Novel HER2-Targeting Antibody-Drug Conjugate Shows Broad Antitumor Activity

Antoine Yver, MD

A novel HER2-targeting antibody-drug conjugate showed promising antitumor activity across multiple tumor types, including HER2-postive breast cancer, according to phase I data presented at the 2016 ESMO Congress.

“Antibody-drug conjugates represent promising drugs with a wider therapeutic window by effecting efficient and specific drug delivery to oncogene expressing tumor cells,” explained lead author Kenji Tamura, MD, PhD, chairman, Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

“DS-8201a is a HER2-targeting antibody-drug conjugate with a novel topoisomerase I inhibitor. Compelling preclinical evidence exists that the HER2 targeting is highly specific,” added Tamura.

The study enrolled 22 patients, including 16 (73%) with breast cancer, 5 (23%) with gastric cancer, and 1 (5%) with carcinoma of the gastroesophageal junction. At the time of the analysis, 17 patients remained on treatment and the median progression-free survival had not been reached.

Among 20 evaluable patients, 7 had a partial response (PR) for an objective response rate (ORR) of 35%. The disease control rate (PR + stable disease) was 90%, including 5 patients with low HER2 expression (IHC2+/FISH- or IHC1+) and 12 patients who had previously received ado-trastuzumab emtansine (T-DM1; Kadcyla).

The disease control rate was 100% among the 15 patients with HER2+ disease (IHC3+ or IHC2+/FISH+). Among 12 evaluable patients with HER2-positive breast cancer who had prior T-DM1, the ORR was 42% and the disease control rate was 92%.

The first part of this 2-part open-label phase I trial was a dose escalating study in which the 22 enrolled patients received doses ranging from 0.8 mg/kg to 8 mg/kg IV of DS-8201a every 3 weeks. The median age was 66 years (range, 38-79). Eighteen patients had received at least 1 prior anti-HER2 treatment, including trastuzumab (Herceptin; n = 18), T-DM1 (n = 13), pertuzumab (Perjeta; n = 5), lapatinib (Tykerb; n = 4).

The primary objectives were to assess the safety and tolerability of DS-8201a and to determine the maximum-tolerated dose (MTD), which was to be used as the recommended phase II dose. Secondary objectives included pharmacokinetics (PK), and efficacy, according to the ORR, and the disease control rate, and to determine the time to response.

The PK profile was favorable, with all patients at 6.4 mg/kg of DS-8201a reaching the target exposure that was based upon preclinical data.

An evaluation of dose limiting toxicities (DLTs) was made during the first treatment cycle that showed no DLT occurred. The MTD was not reached.

“The majority of partial responses were seen in patients receiving 5.4 mg/kg or higher doses of DS-8201a,” said Tamura.

The safety analysis showed that DS-8201a was well tolerated, and the majority of adverse events (AEs) were grades 1 / 2 gastrointestinal and hematological toxicities. There were 7 grade 3 AEs consisting of hypokalemia, anemia, decreased neutrophil count, increased alkaline phosphatase, and cholangitis, each occurring in 1 patient, and decreased lymphocyte counts occurring in 2 patients.

No patients discontinued DS-8201a due to an AE; however, 4 patients receiving 6.4 mg/kg and 2 patients receiving the 8 mg/kg dose of DS-8201a required dose reductions.

Discussant Christine Saura, Vall d'Hebron University Hospital, Barcelona, Spain commented, “I agree with the investigator’s conclusion that this is a promising agent that has demonstrated safety in these patients.”

“This 2-part phase I trial is currently underway, with the part 2 dose expansion ongoing at the dose of 6.4 mg/kg tri-weekly and additional work is in process in Japan and the United States to further refine the recommended phase II dose,” Tamura noted.

In a statement on the results, Antoine Yver, MD, executive vice president and Global Head, Oncology Research and Development at Daiichi Sankyo, the company developing DS-8201a, said, “Despite recent advances in treating HER2+ breast and gastric cancer, there still remains a large unmet need for patients with HER2+ disease whose tumors are no longer controlled by currently approved targeted HER2 treatments or for tumors that express low HER2.These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2.”

Tamura K, Shitara K, Naito Y, et al. Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in breast cancer patients previously treated with T-DM1: phase 1 dose escalation. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA17.