Trastuzumab Deruxtecan Outperforms Trastuzumab Emtansine in DESTINY-Breast03 Follow-Up

Trastuzumab deruxtecan both significantly improved overall survival and yielded progression-free survival that was 4 times greater than trastuzumab emtansine in patients with HER2-positive metastatic breast cancer.

Sara A. Hurvitz, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) yielded superior overall survival (OS) and progression-free survival (PFS) rates in patients with HER2-positive metastatic breast cancer compared with ado-trastuzumab emtansine (Kadcyla; T-DM1) according to updated results from the phase 3 DESTINY-Breast03 trial (NCT03529110) presented during the 2022 San Antonio Breast Cancer Symposium.

At a median follow-up of 28.4 months (range, 0.0-46.9), the median OS was not reached (NR; 95% CI, 40.5-not evaluable [NE]) in the trastuzumab deruxtecan arm (n = 261) compared with NR (95% CI, 34.0-NE) in the 263-patient T-DM1 arm (HR, 0.64; 95% CI, 0.47-0.87; P = .0037). The 1-year and 2-year OS rates in the trastuzumab deruxtecan arm were 94.1% (95% CI, 90.4%-96.4%) and 77.4% (95% CI, 71.7%-82.1%), respectively. Comparatively, in the T-DM1 arm, the 1-year and 2-year OS rates were 86.0% (95% CI, 81.1%-89.8%) and 69.9% (95% CI, 63.7%-75.2%), respectively.

According to updated findings, the median PFS was 28.8 months (95% CI, 22.4-37.9) vs 6.8 months (95% CI, 5.6-8.2) in the trastuzumab deruxtecan arm and the T-DM1 arm, respectively (HR, 0.33; 95% CI, 0.26-0.43; < .000001). The 1-year PFS rates were 75.2% (95% CI, 69.3%-80.2%) vs 33.9% (95% CI, 27.7%-40.2%), respectively. The 2-year rates were 53.7% (95% CI, 46.8%-60.1%) vs 26.4% (95% CI, 20.5%-32.6%), respectively.

“Trastuzumab deruxtecan demonstrated a clinically meaningful and statistically significant improvement in OS versus TDM-1 as well as [a] continued PFS benefit,” Sara A. Hurvitz, MD, a medical oncologist at the University of California, Los Angeles, said in a presentation of the data. “[Trastuzumab deruxtecan] reduced the risk of death by 36%, [the] median PFS was nearly 4 times greater with [traztuzumab deruxtecan] than with TDM-1 and 78.5% of patients experienced a confirmed objective response."

Study authors noted that the first-line standard of care for HER2-positive metastatic breast cancer had been established to be trastuzumab plus taxane with pertuzumab in the CLEOPATRA trial [NCT00567190] and that the EMILIA trial [NCT00829166] established T-DM1 as the standard of care after trastuzumab and a taxane for metastatic, HER2-positive breast cancer in the second-line setting and beyond. However, since the DESTINY-Breast03 trial showcased the efficacy of trastuzumab deruxtecan in this setting last year, this agent is now considered the preferred second-line treatment with T-DM1 as an alternative option.

DESTINY-Breast03 was an open-label, multicenter study that enrolled patients with unresectable or metastatic HER2-positive breast cancer. Patients must have previously undergone treatment with trastuzumab and a taxane in the metastatic or neoadjuvant setting, and have experienced a recurrence within 6 months of therapy. Eligible patients were stratified based on hormone receptor (HR) status, prior treatment with pertuzumab, and history of visceral disease.

Enrolled patients were randomly assigned 1:1 to be treated with either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or T-DM1 3.6 mg/kg every 3 weeks. The primary end point was PFS. OS was the key secondary end point, with overall response rate (ORR), duration of response (DOR), and safety representing other secondary end points.

Baseline patient characteristics were well balanced between the 2 arms; the median age was 54.3 years (range, 27.9-83.1) and 54.2 years (range, 20.2-83.0) in the trastuzumab deruxtecan and T-DM1 arms, respectively. Nearly all patients in both arms were females (both 99.6%), most were Asian (57.1% vs 60.8%), and most had an ECOG performance status of 0 (59.0% vs 66.5%). Patients had positive HR status at a rate of 50.2% and 51.0%, respectively.

