Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors.

Abstract

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…However, only 50-80% of patients with HER2 + BC benefit from this drug, while 20-50% either do not respond from the beginning of the treatment or develop resistance after treatment [10,11]. Moreover, with currently available treatment options, the overall disease-free survival (DFS) statistics of patients with the HER2 + subtype of BC are not adequate [12][13][14][15][16][17][18]. Hence, intense research is ongoing to determine new therapeutic targets or agents to improve the treatment of HER2 + BC patients.…”

A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model

“…It has been shown to exhibit an antitumor effect in mouse models (7). Moreover, in a phase I clinical trial, DS-8201a showed antitumor effects in breast, gastric, gastroesophageal, colorectal, salivary, and non-small cell lung cancer patients (9)(10)(11), including ones who had previously been treated with trastuzumab emtansine (T-DM1), an ADC composed of a tubulin polymerization inhibitor, and an anti-hHER2 antibody. Furthermore, DS-8201a was well-tolerated, and the MTD was not reached during dose escalation (0.8-8.0 mg/kg; refs.…”

“…Furthermore, DS-8201a was well-tolerated, and the MTD was not reached during dose escalation (0.8-8.0 mg/kg; refs. [9][10][11]. Accordingly, DS-8201a is expected to become a new therapy for HER2-positive tumors.…”

Current therapeutic landscape for advanced gastroesophageal cancers

“…DS-8201a is a HER2-targeting antibody-drug conjugate which delivers cytotoxic chemotherapy (DXd, a novel topoisomerase I inhibitor) directly to cancer cells. In trastuzumab pretreated AGC patients, DS-8201a was associated with an ORR of 38%, with an acceptable safety profile (80). The phase II is underway (NCT02564900).…”