Results from the I-SPY 2 Trial of Tucatinib plus Paclitaxel + Pertuzumab + Trastuzumab Followed by Doxorubicin/Cyclophosphamide in High-Risk HER2-Positive Stage II/III Breast Cancer

I-SPY 2 is a phase 2 trial evaluating novel treatments as neoadjuvant therapy for women with high-risk breast cancer.1 Tucatinib is an effective HER2 (ErbB2) tyrosine kinase inhibitor that is active against brain metastases and is selective for HER2 versus epidermal growth factor receptors.1 Safety and efficacy outcomes with tucatinib in combination with paclitaxel, pertuzumab, and trastuzumab are unclear, and were examined in a planned safety run-in of the I-SPY 2 study.1

Women with malignancies that were <2.5 cm in diameter were eligible for screening.1 This treatment regimen was only available to patients who had malignancies that were HER2-positive.1 Treatment consisted of tucatinib (maximum dose, 300 mg) twice daily for 12 weeks, followed by weekly paclitaxel 80 mg/m2 and trastuzumab (2 mg/kg weekly following loading) and pertuzumab (420 mg every 3 weeks following loading), followed by doxorubicin/cyclophosphamide every 2 weeks for 4 cycles.1 Weekly paclitaxel and trastuzumab with pertuzumab for 12 weeks followed by doxorubicin/cyclophosphamide every 2 weeks × 4 was the control arm.1 In a planned 300-patient phase 3 neoadjuvant trial with a pathologic complete response end point, the trial’s purpose will be to demonstrate superiority to control.1 This run-in arm was used to assess the safety of combining tucatinib with paclitaxel plus trastuzumab plus pertuzumab, as well as to track specific adverse events such as liver function test (LFT) increases and gastrointestinal toxicity.1

In the tucatinib therapy group, 20 patients were evaluable.1 Historical controls (n = 329) were registered in the control arm from April 2010.1 The starting dose of tucatinib was 300 mg twice daily.1 After the first 8 patients were enrolled, 3 had grade 3 LFT increases, 2 had grade 2/3 diarrhea, 1 had grade 2 neutropenia, and 1 had grade 3 nausea.1 The tucatinib dose was reduced to 250 mg twice daily after this safety evaluation.1 Three of the 5 extra patients who were enrolled exhibited grade 2/3 LFT abnormalities.1 The protocol was then changed to tucatinib 150 mg twice daily on days 1 to 28, then 250 mg twice daily on days 29 to 84, with 7 patients receiving treatment.1 After 20 participants were enrolled, the safety data were examined and the arm was subsequently suspended due to similar LFT increases regardless of tucatinib dose reduction or schedule.1 Nearly one-third (35%) of patients had reversible grade ≥3 aspartate aminotransferase/alanine aminotransferase elevation.1 Hy’s Law conditions were not met by any of the patients.1 In terms of efficacy, MRI assessment of functional tumor volume revealed that 12 of 14 evaluable patients had a tumor volume reduction of >80% after 12 weeks.1

The purpose of the run-in arm was to determine whether adding tucatinib to the paclitaxel plus trastuzumab plus pertuzumab combination was safe.1 Despite tucatinib dose reduction, the addition of tucatinib resulted in undesirable but reversible LFT increases.1 Tucatinib-containing therapy resulted in a >80% reduction in tumor volume in 86% of patients after 12 weeks.1 Tucatinib exhibited a high level of efficacy when used in combination with paclitaxel plus trastuzumab plus pertuzumab; however, this combination is not viable.1

Reference

  1. Potter DA, Roesch E, Yau C, et al. Evaluation of tucatinib + (paclitaxel + pertuzumab + trastuzumab) followed by AC in high-risk HER2-positive stage II/III breast cancer: results from the I-SPY 2 trial. 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. PD8-07.

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