MBC Outcomes Superior With Trastuzumab Deruxtecan vs Trastuzumab Emtansine

Risks of disease progression and mortality following metastatic breast cancer (mBC) progression were reduced with administration of trastuzumab deruxtecan vs trastuzumab emtansine, according to findings of a DESTINY-Breast03 trial interim data analysis published today in the New England Journal of Medicine.

This interim data analysis from the phase 3 multicenter open-label randomized active-controlled trial evaluated progression-free survival (PFS), as a primary outcome, and overall survival (OS), objective response, and safety, as secondary outcomes. Findings were compared between patients randomized 1:1 who were treated with trastuzumab deruxtecan or trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic breast cancer that progresses during or after treatment with trastuzumab and a taxane or within 6 months of treatment with trastuzumab or a taxane in the neoadjuvant or adjuvant setting.

“Findings from the DESTINY-Breast01 trial indicated that the efficacy of trastuzumab deruxtecan substantially exceeded that of currently available HER2-directed regimens,” the authors wrote, “and provided considerable support for a head-to-head trial comparing trastuzumab deruxtecan with trastuzumab emtansine.”

The current standard of care in HER2-positive mBC is trastuzumab emtansine.

Among the 261 patients in the trastuzumab deruxtecan group and the 263 in the trastuzumab emtansine group, the median ages were 54 years and most were from Asia (57.1% and 60.8%, respectively), had a HER2 status of 3+ (89.7% and 88.2%), and had 1 to 3 prior lines of treatment (84.7% and 84.8%).

PFS was more than twice as high in the trastuzumab deruxtecan vs the trastuzumab emtansine group: 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%), with the risk of disease progression or mortality reduced by 72% with the former (HR, 0.28; 95% CI, 0.22-0.37; P < .0001). Further, investigator-assessed PFS was approximately 3.5 times longer with trastuzumab deruxtecan vs trastuzumab emtansine: 25.1 (95% CI, 22.1-not estimable) vs 7.2 (95% CI, 6.8-8.3) months.

Overall response rate (ORR; comprising complete or partial response) was also superior among those who received trastuzumab deruxtecan compared with trastuzumab emtansine, as was survival 1 year after treatment:

• ORR: 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%)
• 12-month survival: 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%)

The intravenous treatments were dosed every 3 weeks at 5.4 mg/kg of body weight (trastuzumab deruxtecan) and 3.6 mg/kg (trastuzumab emtansine). Patients were enrolled in the study between July 20, 2018, and June 23, 2020, at 169 centers in 15 countries.

More drug-related adverse events (AEs) were seen in the trastuzumab deruxtecan vs the trastuzumab emtansine group, at 98.1% vs 86.6%. For those of any grade, neutropenia (42.8%), nausea (72.8%), fatigue (44.7%), and alopecia (36.2) were some of the most common overall AEs among those receiving trastuzumab deruxtecan; these were thrombocytopenia (51.7%), nausea (27.6%), fatigue (29.5%), and increased aspartate aminotransferase (37.2%) in the trastuzumab emtansine cohort.

Grade 3/4 AEs were also more often seen with trastuzumab deruxtecan vs trastuzumab emtansine—45.1% vs 39.8%—and the most common were neutropenia (19.1%) and thrombocytopenia (24.9%), respectively. Median treatment duration also was longer with trastuzumab deruxtecan vs trastuzumab emtansine: 14.3 (range, 0.7-29.8) vs 6.9 (95% CI, 0.7-25.1) months.

“Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group,” the authors added, “but none of these events were of grade 4 or 5.”

They subsequently noted that their findings on trastuzumab emtansine echo recent research that evaluated its efficacy following a first-line regimen of pertuzumab plus trastuzumab and a taxane for metastatic disease. In particular, that patients who have received trastuzumab emtansine have had longer PFS with fewer or no previous lines of treatment.

“These data showed the superiority of trastuzumab deruxtecan over trastuzumab emtansine,” the authors concluded. “Trastuzumab deruxtecan is an effective new treatment for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane, as well as with pertuzumab when available.”

Reference

Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386:1143-1154. doi:10.1056/NEJMoa2115022