Background: The primary tolerability concern with neratinib (NERLYNX®; N), an irreversible pan-HER tyrosine kinase inhibitor, is diarrhea. Data from the multi-cohort, open-label, phase 2 CONTROL trial [Barcenas et al. Ann Oncol 2020] demonstrated significant improvement in grade 3 diarrhea and diarrhea-related discontinuations vs the ExteNET trial, which did not mandate anti-diarrheal prophylaxis. We report a systematic analysis of tolerability in CONTROL and ExteNET. Methods: Patients (pts) ≥18y with stage I–IIIc HER2+ breast cancer received N (240 mg/d po for 1y) after trastuzumab-based adjuvant therapy and were enrolled sequentially into cohorts assessing different modalities to mitigate diarrhea. Cohorts with complete data were included: loperamide (L); L+budesonide (BL); L+colestipol (CL); CL as needed (CL-PRN); and N dose escalation (DE; 120 mg/d on d1–7, 160 mg/d on d8–14, and 240 mg/d thereafter). Integrated ranking (IR) analysis was performed on 13 endpoints in 4 domains (exposure, diarrhea, adverse events [AEs], quality of life [QoL]) identified with input from clinicians; cohorts were ranked from 1 (best) to 5 (worst). Index scores (IS) based on individual pt data from CONTROL were calculated as supportive analysis to confirm selection of the regimen with best overall tolerability, which was then compared with ExteNET. Results: Of the 5 CONTROL cohorts evaluated, DE ranked best for most endpoints. Average ranks per IR method: L 3.4; BL 3.2; CL 3.0; CL-PRN 3.3; DE 2.0. The IS analysis supported DE as the cohort with best overall tolerability. Comparison of CONTROL DE vs ExteNET showed improvement in tolerability in all domains (table). Conclusions: These analyses suggest superiority of weekly DE vs other anti-diarrheal strategies. A lower rate of grade 3 diarrhea was observed with CONTROL DE vs ExteNET (13.3 vs 39.9%, respectively), as well as a comparable or improved AE profile. The data also reveal greater compliance with N (fewer early discontinuations, longer treatment duration, higher cumulative dose) and reduced impact on QoL with DE, suggesting improved tolerability. Clinical trial information: NCT02400476

*1 pt had grade 4 diarrhea in ExteNET; no grade 4 diarrhea in CONTROL DE. **No grade 4 events observed.