Trastuzumab deruxtecan shows ‘unprecedented efficacy’ in DESTINY-Breast03
medwireNews: Previously treated patients with HER2-positive metastatic breast cancer derive a significant progression-free survival (PFS) benefit from trastuzumab deruxtecan (T-DXd) relative to trastuzumab emtansine (T-DM1), find the DESTINY-Breast03 investigators.
The PFS improvement with T-DXd was “highly statistically significant and clinically meaningful” in this population of patients who had already received trastuzumab and taxane chemotherapy, and the overall survival (OS) data were “encouraging,” presenter Javier Cortés (Vall d'Hebron University, Barcelona, Spain) told the audience at ESMO Congress 2021.
He believes “these data support T-DXd becoming the standard of care for second-line HER2-positive, metastatic breast cancer.”
In the open-label phase 3 trial, the risk for progression or death as assessed by blinded independent review was reduced a significant 72% for the 261 patients who were randomly assigned to receive T-DXd at a dose of 5.4 mg/kg every 3 weeks compared with the 263 given T-DM1 3.6 mg/kg every 3 weeks instead.
The median PFS duration was unreached in the T-DXd group and was 6.8 months in the T-DM1 group, with estimated 12-month rates of 75.8% and 34.1%, respectively.
Cortés emphasized that the significant PFS benefit associated with T-DXd treatment was observed across all predefined subgroups, including those defined by hormone receptor status, prior pertuzumab use, and presence of visceral disease or brain metastases.
The objective response rate was also significantly higher among patients given T-DXd than those who received T-DM1, at 79.7% versus 34.2%, with a near doubling of the complete response rate in the T-DXd group, at 16.1% versus 8.7%. The disease control rates were 96.6% and 76.8%, respectively.
OS also favored treatment with T-DXd over T-DM1, with a hazard ratio for death of 0.56, but the p value did not cross the prespecified boundary for statistical significance, which Cortés attributed to the immaturity of the dataset. The estimated 12-month survival rates were 94.1% and 85.9%, respectively.
With regard to the safety, grade 3 or worse drug-related treatment-emergent adverse events (TEAEs) occurred in a comparable 45.1% of T-DXd-treated participants and 39.8% of those given T-DM1. The most common events of this severity in the T-DXd versus T-DM1 group were neutropenia (19.1 vs 3.1%), thrombocytopenia (7.0 vs 24.9%), leukopenia (6.6 vs 0.4%), and nausea (6.6% vs 0.4%).
The rates of dose reductions and discontinuations due to drug-related TEAEs were higher in the T-DXd than T-DM1 arm, at 21.4% versus 12.6% and 12.8 versus 5.0%, respectively. No deaths in either group were attributed to drug-related TEAEs.
Focusing on adverse events of special interest, Cortés reported that drug-related interstitial lung disease/pneumonitis was more common in the T-DXd compared with the T-DM1 treatment arm, at rates of 10.5% and 1.9%, respectively. But he highlighted that most of the events were grade 1 or 2 in severity, with just two grade 3 cases in the T-DXd group and none at grade 4 or 5 in either group.
Discussant Shanu Modi (Memorial Sloan Kettering Cancer Center, New York, USA) described the efficacy of T-DXd in the DESTINY-Breast03 trial as “unprecedented,” agreeing with the presenting author that the data support the agent as a new second-line option.
She acknowledged that it is not yet known whether T-DM1 or other drugs will work after T-DXd and how the sequencing will affect OS, but she stressed that “this current data vacuum should not be a reason for withholding a better drug.”
Modi also discussed the safety results, describing them as “reassuring.”
The use of T-DXd in this early-line setting appeared to be associated with less lung toxicity than that observed in previous studies, “resetting the risk–benefit analysis in its favor,” commented the discussant.
But she stressed that “vigilance and early intervention is absolutely mandatory to deliver T-DXd therapy safely.”
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