Abstract PD3-07: Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers

Abstract

Background DS-8201a is a HER2 targeting antibody-drug conjugate (ADC) with high drug to antibody ratio (8:1), a novel linker and topoisomerase I inhibitor as the payload. In preclinical studies, DS-8201a showed efficacy against both trastuzumab emtansine (T-DM1) resistant HER2 positive breast cancer (BC) and against BC with low HER2 expression. The current phase 1 trial is comprised of dose escalation (Part 1) and dose expansion (Part 2) cohorts including patients (pts) with BC, gastric cancer and other HER2 expressing tumors. Only the results from BC cohorts are presented here. Methods Part 1 used a modified continual reassessment model to identify the recommended phase 2 dose (RP2D) of DS8201a in pts with BC or gastric cancer of any HER2 status. Two out of planned 4 expansion cohorts included BC: T-DM1-treated HER2 positive BC (Cohort 2a; IHC 3+ or IHC 2+/ISH +) and HER2 low BC (Cohort 2c, IHC 2+/ISH- or IHC 1+). Efficacy endpoints of objective response rate (ORR), disease control rate (DCR: CR + PR + SD), durability of response, progression free survival (PFS) and adverse events (AEs) were assessed. Results Overall, 146 subjects were included (24 Part 1; 122 Part 2). DS-8201a was administered up to 8.0 mg/kg in Part 1 without any DLTs, maximum tolerated dose was not reached. Based on available results, the dose levels of 5.4 and 6.4 mg/kg IV every 3 weeks were chosen for Part 2. In Part 2, a total of 56 BC pts were enrolled; 46 pts in Cohort 2a and 10 pts in Cohort 2c. The median age was 56 and number of prior regimens in the metastatic setting was 5 (range: 1-16). 37 BC pts had follow-up imaging scans and were evaluable for response at the time of data cutoff. Confirmed ORR was 41% (15/37) including 1 CR; DCR was 97% (36/37). The median duration of treatment was not reached. For Cohort 2a, where all pts had received prior T-DM1, treatment with DS-8201a achieved a higher ORR of 41% (11/27) and DCR of 100% (27/27) compared to the reported response these patients had to their prior T-DM1 treatment with ORR of 23% (5/22) and DCR of 73% (16/22). In the subset of 24 pts from cohort 2a who had received prior treatment with pertuzumab and T-DM1, the confirmed ORR was 44% (11/25). In Cohort 2c, confirmed ORR was 40% (4/10), DCR was 90% (9/10). Of the 46 BC pts in Part 2 who received at least one dose of DS-8201a, 4 pts discontinued treatment due to disease progression and 3 pts discontinued due to AE. The most common AEs of any grades were nausea, decreased appetite, vomiting, alopecia, and diarrhea. Only 2 pts experienced grade 4 AEs (thrombocytopenia and neutropenia) and 46 % (21/46) experienced grade 3 AEs (most commonly anemia, neutropenia, thrombocytopenia, leukopenia, lymphocytepenia, and vomiting). Conclusions DS-8201a was well tolerated and has significant activity in pts with T-DM1 and T-DM1/ pertuzumab pretreated HER2 positive BC and in pts with HER2 low BC, with durable disease control. Promising efficacy of this ADC in BC warrants further investigation. Citation Format: Modi S, Tsurutani J, Takahashi S, Iwata H, Park H, Redfern CH, Doi T, Li B, Iwasa T, Taira S, Hattori M, Ma CX, Fisher JM, Naito Y, Yonemori K, Kawasaki Y, Saito K, Jikoh T, Shahidi J, Lee CC, Yver A, Tamura K. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-07.

Update Mammakarzinom 2019 Teil 5 – diagnostische und therapeutische Herausforderungen neuer personalisierter Therapien bei Patientinnen mit fortgeschrittenem Mammakarzinom

“…Bei dem großen Erfolg der Anti-HER2-Therapien auch bei Einsatz nach mehreren Therapielinien wird natürlich weiter nach effektiven Anti-HER2-Therapien gesucht, sodass HER2-positive Patientinnen auch nach einem Progress mit einer wirksamen Anti-HER2-Therapie weiterbehandelt werden können. Ein Beispiel, das bereits in der Vergangenheit vorgestellt worden war, ist das ADC DS-8201a, das Trastuzumab mit einem Topoisomerase-Inhibitor verbindet und gute Wirksamkeit in frühen Therapiestudien zeigte [16][17][18]. Kürzlich wurden nun 2 weitere Anti-HER2-Therapien vorgestellt, Pyrotinib [19] und Margetuximab [20].…”

Update Breast Cancer 2018 (Part 4) – Genomics, Individualized Medicine and Immune Therapies – in the Middle of a New Era: Treatment Strategies for Advanced Breast Cancer

“…DS-8201a is an HER2-targeted antibody-drug conjugate incorporating a humanised HER2 antibody that is attached to a topoisomerase-I inhibitor (deruxtecan) with a high ratio of active substance to antibody of 7 : 8. Data from the phase I study were already presented at the SABCS, revealing a manageable safety profile and promising anti-tumour activity 47 . In the presented study 46 , the response rate in patients with HER2 overexpression was 64.2% and in those with non-overexpression 38.5% 46 .…”

“…DS-8201a ist ein HER2-gerichtetes Antikörper-Wirkstoff-Konjugat mit einem humanisierten HER2-Antikörper, der an einen Topoisomerase-I-Inhibitor (Deruxtecan) mit einem hohen Wirkstoff-Antikörper-Verhältnis von 7 zu 8 gebunden ist. Daten der Phase-I-Studie waren bereits beim SABCS präsentiert worden und hatten ein kontrollierbares Sicherheitsprofil sowie eine vielversprechende Antitumoraktivität gezeigt 47 . In der vorgestellten Studie 46 hatten Patientinnen mit einer HER2-Überexpression eine Ansprechrate von 64,2% und solche ohne eine HER2-Überexpression immerhin eine Ansprechrate von 38,5% 46 .…”

DNA damaging agent-based antibody-drug conjugates for cancer therapy

“…An advantage is that DX-8951f is not an MDR1 substrate [46, 47]. Four ADCs [Sacituzumab govitecan/IMMU-132 [48], designated as a breakthrough therapy by the FDA; Labetuzumab govitecan/IMMU-130 [49]; DS-8201a [50] and U3-1402 [51]] that employed camptothecin analogues as their payload are being tested in clinical trials.…”

“…The first-in-human anti-CEACAM5 ADC, SAR408701 (payload = DM4), has advanced to phase II trial. In the phase I/II trial of labetuzumab govitecan (payload = SN38), 41 out of 86 patients showed stabilized disease [50, 73]. …”