical activity of T-DXd,” Bardia said in an interview.
The duration of response also consistently favored T-DXd across all time to progression subgroups: 12 months (15.7 vs 11.1 months).
The PFS2 analysis revealed sustained benefit with T-DXd, showing a median of 20.3 months vs 14.0 months with TPC (HR, 0.62; 95% Cl, 0.52-0.74; P
Bardia noted that although specific data on subsequent treatments were still being analyzed, the PFS2 benefit with T-DXd regardless of time to progression on first-line therapy suggests limited cross-resistance with subsequent treatments.
The efficacy of T-DXd was consistent regardless of disease burden, including in patients with less than three vs more than three metastatic sites, presence of liver metastases, baseline tumor size, and visceral metastases.
Safety of T-DXd Across Subgroups
“The safety profile in the subgroups was consistent with the overall study population,” Bardia noted during his presentation. “This included the incidence of pneumonitis, which showed no significant variation based on time to disease progression on first-line endocrine therapy or disease burden.”
Grade ≥ 3 treatment-emergent adverse events were observed in similar proportions across time to progression subgroups: 55.4% vs 42.4% for T-DXd vs TPC in 12 months group (n = 329).
Bardia emphasized that the study included a significant proportion of patients with challenging disease characteristics: Approximately one third had de novo metastatic disease, two thirds had liver metastases, and about one third had primary endocrine-resistant disease according to European Society For Medical Oncology criteria. The safety profile remained consistent regardless of these baseline characteristics.
Addressing the safety profile of T-DXd, “I generally think T-DXd is a tougher drug than capecitabine, for example, and I choose T-DXd in patients with symptoms or concern regarding rapid progression,” Carey said.
In the interview, Carey provided practical insights regarding treatment sequencing.
“T-DXd is a good choice early in chemotherapy lines for these patients. I use it as first-line chemotherapy for more aggressive or symptomatic endocrine-resistant cancers and as second-line chemotherapy for the others, but we should still use endocrine therapy-based options until endocrine resistance is evident.”
She added that the sequencing decisions are not always straightforward.
“There are little data suggesting that sequence matters, and capecitabine, for example, is an easier drug for patients to start with than T-DXd.”
Future Directions
Bardia revealed that biomarker analyses looking at PIK3CA and other mutations are planned to investigate potential factors predicting response to T-DXd.
These results suggest that “T-DXd could be an effective option earlier in the treatment sequence for HR+/HER2-low or ultra-low metastatic breast cancer patients following progression on one or more endocrine-based therapies,” he concluded. The consistent benefit observed across subgroups, including those with primary endocrine resistance and rapid progression, provides clinically relevant information for treatment decision-making.
The DESTINY-Breast06 trial was funded by AstraZeneca and Daiichi Sankyo. Bardia reported receiving grant funding from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, Menarini, Merck, Novartis, Pfizer, and Sanofi; and consulting fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, Menarini, Merck, Novartis, Pfizer, and Sanofi. Carey had no financial relationships to disclose.
Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.
Source link : https://www.medscape.com/viewarticle/t-dxd-shows-consistent-benefit-across-endocrine-resistant-hr-2024a1000ojy?src=rss
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Publish date : 2024-12-19 10:42:52
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