TRADE: a phase II trial to assess the tolerability of abemaciclib dose escalation in early-stage HR-positive/HER2-negative breast cancer

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BACKGROUND: Adjuvant abemaciclib with endocrine therapy (ET) improves clinical outcomes in patients with high-risk node-positive early-stage hormone receptor-positive/HER2-negative (HR-positive/HER2-negative) breast cancer (BC), based on the monarchE trial. Patients may experience tolerability issues at the standard abemaciclib dose [150 mg twice daily (b.i.d.)], potentially leading to early treatment discontinuation, particularly within the initial weeks of therapy. TRADE is a prospective, single-arm, phase II study evaluating whether dose escalation of adjuvant abemaciclib improves drug tolerability. PATIENTS AND METHODS: Eligible patients had node-positive HR-positive/HER2-negative BC and were candidates for adjuvant abemaciclib with ET. Participants initiated abemaciclib at 50 mg b.i.d. for 2 weeks, then escalated to 100 mg b.i.d. for 2 weeks, then escalated to the final dose level (150 mg b.i.d.). Dose escalation required the absence of ongoing grade 3-4 or persistent grade 2 toxicity. The primary endpoint, measured at 12 weeks, was a composite rate of abemaciclib discontinuation for any reason or inability to reach or maintain the target dose. RESULTS: In 89 evaluable patients, the initial dose escalation strategy significantly reduced the composite rate at 12 weeks versus a historical value of 40% from monarchE. In total, 26/89 participants (29.2%, 90% confidence interval 21.3% to 38.2%, P = 0.023) met the endpoint: 6 (6.7%) for early discontinuation, 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The majority (70.8%) reached and maintained 150 mg b.i.d. dosing. CONCLUSION: Use of an adjuvant abemaciclib dose escalation strategy allowed more patients to reach and maintain target dosing at 12 weeks than observed in monarchE. Early discontinuation was infrequent, and 93.3% of patients were continuing therapy at 12 weeks. This dosing strategy could be considered when initiating adjuvant abemaciclib.