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HER2 antibody-drug conjugate T-DXd promising in T-DM1 pretreated patients

SABCS 2019
Phase 2, DESTINY-Breast01

Results from the phase 2 clinical trial DESTINY-Breast01 showed that the investigational human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) has durable objective responses in patients with HER2-positive breast cancer who were heavily pretreated. Although T-DXd had a generally manageable safety profile, interstitial lung disease (ILD) was identified as a risk warranting proactive awareness and management.

Despite the fact that HER2-directed therapies like trastuzumab, pertuzumab, and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs is almost inevitable. Once patients develop resistance, it is not clear what treatment should be given, highlighting the unmet medical need for new and improved therapies for these patients. T-DXd is an antibody-drug conjugate with an HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, it has shown to yield an objective response rate of 59% in patients with advanced HER2-positive breast cancer who were previously treated with T-DM1 [1]. Krop et al. conducted a phase 2 study in which 253 patients with metastatic HER2-positive breast cancer previously treated with T-DM1 were included [2]. Median age of the patients was 55 years, 34.2% was Asian, 28.8% North American, and 37% European; 52.7% was HER2+ and 45.1% was HER2- (of 2.2% of patients, the HER2 status was unknown). The median prior lines of cancer therapy was 6 (range 2-27). The trial consisted of 3 parts, I, IIa, and IIb. In total, 184 patients received the recommended phase 2 dose of 5.4 mg/kg T-DXd. Median treatment duration was 6.9 months.

The results showed that the overall response rate (ORR) was 60.9%, and that 6% had a complete response versus 54.9% with a partial response (see Table). The median progression-free survival was 16.4 months (95% CI 12.7-NE). Median overall survival was not reached.

Table. Primary endpoint: ORR in the intention-to-treat population (n=184) [2]

ORR, overall response rate; ICR, independent central review

Treatment-emergent adverse events (AEs) occurred in 99% of patients of which 51% were grade ≥3. The most common any-grade treatment-emergent AEs were gastrointestinal AEs such as nausea (77%), vomiting (45%), constipation (34%), decreased appetite (29%), and diarrhoea (27%). Other treatment-emergent AEs were alopecia (48%) and fatigue (48%). The most common grade ≥3 AEs were decreased neutrophil count (17%), nausea (7.6%), anaemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%).

Noteworthy, ILD of any grade occurred in 13.6% of patients; 2.7% of cases was grade 1, 8.2% was grade 2, 0.3% was grade 3, 0% was grade 4, and 2.2% was grade 5. Of these total 25 events, the mean time to investigator-reported onset was 193 days (range 43-535 days); 7 patients recovered, 2 were recovering, 12 were either outcome unknown or not followed until resolution, and 4 patients died. Of these 4 fatal cases, onset of ILD was from 63-148 days, 3 patients received steroids as part of the treatment, and death occurred 9-60 days after diagnosis of ILD. Researchers recommend to monitor patients for symptoms, hold T-DXd, and start steroids as soon as ILD is suspected [2].

1. Tamura K, et al. Lancet Oncol. 2019;20(6);816-826.
2. Krop IA, et al. GS1-03. SABCS 2019.

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