Background

Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here.

Methods

All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS.

Results

Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below.

Conclusion

Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted.

Updated Results for DESTINY-Breast01
1 Aug 2019 datacut8 Jun 2020 datacut
Patients remaining on treatment, n/N (%) 79/184 (42.9%) 37/184 (20.1%) 
Median duration of follow-up 11.1 months 20.5 months 
ORR 60.9% 61.4% 
CR 6.0% 6.5% 
PR 54.9% 54.9% 
SD 36.4% 35.9% 
Duration of response, median (95% CI) 14.8 months (13.8-16.9) 20.8 months (15.0-NE) 
PFS, median (95% CI) 16.4 months (12.7-NE) 19.4 months (14.1-NE) 
OS   
Median (95% CI) NE (NE-NE) 24.6 months (23.1-NE) 
Point estimate at 12 mo (95% CI) 86.2% (79.8-90.7) 85% (79-90) 
Point estimate at 18 mo (95% CI) – 74% (67-80) 
   
Safety   
Patients with a TEAE, n (%) 183 (99.5%) 183 (99.5%) 
Grade ≥3 105 (57.1%) 113 (61.4%) 
Associated with discontinuation 28 (15.2%) 34 (18.5%) 
Associated with death 10 (5.4%) 10 (5.4%) 
Drug-related ILD per ILD adjudication committeea 25 (13.6%) 28 (15.2%) 
Grade 5 drug-related ILD per ILD adjudication committee 4 (2.2%) 5 (2.7%) 
Updated Results for DESTINY-Breast01
1 Aug 2019 datacut8 Jun 2020 datacut
Patients remaining on treatment, n/N (%) 79/184 (42.9%) 37/184 (20.1%) 
Median duration of follow-up 11.1 months 20.5 months 
ORR 60.9% 61.4% 
CR 6.0% 6.5% 
PR 54.9% 54.9% 
SD 36.4% 35.9% 
Duration of response, median (95% CI) 14.8 months (13.8-16.9) 20.8 months (15.0-NE) 
PFS, median (95% CI) 16.4 months (12.7-NE) 19.4 months (14.1-NE) 
OS   
Median (95% CI) NE (NE-NE) 24.6 months (23.1-NE) 
Point estimate at 12 mo (95% CI) 86.2% (79.8-90.7) 85% (79-90) 
Point estimate at 18 mo (95% CI) – 74% (67-80) 
   
Safety   
Patients with a TEAE, n (%) 183 (99.5%) 183 (99.5%) 
Grade ≥3 105 (57.1%) 113 (61.4%) 
Associated with discontinuation 28 (15.2%) 34 (18.5%) 
Associated with death 10 (5.4%) 10 (5.4%) 
Drug-related ILD per ILD adjudication committeea 25 (13.6%) 28 (15.2%) 
Grade 5 drug-related ILD per ILD adjudication committee 4 (2.2%) 5 (2.7%) 

a1 grade 1 and 1 grade 3 event are pending adjudication and are not included.

Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-06.