Trastuzumab Deruxtecan Continues to Best T-DM1 Survival Rates With Longer Follow-Up in HER2+ Metastatic Breast Cancer

Sara A. Hurvitz, MD

Patients with HER2-positive metastatic breast cancer experienced a significant survival benefit when treated with fam-trastuzumab deruxtecan-nxki (Enhertu) 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 overall survival (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 progression-free survival (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; P < .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.