234P CDK 4/6 inhibitors (CDK4/6i) for metastatic breast cancer (mBC): The Likelihood of being Helped or Harmed (LHH) as a patient-centred tool to assess clinical impact and safety

Abstract

In mBC CDK4/6i changed clinical practice: Palbociclib (Pal), Ribociclib (Rib) and Abemaciclib (Abe) are currently approved and Dalpiciclib (Dal) showed promising efficacy. Since direct comparisons are not available, we undertook this analysis to provide an overview of LHH as decision tool. Inclusion criteria were: Participants: hormone-receptor-positive/HER2 negative advanced or mBC; Intervention: CDK 4/6i in addition to hormonal therapy; Comparator: Placebo; Outcomes: Progression-free survival (PFS), adverse events (AEs), dose reduction and discontinuation; Study design: phase III randomized controlled trials (RCTs). Effect sizes were computed with a random effect model. LHH was computed from the number needed to treat/harm (NNT/NNH): a higher LHH indicates how the drug is more likely to benefit than to harm. NNT was computed for PFS at specified time-points. A subgroup analysis for different drugs and a sensitivity analysis for hormonal therapy were performed. 8 RCTs where included. Cumulative NNT was 4.5 (95% CI 4.0-5.1), similar between different CDK4/6i. Pooled LHH for G3-4 neutropenia was 0.4 (95% CI 0.3-0.7), with P, R and D having lower LHH (0.4) compared to A (1.0). Pooled LHH for febrile neutropenia was 24.8 (95% CI 14.1-62.5); 22.1 for P, 15.7 for R and 27.0 for A. Cumulative LHH for any grade diarrhea was 1.0 (95% CI 0.5-10.0), with P showing the best LHH (4.9) in contrast to A (0.4). Pooled LHH for dose reduction and discontinuation were 0.6 (95% CI 0.5-0.8) and 4.5 (95% CI 2.2-25.0); between approved agents, P had the highest LHHs, respectively 0.7 and 9.7. Drugs were similar in terms of all G3-4 AEs (LHH 0.5, 95% CI 0.3-0.6) and G3-4 fatigue (LHH 17.2, 95% CI 10.4-31.3), cumulative LHH for G3-4 hepatotoxicity was 3.8 (95% CI, 1.9-16.7). LHH demonstrated similar efficacy but differences in safety and manageability for different CDK4/6i. A showed better LHH for haematological toxicities but lower for diarrhea. P confirmed to be a manageable drug, with higher LHH for dose reductions and discontinuation. This analysis showed that LHH could be considered as a synthesis tool to help choosing the best therapy where multiple options are available.