The FDA has granted fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) breakthrough therapy designation for adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more HER2-targeting agents in prior lines of therapy, according to a press release from AstraZeneca.1

T-DXd demonstrated promising efficacy in this patient population in the phase 3 DESTINY-Breast03 trial (NCT03529110).2 The HER2-directed antibody drug conjugate yielded a 12-month progression-free survival (PFS) rate of 75.8% (95% CI, 69.8%-80.7%) compared with 34.1% (95% CI, 27.7%-40.5%) with ado-trastuzumab emtansine (T-DM1; Kadcyla). The median PFS was not reached in the T-DXd arm and was 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm.

The trial enrolled patients who had been diagnosed with unresectable or metastatic HER2-positive breast cancer and had been previously treated with trastuzumab (Herceptin) and a taxane in the advanced or metastatic setting. Additionally, patients were allowed to have clinically stable, treated brain metastases.

Patients were randomized 1:1 and were stratified based on hormone receptor status, prior treatment with pertuzumab (Perjeta), and history of visceral disease. The 2 treatment arms included a 5.4 mg/kg dose of T-DXd every 3 weeks (n = 261) or 3.6 mg of T-DM1 every 3 weeks (n = 263).

The primary end point of the study was PFS by blinded independent central review (BICR), with key secondary end points including overall response rate (ORR) by BICR, duration of response by BICR, investigator-assessed PFS, and safety.

Of the patients who were treated with T-DXd (n = 257), 132 are receiving ongoing treatment and 125 have discontinued due to death (n = 3), adverse effect (AE; n = 35), progressive disease (n = 66), clinical progression (n = 4), patient withdrawal (n = 13), or physician decision. Additionally, of the patients who were treated with T-DM1 (n = 261), 47 are receiving ongoing treatment and 214 have discontinued due to death (n = 3), AEs (n = 17), progressive disease (n = 158), clinical progression (n = 12), patient withdrawal (n = 11), or physician decision (n = 8). The median follow ups were 16.2 months and 15.3 months for the T-DXd and T-DM1 arms, respectively.

Additional findings from the trial indicated that patients in the T-DXd arm had an investigator-assessed median PFS of 76.3 months (95% CI, 22.1not evaluable [NE]) vs 7.2 months (95% CI, 6.8-8.3) reported in the T-DM1 arm (HR, 0.27; 95% CI, 0.20-0.35; P = 6.5 10-24). Additionally, the 12-month investigator-assessed PFS rates were76.3% (95% CI, 70.4%-81.2%) and 34.9% (95% CI, 28.8%-41.2%) in the T-DXd and T-DM1 arms, respectively.

Moreover, the median OS was NE for both treatment arms, and the 12-month OS rates were 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%) in the T-DXd and T-DM1 arms, respectively (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). Those who were treated with T-DXd had a confirmed ORR of 79.7%, including a complete response (CR) rate of 16.1% and partial response rate (PR) of 63.6%, compared with 34.2% in the T-DM1 cohort, including a CR rate of 8.7% and a PR rate of 25.5%.

The most common any-grade blood and lymphatic AEs were neutropenia (42.8%), anemia (30.4%), and leukopenia (30.0%) and common gastrointestinal toxicities included nausea (72.8%) and vomiting (44.0%). Moreover, the most common grade 3 or higher blood and lymphatic AEs included neutropenia (19.1%), thrombocytopenia (7.0%), and leukopenia (6.6%). Grade 3/4 gastrointestinal AEs included nausea (6.6%), vomiting (1.6%), and diarrhea (0.4%).

Originally posted here:
Trastuzumab Deruxtecan Granted Breakthrough Therapy Designation by FDA for Pretreated Unresectable/Metastatic HER2-Positive Breast Cancer - Cancer...

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