In terms of prior therapies, most patients in both the trastuzumab deruxtecan and T-DM1 arms had received prior treatment with trastuzumab (Herceptin; 99.6% vs 99.6% and pertuzumab (Perjeta; 62.1% vs 60.1%). Patients underwent a median of 2 (range, 0-16) prior lines of therapy in the T-Dxd arm compared with 2 (range, 0-15) in the T-DM1 arm.

Additional data from the trial showed that treatment with trastuzumab deruxtecan was favorable compared with T-DM1 in terms of OS all major subgroups evaluated. The most pronounced survival benefit with trastuzumab deruxtecan was observed among patients with no baseline visceral disease (HR, 0.44; 95% CI, 0.19-1.02), those with brain metastases at baseline (HR, 0.54; 95% CI, 0.29-1.03), and those who underwent at least 3 prior lines of systemic therapy (HR, 0.55; 95% CI, 0.34-0.89).

Trastuzumab deruxtecan also outperformed T-DM1 across other efficacy end points. The ORR was 78.5% (95% CI, 73.1%-83.4%), including a 21.1% complete response (CR) rate, compared with a 35.0% ORR (95% CI, 29.2%-41.1%) with a 9.5% CR rate, in the T-DM1 arm (P < .0001). The clinical benefit rates were 89.3% (95% CI, 84.9%-92.8%) and 46.4% (95% CI, 40.2%-52.6%), respectively (P < .0001). The median DOR was 36.6 months (95% CI, 22.4-NE) in the trastuzumab deruxtecan arm compared with 23.8 months (95% CI, 12.6-34.7) in the control group.

Regarding adverse effects (AEs), any grade treatment-emergent AEs (TEAEs) occurred in nearly all patients in both the trastuzumab deruxtecan and T-DM1 arms (99.6% vs 95.4%, respectively). Serious TEAEs (25.3% vs 22.2%), TEAEs associated with drug discontinuation (21.4% vs 9.2%), and TEAEs associated with drug interruption (52.9% vs 29.1%) were all present in both arms. Six patients in both arms experienced TEAEs that were associated with death, although none of these were drug related.

The most common any-grade TEAEs in the trastuzumab deruxtecan arm were nausea (77.0%), vomiting (51.8%), and alopecia (39.7%). Commonly occurring grade 3 or higher TEAEs in this arm included decreased neutrophil count (16.0%), anemia (9.3%), and decreased platelet count (7.8%).

In the T-DM1 arm, any-grade TEAEs included decreased platelet count (43.7%), increased aspartate aminotransferase (41.1%), and increased alanine aminotransferase (31.8%). Grade 3 or greater TEAEs consisted of decreased platelet count (19.9%), anemia (6.5%), and increased aspartate aminotransferase (5.4%).

Rates of grade 3 or greater TEAEs were similar between the trastuzumab deruxtecan and T-DM1 arms (56.4% vs 51.7%, respectively). The most common drug-related TEAEs responsible for treatment discontinuation with trastuzumab deruxtecan were pneumonitis (5.8%), interstitial lung disease (ILD) (5.1%), and pneumonia (1.9%), while, in the T-DM1 arm, the driving TEAEs were decreased platelet counts (1.5%), pneumonitis (1.1%), and thrombocytopenia (1.1%).

Study authors noted that the rates of ILD and pneumonitis were consistent with other trials assessing trastuzumab deruxtecan in metastatic breast cancer. However, the rate of ILD/pneumonitis had increased from 10.5% to 15.2% since the PFS interim analysis. The rate of grade 3 events stayed consistent (0.8%), and there were no grade 4 or 5 drug-related ILD/pneumonitis events.

The median duration of treatment with trastuzumab deruxtecan was 18.2 months (range, 0.7-44.0). In the T-DM1 arm, the median treatment duration was 6.9 months (range, 0.7-39.3).

At the data cutoff, 29.2% of patients in the trastuzumab deruxtecan arm were still undergoing treatment with the agent, compared with 6.9% of patients in the T-DM1 arm. Patients receiving trastuzumab deruxtecan primarily discontinued treatment due to progressive disease (36.6%), AEs (21.0%), and patient withdrawal (6.6%). In the T-DM1 arm, patients discontinued treatment for reasons including disease progression (68.2%), AEs (8.0%), and clinical progression (5.4%). The median PFS2 was 40.5 months (95% CI, 40.5-NE) vs 25.7 months (95% CI, 18.5-34.0), respectively (HR, 0.47; 95% CI, 0.35-0.62).

Reference

Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-02.

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