A phase I/II study of epertinib plus trastuzumab with or without chemotherapy in patients with HER2-positive metastatic breast cancer

by Selleckchem | May 15 2023

Background: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC).

Methods: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety.

Results: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C.

Conclusion: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases.

Comments：

In this study, the safety, tolerability, pharmacokinetics, and antitumor activity of daily oral epertinib were evaluated in combination with trastuzumab, with trastuzumab plus vinorelbine, or with trastuzumab plus capecitabine in patients with HER2-positive metastatic breast cancer. The study enrolled patients who had received prior HER2-directed therapy and had or did not have brain metastases. The dose-escalation phase determined the tolerability of each combination, and the study established a dose for further investigation. Patients were then recruited to expansion cohorts in each of the three arms to further explore efficacy and safety.

The recommended doses of epertinib in arms A, B, and C were 600 mg, 200 mg, and 400 mg, respectively. The most frequent grade 3/4 adverse event was diarrhea in all arms, which was manageable with medical intervention and dose modification. The objective response rate in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67%, with trastuzumab plus vinorelbine was 0%, and with trastuzumab plus capecitabine was 56%. Notably, patients previously treated with T-DM1 and capecitabine responded in the arm A and arm C expansion cohorts, respectively. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C.

In conclusion, the study demonstrated the safety, tolerability, and encouraging antitumor activity of epertinib in combination with trastuzumab or with trastuzumab plus capecitabine in patients with pre-treated HER2-positive MBC, with or without brain metastases. The study supports further evaluation of these combinations in this patient population.