Abstract GS3-01: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03

Abstract

Background: T-DXd is a HER2-targeting antibody-drug conjugate approved for the treatment of pts with advanced HER2+ mBC based on the DESTINY-Breast01 study (NCT03248492). DESTINY-Breast03 (NCT03529110) isa randomized, multicenter, open-label, phase 3 study assessing the efficacy and safety of T-DXd vs. T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. In the primary analysis, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS vs. T-DM1 (Corteset al, ESMO 2021). In this exploratory analysis, we provide additional efficacy and safety data in subgroups, including in pts with brain metastases (BMs). Methods: Pts were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 Q3W. Pts with clinically stable BMs were eligible. Lesions were measured per modified Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR). PFS and overall response rate (ORR) were analyzed for subgroups.Sites of progression and post-end-of-study therapies were also investigated. Results: At data cutoff (May 21, 2021), 524 pts were randomly assigned to T-DXd (n=261) orT-DM1 (n=263). T-DXd demonstrated superior PFS by BICR vs. T-DM1 (HR, 0.28 [95%CI, 0.22-0.37]; P=7.8 x 10-22); median (m) PFS by BICR was not reached (95% CI, 18.5-NE) for T-DXd compared with 6.8 mo (95% CI, 5.6-8.2) forT-DM1. For pts with stable BMs at baseline (n=82), mPFS was 15.0 mo (95% CI,12.5-22.2) for T-DXd vs. 3.0 mo (95% CI, 2.8-5.8) for T-DM1 (HR, 0.25 [95% CI,0.31-0.45)]. Overall, confirmed ORR for T-DXd was 79.7% vs. 34.2% for T-DM1.For patients with stable BMs at baseline, ORR was 67.4% for T-DXd vs. 20.5% forT-DM1. Consistent PFS and ORR benefit was also observed across other subgroups(Table 1). At data cutoff, 84 (32.2%) pts treated with T-DXd had progressive disease (PD) versus 155 (58.9%) with T-DM1. In pts with stable BMs in the T-DXd arm, 48.8% of pts (21/43) had PD. In pts with stable BMs in the T-DM1 arm, 69.2%of pts (27/39) had PD. Data on sites of progression will be presented. Further analyses are underway and will be presented. Overall, the safety profile of T-DXd was manageable and comparable with its known safety profile. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 27 (10.5%) pts treated with T-DXd and 5 (1.9%) pts treated with T-DM1 overall, with no grade 4 or 5 events. Additional new safety data will be presented. Conclusion: DESTINY-Breast03,the first-reported randomized phase 3 trial comparing T-DXd to standard of care, met the primary endpoint with T-DXd demonstrating superior PFS vs. T-DM1and T-DXd had a manageable safety profile. In this exploratory analysis, consistent PFS and ORR benefit with T-DXd vs. T-DM1 was observed across subgroups in pts with HER2+ mBC previously treated with trastuzumab and taxane, including in pts with BMs. Table 1.Subgroup Analyses forPFS and ORR of T-DXd versus T-DM1PFS by BICR HR (95% CI)Absolute ORR Difference (T-DXd-T-DM1) (95% CI)All patients (N=524)0.28 (0.22-0.37)45.5 (37.6-53.4)Hormone receptorPositive (n=272)0.32 (0.22-0.46)47.3 (36.1-58.4)Negative (n=248)0.30 (0.20-0.44)43.2 (31.5-55.0)Prior pertuzumabYes (n=320)0.31 (0.22-0.43)46.7 (36.5-56.9)No (n=204)0.30 (0.19-0.47)43.6 (30.5-56.7)Prior lines of therapya0-1 (n=258)0.33 (0.23-0.48)39.3 (27.3-51.2)≥2 (n=266)0.28 (0.19-0.41)51.6 (40.9-62.4)Visceral disease Yes (n=384)0.28 (0.21-0.38)48.3 (39.1-57.6)No (n=140)0.32 (0.17-0.58)39.1 (23.6-54.6)Brain metastases at baseline Yes (n=82)0.25 (0.13-0.45)46.9 (25.6-68.3)No (n=442)0.30 (0.22-0.40)45.5 (36.9-54.1) Citation Format: Sara Hurvitz, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako, Sunil Verma, Javier Cortés. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-01.

Update Breast Cancer 2022 Part 2 – Advanced Stage Breast Cancer

“…Nevertheless, patients in the comparator arm (T-DM1) with these criteria for brain metastases had a median PFS of only 3 months (95 % CI: 2.8-5.8). The median PFS for patients with brain metastases was improved by T-DXd to 20.9 months (95 % CI: 8.7-36.6) (HR = 0.25; 95 % CI: 0.13-0.45) [44]. Of 82 patients with brain metastases, 72 had a target lesion in the brain, 36 in the T-DXd arm and 36 in the T-DM1 arm.…”

“…both populations, PFS was improved by tucatinib with a hazard ratio of 0.36 (95 % CI: 0.22-0.57) for patients with active brain metastases and a hazard ratio of 0.31 (95 % CI: 0.14-0.67) for patients with stable brain metastases [43]. Detailed data have now been published for patients who had brain metastases at the start of treatment in the DESTINY-B03 trial (n = 82) [44]. The exclusion criteria relating to brain metastases are listed in ▶ Table 1.…”

Emerging treatment strategies for metastatic triple-negative breast cancer

“… 98 Updated results from exploratory subgroup analysis of the study demonstrated that T-DXd induced PFS and ORR improvements versus T-DM1 across patients irrespective of hormone receptor status, prior pertuzumab, number of prior lines of therapy, presence or absence of visceral disease, or presence of brain metastases. 99 …”

Trastuzumab Deruxtecan Improves Progression-Free Survival and Intracranial Response in Patients with HER2-Positive Metastatic Breast Cancer and Brain Metastases

“…The phase III DESTINY-Breast03 trial is the first head-to-head trial comparing T-DXd with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer in the second-line setting, after prior treatment with trastuzumab and a taxane. 1 , 2 …”

“…In the current analysis, Sara A. Hurvitz, M.D., of the David Geffen School of Medicine at the University of California, Los Angeles, presented findings from key patient subgroups in the DESTINY-Breast03 trial, including patients with brain metastases. 2 …”