The TRADE study: A phase 2 trial to assess the tolerability of abemaciclib dose escalation in early-stage HR+/HER2- breast cancer.

517 Background: The CDK4/6 inhibitor abemaciclib (abema) is approved with adjuvant endocrine therapy (ET) for high-risk node positive hormone receptor positive (HR+) HER2- breast cancer. This regimen reduces cancer recurrence, yet therapy may be complicated by toxicity, limiting patient (pts) ability to maintain dose or continue medication. In the phase III monarchE study, 25.8% of pts discontinued abema early for reasons other than recurrence, 18.5% for adverse events (AEs), and 43.6% required dose reduction. Experiences with other targeted therapies suggest initial dose escalation may reduce toxicity and discontinuation. TRADE is a prospective, single-arm, phase 2 study evaluating whether a dose-escalation strategy of adjuvant abema improves drug tolerability. Methods: Eligible pts had node-positive HR+/HER2- breast cancer and were candidates for adjuvant abema with ET. All pts started abema at 50 mg BID for 2 weeks (wks), escalated to 100 mg BID for 2 wks, then escalated to final dose of 150 mg BID onwards. Escalation required absence of ongoing grade 3/4 or persistent grade 2 toxicity; anti-diarrheal medication was used as needed. The primary endpoint, measured at 12 wks, was a composite rate of discontinuation of abema for any reason or inability to reach or maintain the 150 mg dose. Based on assumptions from monarchE, the experimental hypothesis was that a dose-escalation schedule of abema would significantly reduce rate of the composite primary endpoint at 12 wks from 40%. Results: 90 pts enrolled, 89 evaluable for the primary endpoint (1 progression before 12 wks). Median age was 58 [range 24-78], 4% were Black, 3% were Hispanic. 48% had stage II disease, 52% had stage III, all received AI, 14% concurrent OFS. The study achieved the predefined primary endpoint with 26 pts (29.2%; 90% CI [21.3-38.2]; p=0.046) meeting the composite endpoint at 12 wks: 6 (6.7%) for early discontinuation (3 [3.4%] for toxicity), 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The most frequent >grade 2 treatment related AEs by 12 wks were neutropenia (23.3%), diarrhea (22.2%), and fatigue (20%). Rates of clinically significant diarrhea (> grade 2) within 0-4, 4-8, and 8-12 wks were 5.6%, 14.6%, 15.3%, in contrast to rates from monarchE of 20.5%, 12.1%, 7.3% in the same periods. Conclusions: The TRADE study is a positive trial meeting its primary endpoint. Use of an adjuvant abema dose escalation strategy allowed a greater number of pts (70.8%) to reach and maintain the 150 mg dose at 12 wks than in monarchE. Early discontinuation was infrequent, and 93.3% were continuing therapy at 12 wks. Reduced incidence and severity of clinically important toxicity such as diarrhea was observed. This dosing strategy could be considered when initiating adjuvant abemaciclib. Further follow-up will assess long-term tolerability, dosing maintenance beyond 12 wks, and correlative analyses. Clinical trial information: NCT06001762 .