T-DXd as Second-Line Standard in HER2+ Metastatic Breast Cancer Supported by Subgroup Analysis

Compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) as second-line therapy in patients with HER2-positive metastatic breast cancer across all patients subgroups, including those with and without baseline brain metastases, fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to prolonged progression-free survival (PFS) and higher responses, according to findings from an exploratory analysis of the phase 3 DESTINY-Breast03 trial (NCT03529110) that were presented at the 2021 San Antonio Breast Cancer Symposium.1

At a median follow-up of 15.9 months, the median PFS was 15.0 months (95% CI, 12.5-22.2) with T-DXd vs 3.0 months (95% CI, 2.8-5.8) with T-DM1 in patients with baseline brain metastases (HR, 0.25; 95% CI, 0.13-0.45). The 12-month PFS rates were 72.0% (95% CI, 55.0%-83.5%) vs 20.9% (95% CI, 8.7%-36.6%), respectively.

The median PFS was not evaluable ([NE]; 95% CI, 22.2-NE) with T-DXd vs 7.1 months (95% CI, 5.6-9.7) with T-DM1 in patients without baseline brain metastases (HR, 0.30; 95% CI, 0.22-0.40). The 12-month PFS rates were 76.5% (95% CI, 70.0%-81.8%) vs 36.4% (95% CI, 29.4%-43.4%), respectively.

“These data support T-DXd becoming the standard of care for the second-line treatment of patients with HER2-positive metastatic breast cancer,” Sara A. Hurvitz, MD, lead study author and associate professor at the David Geffen School of Medicine at the University of California Los Angeles (UCLA); medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit; co-director of the Santa Monica-UCLA Outpatient Oncology Practices; and director of the Breast Cancer Clinical Trials Program at UCLA, said in a presentation of the data.

In DESTINY-Breast03, 524 patients with HER2-positive metastatic breast cancer who had been previously treated with trastuzumab (Herceptin) and a taxane were randomized to receive 5.4 mg/kg of T-DXd every 3 weeks (n = 261) or 3.6 mg/kg of T-DM1 every 3 weeks (n = 263). Patients with clinically stable, treated brain metastases were eligible for enrollment.

Baseline characteristics were well balanced between the T-DXd and T-DM1 arms: 50.2% vs 51.0% of patients had a positive hormone receptor, 23.8% vs 19.8% had a history of brain metastases, 16.5% vs 14.8% had baseline brain metastases, and 70.5% vs 70.3% had visceral disease, respectively. The median age was 54.3 years (range, 27.9-83.1) vs 54.2 years (range, 20.2-83.0), respectively.

Notably, Asian patients represented the majority of patients enrolled in the study, at 57.1% in the T-DXd arm vs 60.8% in the T-DM1 arm.

Approximately half of the patients had received only 1 prior line of therapy in the metastatic setting (50.6% vs 47.9%, respectively). The percentage of patients who received at least 2 prior therapies was 49.4% in the T-DXd arm vs 52.1% in the T-DM1 arm.

In the T-DXd arm, 99.6% of patients had prior trastuzumab and 62.1% of patients had prior pertuzumab (Perjeta); these rates were 99.6% vs 60.1%, respectively, in the T-DM1 arm.

The primary end point was PFS by blind independent central review (BICR). A key secondary end point was overall survival (OS); other secondary end points included objective response rate (ORR) by BICR and investigator assessment, duration of response by BICR, PFS by investigator assessment, and safety.

Primary results from the study, which were presented during the 2021 ESMO Congress, demonstrated that the median PFS was not reached (95% CI, 18.5-NE) with T-DXd vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 in the overall population (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22).2 The 12-month PFS rate was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%), respectively.

At data cutoff, 32.2% of patients in the T-DXd arm vs 58.9% of patients in the T-DM1 arm had progressive disease.

The median OS was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). The 12-month OS rates were 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%), respectively.

Moreover, the confirmed ORR was 79.7% (95% CI, 74.3%-84.4%) with T-DXd vs 34.2% (95% CI, 28.5%-40.3%) with T-DM1 (P < .0001); the complete response (CR) rates were 16.1% vs 8.7%, respectively.

Updated findings demonstrated that the PFS and confirmed ORR data also favored T-DXd across patient subgroups: hormone receptor status (positive vs negative), prior pertuzumab treatment (yes vs no), visceral disease (yes vs no), prior lines of therapy (0-1 vs ≥ 2), and patients with brain metastases (yes vs no).

“Over 67% of patients in each subgroup had an objective response with T-DXd, with most [patients in each subgroup] exceeding three-quarters of patients having an objective response,” said Hurvitz.

Among patients with brain metastases, the confirmed ORR was 67.4% (95% CI, 51.5%-80.9%) with T-DXd vs 20.5% (95% CI, 9.3%-36.5%) with T-DM1. Among patients without brain metastases, the confirmed ORR was 82.1% (95% CI, 76.4%-87.0%) vs 36.6% (95% CI, 30.3%-43.3%), respectively.

Notably, patients with brain metastases experienced a lower rate of progressive disease with T-DXd vs T-DM1, at 48.8% vs 69.2%, respectively.

Regarding intracranial responses, the CR rate was 27.8% with T-DXd vs 2.8% with T-DM1. The intracranial partial response rates were 36.1% vs 30.6%, respectively. T-DXd also led to a lower rate of intracranial progressive disease vs T-DM1, at 2.8% vs 22.2%, respectively.

“These data regarding the intracranial objective response are very intriguing and exciting, but we need larger studies that are ongoing to look at the activity of T-DXd in untreated and actively progressing brain metastases,” said Hurvitz, stating that currently, level 1 evidence exists only for tucatinib (Tukysa) as a treatment option for patients with brain metastases in need of second-line therapy.

Regarding safety, treatment-emergent adverse effects (TEAEs) occurred in 99.6% of patients on T-DXd vs 95.4% of patients on T-DM1; grade 3 or greater TEAEs occurred in 52.1% vs 48.3% of patients, respectively. Despite this, the exposure-adjusted incidence rates (EAIRs) were lower with T-DXd vs T-DM1. 

The median treatment duration was 14.3 months (range, 0.7-29.8) with T-DXd vs 6.9 months (range, 0.7-25.1) with T-DM1.

TEAEs leading to discontinuation occurred in 13.6% of patients on T-DXd vs 7.3% of patients on T-DM1, but EAIRs were comparable (0.12 vs 0.11, respectively).

Most TEAEs were hematologic or gastrointestinal in nature. The most common grade 3 or higher TEAEs with T-DXd were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%), and anemia (5.8%). The most common grade 3 or higher TEAEs with T-DM1 were thrombocytopenia (24.9%), aspartate aminotransferase increase (5.0%), alanine aminotransferase increase (4.6%), and anemia (4.2%).

Regarding interstitial lung disease (ILD)/pneumonitis, any-grade events occurred in 10.5% of patients on T-DXd vs 1.9% of patients on T-DM1, which was comparable to the rates that were reported in the Asia (10.9% vs 2.5%, respectively) and non-Asia (10.0% vs 1.0%, respectively) subgroups.

No grade 4 or 5 drug-related ILD/pneumonitis occurred with T-DXd.

Following the presentation, Hurvitz addressed questions from the audience, explaining that investigators are in the process of collecting data on the site of first progression and central nervous system–PFS, which will be presented at an upcoming medical meeting.

_References

_{Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract GS3-01.}

_{Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract LBA1.}