Trastuzumab deruxtecan safe for HER2-positive metastatic breast cancer, analysis shows
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CHICAGO — Trastuzumab deruxtecan exhibited a tolerable safety profile with longer follow-up among patients with HER2-positive unresectable and/or metastatic breast cancer in the DESTINY-Breast03 trial, a study at ASCO Annual Meeting showed.
The HER2 antibody-drug conjugate, whose full name is fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo), also demonstrated lower exposure-adjusted incidence rates of grade 3 or higher and serious adverse events compared with trastuzumab emtansine (Kadcyla, Genentech), a standard treatment for patients who experience progression after treatment with anti-HER2 antibodies and a taxane.
“This reassures us that trastuzumab deruxtecan is safe and can very successfully be given to patients in earlier-line settings,” Erika Hamilton, MD, director of breast cancer and gynecologic cancer research for Sarah Cannon Research Institute at Tennessee Oncology, told Healio. “When compared with benefit and duration on study, serious events were lower per patient year than with trastuzumab emtansine.”
Background and methods
In the primary analysis of the multicenter, randomized phase 3 DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated a 72% reduction in risk for progression (HR = 0.28; 95% CI, 0.21-0.37) vs. trastuzumab emtansine (T-DM1) among patients who received trastuzumab (Herceptin, Genentech) and/or a taxane in the metastatic setting or relapsed within 6 months of neoadjuvant/adjuvant HER2-directed therapy, Hamilton said. T-DXd also demonstrated a safety profile consistent with previous studies.
Based on these results, the agent received expanded FDA approval last month for patients in this earlier metastatic setting.
“The purpose of this analysis was to update safety information from the DESTINY-Breast03 trial and look more closely at adverse events of interest,” Hamilton said.
Among patients randomly assigned to the antibody-drug conjugates, 116 (45.1%) remained on T-DXd and 39 (14.9%) remained on T-DM1 as of data cutoff Sept. 7, 2021. Patients in the T-DXd group had a longer median treatment duration (16.1 months vs. 6.9 months).
Key findings
Results showed similar rates in T-DXd and T-DM1 groups of any-grade (99.6% vs. 95.4%), grade 3 or higher (53.3% vs. 49.8%) and serious (21% vs. 19.2%) adverse events.
The T-DXd group had higher rates of nausea (grade 3, 6.6% vs. 0.4%), vomiting (grade 3, 1.6% vs. 0.8%) and alopecia, most cases of which were grade 1 or grade 2, but a similar rate of fatigue compared with the T-DM1 group.
“All of these side effects have the pattern of peaking in the first cycle or two and then remaining very stable over time,” Hamilton noted. “This emphasizes the need for upfront and continued supportive care to minimize these effects while on treatment with T-DXd.”
The T-DXd group had lower exposure-adjusted incidence rates (EAIRs) — a standardized measure of risk per patient year — for grade 3 or higher (0.42 vs. 0.7) and serious (0.17 vs. 0.27) adverse events.
“EAIRs were lower in the T-DXd arm for all categories examined except for drug discontinuation, where the rate for T-DXd was higher and driven by the approximately 8% of patients who discontinued for interstitial lung disease [ILD]/pneumonitis,” Hamilton said.
Researchers had been closely following ILD and pneumonitis following fatal cases reported in the first DESTINY-Breast01 disclosure, according to Hamilton.
“In [DESTINY-Breast03], even with further follow-up, we observed a 10.9% rate of all-grade [interstitial lung disease]/pneumonitis with T-DXd vs. 1.9% with T-DM1,” Hamilton told Healio. “Importantly, we see no cases of grade 4 or grade 5 pneumonitis with T-DXd and, in fact, the rate for grade 3 cases with T-DXd remains 0.8%, with no new severe cases. This is very reassuring as we move T-DXd up into earlier lines.”
Researchers reported a median time to first adjudicated, drug-related interstitial lung disease/pneumonitis event of 5.9 months for T-DXd vs. 9.5 months for T-DM1. Most events had resolved by data cutoff (57.1% vs. 80%) and follow-up continues.
The T-DXd group had a longer median time to treatment-related adverse events that led to drug discontinuation (224 days vs. 147 days) or dose reduction (96 days vs. 19 days).
Next steps
Other ongoing trials are examining T-DXd in even earlier-line settings, Hamilton told Healio.
“DESTINY-Breast07, for example, is looking at T-DXd in combinations in the first-line metastatic setting, and DESTINY-Breast09 is looking at T-DXd either alone or with pertuzumab [Perjeta, Genentech] in the first-line setting vs. a taxane/trastuzumab/pertuzumab,” she said. “Additionally, trials in the curative setting are looking at T-DXd vs. T-DM1 for high-risk residual disease, as well as T-DXd trials in the neoadjuvant setting.”
Perspective
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Danielle Sterrenberg, MD
DESTINY-Breast03 evaluated the use of T-DXd vs. T-DM1 among patients with unresectable or metastatic HER2-positive disease who had progressed following taxane- and Herceptin-based therapy. In this practice-changing study, researchers randomly assigned 524 previously treated patients to 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 every 3 weeks, with a primary endpoint of PFS.
By investigator review, median PFS was 25.1 months on T-DXd vs. 7.2 months on T-DM1. This was highly statistically significant, with a HR of 0.2649, and the benefit was seen across all subgroups, including those with brain metastasis. In addition, researchers observed no new safety signals.
In this updated safety analysis, T-DXd again demonstrates a tolerable safety profile, with similar rates of interstitial lung disease at the prior data cutoff point. This confirms the practice-changing results of DESTINY-Breast03 and further solidifies that T-DXd could be considered the standard of care for patients with metastatic or unresectable HER2-positive breast cancer following taxane- and Herceptin-based therapy.
Given the marked improvement seen in DESTINY-Breast03 and the tolerable safety profile, we need to elucidate whether this benefit could occur in the first-line metastatic setting or even in the management of early-stage, HER2-positive breast cancer.
Reference:
Cortés J, et al. Abstract LBA1. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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Hamilton EP, et al. Abstract 1000. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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