Antoine Yver, MD

The investigational HER2-targeting antibody-drug conjugate DS-8201 has received an FDA breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression after ado-trastuzumab emtansine (T-DM1; Kadcyla).

According to the manufacturer of DS-8201, Daiichi Sankyo, the antibody-drug conjugate is composed of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker.

“The breakthrough therapy designation for DS-8201 in HER2-positive metastatic breast cancer acknowledges the unmet medical need these patients face when currently approved treatments no longer control their disease,” Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo, said in a statement.

The FDA awarded the breakthrough designation based on an ongoing, dose escalation/expansion phase I study, preliminary data from which were presented at the 2017 ASCO Annual Meeting by Toshihiko Doi, MD, PhD, of Japan’s National Cancer Center Hospital East.

“In preliminary results in the first-in-human phase I trial, DS-8201 demonstrated promising antitumor activity and a favorable safety profile,” Doi said in his presentation at ASCO.

In part 1 of the study, investigators used a modified continuous reassessment method to identify the expansion dose in patients with breast or gastric cancer. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: HER2-positive breast cancer previously treated with T-DM1, HER2-positive gastric cancer treated with trastuzumab, low-HER2—expressing breast cancer, and other HER2-expressing solid tumors.

Twenty-four patients were included in part 1 and 65 patients with breast, gastric, colorectal, salivary, and non—small cell lung cancer participated in part 2. The median number of prior therapies was 4.

Doi et al administered DS-8201 at doses from 0.8 mg/kg to 8.0 mg/kg in Part 1. Doses of 6.4 mg/kg and 5.4 mg/kg every 3 weeks were chosen for Part 2. There was no dose-limiting toxicity, and maximum-tolerated dose was not reached in Part 1.

In patients with breast cancer, the overall response rate (ORR) in patients receiving the Part 2 doses was 42.2% and the disease control rate was 97.8%. Among patients with prior T-DM1, the ORR was 45.7% and the DCR was 100%, and in those with prior T-DM1 plus pertuzumab, the corresponding rates were 46.7% and 100%, respectively.

The median progression-free survival for patients with breast cancer was 45.4 weeks (95% CI, 32.1 — not reached).

Doi said that more than 90% of patients with breast cancer remain on-study. Eleven patients have discontinued, including 6 due to progressive disease and 3 due to AEs.

Among all patients receiving the Part 2 doses, 43.6% experienced grade 3/4 treatment-emergent adverse events (AEs), but investigators did not observe any dose-limiting toxicities or cardiac toxicity. The most common grade 3 AEs (≥5%) were anemia (14.3%), decreased neutrophil count (12.0%), decreased white blood cell count (9.0%), and decreased platelet count (8.3%). Grade 4 AEs included decreased platelet count (3.8%), decreased neutrophil count (3%), anemia (1.5%), and decrease white blood cell count (1.5%).

Breakthrough therapy designation is designed to expedite the development and review of medicines that may demonstrate substantial benefit over currently available treatments in order to ensure that patients with serious diseases have access to new treatments as soon as possible.

Daiichi Sankyo has initiated the pivotal phase II DESTINY-Breast01 study evaluating the safety and efficacy of DS-8201 in patients with HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1.

Doi T, Iwata H, Tsurutani J, et al. Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors. J Clin Oncol 35, 2017 (suppl; abstr 108).