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
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,003 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,004 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,008 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».