Trastuzumab Emtansine (T-DM1) Plus S-1 in Patients with Trastuzumab-Pretreated HER2-Positive Advanced or Metastatic Breast Cancer: A Phase Ib Study.

Abstract

BACKGROUND:

In treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, the efficacy of capecitabine combined with HER2-directed agents such as trastuzumab and lapatinib is supported by some evidence. The combination of T-DM1 and S-1, another oral 5-FU, may be a safe alternative treatment for metastatic breast cancer.

OBJECTIVES:

The optimal dose of S-1 was evaluated in combination with T-DM1 for patients with HER2-positive advanced or metastatic breast cancer. The safety and clinical response of this combination treatment were also assessed.

METHODS:

This 3 + 3 dose-escalation study of S-1 given for the first 2 of 3 weeks, in combination with T-DM1 (3.6 mg/kg given every 3 weeks) to patients with trastuzumab-pretreated HER2-positive advanced or metastatic breast cancer was designed to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. We also evaluated the safety and clinical activity of this combination treatment in multiple cycles. Two different dose levels of S-1 (65 and 80 mg/m2/day) were planned, although the capecitabine arm was abandoned because of slow recruitment.

RESULTS:

Twelve out of the 13 patients enrolled were evaluable for DLT. One DLT (grade ≥3 non-hematological adverse events) occurred at dose level 0, leading to the expansion of this cohort to 6 patients, with an additional DLT (≥7 days discontinuation of medication), while no DLT occurred at dose level 1. As a result, the maximum tolerable dose of S-1 was determined to be 80 mg/m2/day for 14 days with T-DM1 3.6 mg/kg, repeated every 3 weeks. Two patients had grade 3 thrombocytopenia at dose level 0, and 1 patient at dose level 1.

CONCLUSIONS:

S-1 can be safely combined with the clinically relevant dose of T-DM1 in patients with HER2-positive advanced or metastatic breast cancer. Further evaluation with a larger sample size is required for efficacy assessment.

• Authors: Yasuyuki Kojima, Reiko Yoshie, Hisanori Kawamoto, Arata Shimo, Tomoko Uejima, Tsuguo Iwatani, Ai Motoyoshi, Yoshihide Kanemaki, Narikazu Boku, Koichiro Tsugawa
• Journal: Oncology (Oncology) Vol. 96 Issue 6 Pg. 309-317 ( 2019) ISSN: 1423-0232 [Electronic] Switzerland
• PMID: 30893699 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2019 S. Karger AG, Basel.

Chemical References

• Drug Combinations
• Maytansine
• S 1 (combination)
• Tegafur
• Oxonic Acid
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Breast Neoplasms (drug therapy, genetics)
• Drug Combinations
• Female
• Humans
• Maytansine (administration & dosage, adverse effects, analogs & derivatives)
• Middle Aged
• Neoplasm Metastasis
• Oxonic Acid (administration & dosage, adverse effects)
• Receptor, ErbB-2 (genetics)
• Tegafur (administration & dosage, adverse effects)
• Trastuzumab (administration & dosage, adverse effects)
• Treatment Outcome