Abstract P4-10-09: Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial
Notice bibliographique
Résumé
Abstract Introduction: P and trastuzumab (T) are approved for the treatment of early and advanced breast cancer (BC) pts. Skin rash and diarrhea are frequent adverse events (AE) with P. With the use of lapatinib, we demonstrated that early development of rash correlates with pathologic complete response in the NeoALTTO trial and is both a prognostic and predictive marker in the ALTTO trial. In this subanalysis of the CLEOPATRA trial, we investigated if incidence of rash and diarrhea associates with progression free survival (PFS) or overall survival (OS) and if it can predict the benefit of P+T. Methods: In the CLEOPATRA phase III trial, advanced HER2-positive BC pts where randomized between first-line T vs P+T with at least 6 cycles of docetaxel. We evaluated whether rash (any grade) and/or diarrhea (any grade or grade ≥3) were prognostic in pts receiving P+T and/or predictive of benefit from P+T vs T. To deal with immortal-time bias, we performed a landmark analysis removing pts progressing/dying before a minimum of 46 days (median time to rash/diarrhea occurrence) after treatment initiation (cohort 1), and after end of docetaxel treatment (cohort 2). Survival endpoints were PFS and OS according to study definition. We also investigated if age (<50 or ≥50 years) influences the incidence of diarrhea or rash and if the 2 AEs are associated with one another. For both AEs, the earliest event was considered for analysis. Results: Of the 808 patients in the CLEOPATRA study, cohort 1 included 777 pts (T: 379; P+T: 398) and cohort 2 included 518 pts (T: 232; P+T: 286). The table summarizes the incidence and impact of rash and diarrhea by treatment arm and their effect on outcomes after a median PFS and OS follow-up of 43.6 (IQR 22.9-50.5) and 48.4 (IQR 43.5-55.0) months, respectively, in cohort 1. It shows that rash is prognostic for both PFS and OS (P+T treated) but not predictive of P+T benefit vs T; while diarrhea is not prognostic but predicts P+T PFS benefit. In cohort 2, diarrhea and rash were prognostic for PFS (rash, HR 0.42 [95% CI 0.29-0.60], p<0.001; diarrhea 0.48 [0.35-0.65], p<0.001) and only rash for OS (rash, 0.50 [0.29-0.86], p=0.013; diarrhea, 0.64 [0.39-1.03], p=0.064), but neither were predictive of P+T benefit for PFS (rash, p for interaction of any grade x treatment [pint]=0.695; diarrhea, pint=0.194) nor OS (rash, pint=0.841; diarrhea, pint=0.155). Younger age (<50 years) was not associated with diarrhea (OR 1.01 [95% CI 0.76-1.35], p=0.932), rash (1.07 [0.79-1.45], p=0.69) or both (0.92 [0.67-1.27], p=0.635). Having diarrhea (any grade) was associated with having rash (any grade; p<0.001, Cramér’s V 0.24).Conclusion: Rash is prognostic both for PFS and OS, but not predictive of pertuzumab benefit. Conversely, diarrhea predicts PFS benefit of P when occurring during docetaxel administration but is prognostic only after docetaxel withdrawal. These results may be used to reassure pts experiencing these AEs during treatment. Incidence and Impact of Diarrhea and/or Rash on PFS and OS in cohort 1Patients, n (%)PFS, % at 2 yrsOS, % at 2 yrsPrognostic role (pertuzumab treated)RashYes, any grade169 (42.5)48.587.3No, any grade229 (57.5)37.478.0HR (95% CI), p-value (any grade vs. no)NA0.71 (0.56-0.91), p<0.0060.66 (0.48-0.91), p<0.001DiarrheaYes, any grade238 (59.8)42.683.5No, any grade160 (40.2)41.679.6Yes, grade ≥337 (9.3)50.480.8No, grade ≥3361 (90.7)41.482.1HR (95% CI), p-value (any grade vs. no)NA0.97 (0.77-1.24), p<0.8340.93 (0.68-1.28), p=0.677Predictive role (overall cohort 1)RashYes, any grade271 (34.9)45.584.6No, any grade506 (65.1)28.872.0pintNAp=0.477p=0.711DiarrheaYes, any grade406 (52.2)39.479.3No, any grade371 (47.8)29.673.4Yes, grade ≥357 (7.3)40.574.8No, grade ≥3720 (92.7)34.376.7pint (any grade vs. no)NAp=0.049p=0.564 Citation Format: Arlindo R. Ferreira, Noam Pondé, Matteo Lambertini, Christian Maurer, Samuel Martel, Luis Costa, Evandro De Azambuja. Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-09.
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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 | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
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 ».