Abstract P5-18-02: Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer
Bibliographic record
Abstract
Abstract Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy and in combination with capecitabine for HER2+ metastatic breast cancer. Diarrhea is the most frequently reported on-target side effect associated with neratinib; in the ExteNET adjuvant trial, where no mandatory anti-diarrheal prophylaxis was used, 39.8% of patients reported grade 3 diarrhea and 16.8% of patients discontinued neratinib due to diarrhea. The CONTROL trial (Clinicaltrials.gov: NCT02400476) was designed to investigate pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or neratinib dose escalation (DE) for the prevention of neratinib-associated diarrhea. Data for the loperamide, budesonide and colestipol cohorts have been reported previously [Barcenas et al. Ann Oncol 2020]. The final findings for the two DE regimen cohorts are reported here. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer received oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) neratinib DE + loperamide PRN (two cohorts). DE1 schedule: neratinib 120 mg/day for week 1, 160 mg/day for week 2, then 240 mg/day from week 3 onwards to complete 12 months of treatment. DE2 schedule: neratinib 160 mg/day for weeks 1&2, 200 mg/day for weeks 3&4, then 240 mg/day from week 5 onwards up to 12 months. Both DE cohorts included loperamide PRN. Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Results: A total of 563 patients were enrolled in CONTROL. All preventive strategies reduced the incidence of grade 3 diarrhea compared with that seen in ExteNET (historical control: 39.8%). Median cumulative duration of grade 3 diarrhea ranged from 2-3.5 days across the CONTROL study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET). The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for loperamide alone. Adoption of neratinib DE, particularly the 2-week DE schedule (DE1), most markedly reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET (see Table). Conclusions: Neratinib DE + loperamide PRN during the first 2 weeks of treatment (DE1 cohort) was associated with the lowest rates of grade 3 diarrhea (13.3%) and diarrhea-related discontinuations (3.3%) compared with all other anti-diarrheal strategies investigated in CONTROL. These final findings from the study show improved tolerability of neratinib with all diarrhea prophylaxis strategies and suggest that neratinib DE1 with loperamide PRN allows patients to stay on treatment longer and receive the full benefit of neratinib therapy. Table. Patient disposition and diarrhea characteristics: ExteNET vs CONTROL DE cohortsExteNET(n=1408)CONTROL DE1 (n=60)CONTROL DE2 (n=62)Patients completing 1 year of neratinib treatment, %617874Median duration of treatment, months (range)11.6 (2.5–11.9)12.0 (0.2–12.4)11.9 (0.3–14.5)Diarrhea, %Grade 339.813.327.4Grade 4<100Median cumulative duration of grade 3 diarrhea,a days52.52Discontinuations due to diarrhea, %16.83.36.5Dose reductions due to diarrhea, %26311Dose holds due to diarrhea, %341213aNo grade 4 diarrhea was reported in CONTROL. Citation Format: Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, Carlos H Barcenas. Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-02.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".