T-DXd ups PFS vs T-DM1 in HER2-positive metastatic breast cancer

Trastuzumab deruxtecan (T-DXd) reduces the risk of disease progression or death by 72 percent vs trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer whose disease progressed during or after treatment with an anti–HER-2 antibody, the first interim analysis of the DESTINY-Breast03 trial has shown.

The phase III, multicentre, open-label, randomized trial included 524 patients with HER2-positive, unresectable or metastatic breast cancer that had progressed during or after treatment with trastuzumab and a taxane, or that had progressed within 6 months after neoadjuvant or adjuvant treatment with trastuzumab or a taxane. The patients were randomized 1:1 to receive T-DXd (n=261; median age, 54.3 years) or T-DM1 (n=263; median age, 54.2 years). [N Engl J Med 2022;386:1143-1154]

After a median follow-up of 16.2 months in the T-DXd group and 15.3 months in the T-DM1 group, median progression-free survival (PFS) by blinded independent central review (the trial’s primary endpoint) was not reached in the T-DXd group vs 6.8 months in the T-DM1 group. At 12 months, PFS rate was 75.8 percent vs 34.1 percent (hazard ratio [HR], 0.28; 95 percent confidence interval [CI], 0.22 to 0.37; p<0.001).

Investigator-assessed median PFS was 25.1 months in the T-DXd group vs 7.2 months in the T-DM1 group (HR, 0.26; 95 percent CI, 0.20 to 0.35; p<0.001).

The PFS benefit (by blinded independent central review) with T-DXd was similar across all prespecified subgroups assessed, including in patients with hormone receptor positive (HR, 0.32; 95 percent CI, 0.22 to 0.46) or negative (HR, 0.30; 95 percent CI, 0.20 to 0.44) status, with (HR, 0.30; 95 percent CI, 0.22 to 0.43) or without previous pertuzumab treatment (HR, 0.30; 95 percent CI, 0.19 to 0.47), with (HR, 0.28; 95 percent CI, 0.21 to 0.38) or without visceral disease (HR, 0.32; 95 percent CI, 0.17 to 0.58), with (HR, 0.38; 95 percent CI, 0.23 to 0.64) or without stable brain metastases (HR, 0.27; 95 percent CI, 0.19 to 0.37), as well as those who had received 0–1 prior line of therapy (HR, 0.33; 95 percent CI, 0.23 to 0.48) and those who had received ≥2 prior lines of therapy (HR, 0.28; 95 percent CI, 0.19 to 0.41).

Overall survival (OS) rate at 12 months was 94.1 percent with T-DXd vs 85.9 percent with T-DM1 (HR, 0.55; 95 percent CI, 0.36 to 0.86; p=0.007; prespecified significance boundary [p<0.000265] not reached).

Overall response rate (ORR) was 79.7 percent in the T-DXd group vs 34.2 percent in the T-DM1 group, with complete response (CR) achieved in 16.1 percent vs 8.7 percent of the patients. Disease control rate was 96.6 percent vs 76.8 percent.

Grade 3/4 drug-related adverse events (AEs) occurred in 45.1 percent vs 39.8 percent of patients in the T-DXd vs T-DM1 group. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5 percent vs 1.9 percent of the patients, but none of these events were of grade 4/5.

“The incidence of adjudicated drug-related interstitial lung disease or pneumonitis was lower in this trial than in previous trials,” the investigators noted. “Careful monitoring is essential in clinical use of T-DXd.”

“These data showed the superiority of T-DXd over T-DM1 in reducing the risk of progression or death in patients with HER2-positive metastatic breast cancer who had been previously treated with trastuzumab and a taxane,” they concluded. “T-DXd is an effective new treatment for patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, as well as with pertuzumab when available.”