Trastuzumab Deruxtecan Tops Trastuzumab Emtansine as Second-Line Therapy in HER2-Positive Metastatic Breast Cancer

JHOP - December 2021 Vol 11, No 6 - ESMO 2021 Highlights
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Previously treated patients with HER2-positive metastatic breast cancer have improved progression-free survival (PFS) from trastuzumab deruxtecan-nxki (Enhertu) compared with ado-trastuzumab emtansine (Kadcyla), according to data from the phase 3 DESTINY-Breast03 clinical trial.

In findings announced at the 2021 European Society for Medical Oncology Congress, the risk for disease progression or death, as assessed by an independent review, was reduced by 72% in patients who received trastuzumab deruxtecan compared with those who received trastuzumab emtansine (P = 7.8 × 10-22).

The improvement in PFS with trastuzumab deruxtecan was “highly statistically significant and clinically meaningful,” said Javier Cortés, MD, PhD, Founder and Director, International Breast Cancer Center, Barcelona, Spain. He also called the overall survival data “encouraging.”

The hazard ratio (HR) for overall survival favored trastuzumab deruxtecan over trastuzumab emtansine (HR, 0.56) but did not achieve the prespecified boundary for significance (P <.000265) based on 86 events, which Dr Cortés attributed to the immaturity of the data set. The estimated 12-month survival rates were 94.1% and 85.9%, respectively.

“These data support trastuzumab deruxtecan becoming the standard of care for second-line HER2-positive, metastatic breast cancer,” he said.

The open-label DESTINY-Breast03 study randomized 524 patients who had previously received a taxane and pertuzumab from 50 countries to trastuzumab deruxtecan, 5.4 mg/kg, or to trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. Approximately 50% of the patients in each arm had received 1 previous therapy in the metastatic setting, and 8.8% and 6.8%, respectively, had ≥5 previous lines in the trastuzumab deruxtecan and trastuzumab emtansine arms.

An interim PFS analysis showed that the efficacy boundary (P <.000294) for superiority of trastuzumab deruxtecan had been met, based on 245 events, and the Independent Data Monitoring Committee recommended to unblind the study. The median follow-up for the primary end point was 16.2 months in the trastuzumab deruxtecan arm and 15.3 months in the trastuzumab emtansine arm. At the time of analysis, treatment was ongoing in 132 and 47 patients in the 2 arms, respectively.

The median PFS duration was not reached in the trastuzumab deruxtecan arm versus 6.8 months in the trastuzumab emtansine arm, with estimated 12-month rates of 75.8% and 34.1%, respectively. The significant PFS benefit associated with trastuzumab deruxtecan was consistent across all predefined subgroups, including those defined by hormone receptor status, previous pertuzumab use, and the presence of visceral disease or brain metastases.

The objective response rate was 79.7% in the trastuzumab deruxtecan arm versus 34.2% in the trastuzumab emtansine arm (P <.0001). Nearly twice as many complete responses occurred in the trastuzumab deruxtecan arm compared with the trastuzumab emtansine arm (16.1% vs 8.7%).

Grade ≥3 treatment-emergent adverse events occurred in 45.1% of the trastuzumab deruxtecan group and 39.8% in the trastuzumab emtansine group, with the most common events being 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%), respectively.

The rates of dose reductions (21.4% vs 12.6%) and discontinuations because of drug-related adverse events were higher in the trastuzumab deruxtecan versus the trastuzumab emtansine arm (12.8% vs 5.0%). No deaths were reported in either group attributable to drug-related adverse events.

Drug-related interstitial lung disease or pneumonitis was more common in the trastuzumab deruxtecan versus the trastuzumab emtansine treatment arm (10.5% and 1.9%, respectively). Most of these events were grade 1 or 2, with just 2 grade 3 cases in the trastuzumab deruxtecan group and no grade 4 or 5 in either group.

“We’ve entered an exciting era of the next generation of antibody–drug conjugates,” commented invited discussant Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York City, who described the efficacy observed with trastuzumab deruxtecan as “unprecedented.”

She said, “I think the PFS curves from DESTINY-Breast03 are absolutely startling. I don’t believe I’ve seen a hazard ratio like this in HER2-positive breast cancer before. Most important, there was an absence of high-grade events [with trastuzumab deruxtecan],” emphasizing the far lower rate of lung toxicity with this new drug in this early-line setting than observed in a predecessor study known as DESTINY-Breast01, “resetting the risk-benefit analysis in its favor.”

Based on these new data, she said that “Trastuzumab deruxtecan is now my preferred antibody–drug conjugate in the second-line setting.”

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