20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study
Notice bibliographique
Résumé
Abstract Background In Phase 3 trials, the assessment for primary endpoint of overall survival (OS) necessitates extended follow-up periods, a larger pool of events, and higher associated costs. Hence, we sought to determine whether shorter intermediate (IEs) such as Objective Response (OR), Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients receiving immune checkpoint (ICI)-based therapy. Methods We included all International mRCC Database Consortium (IMDC) patients who received contemporary first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last follow-up. OR included investigators-assessed complete or partial response per RECIST1.1 criteria. First, we assessed the endpoint correlations across all follow-up times of individual patient data using Kendall’s Tau (KT) correlation by a Clayton copula. A KT >0.49 indicates a strong correlation (Wicklin R., 2023). Then we evaluated associations of OS with TTF and TTNT status at the 6-month landmark using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by ICI type and years of ICI start. The KT correlation was estimated by the R GJRM package (https://www.r-project.org/). All other statistical analyses were done with SAS 9.4 software (SAS Institute, Cary, NC). Results The cohort consisted of 1667 patients with a median follow-up of 15.4 months (IQR: 7.1-28.6). For the 6-month landmark analysis in OS, patients who died or had less than 6 months of follow-up were excluded, affecting 278 for OR, 373 for TTF, and 380 for TTNT. Median age at 1L start was 63 years (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. A total of 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Over the entire follow-up of individual patient data, the Kendall’s Tau correlation was 0.49 (95%CI: 0.45-0.52) for TTF with OS and 0.67 (95%CI: 0.64-0.69) for TTNT with OS. The Kendall’s Tau correlations between endpoints were also similar in subgroup analyses by IMDC risk group and type of regimen and the strongest in the ICI+TKI subgroup with a Kendall’s Tau correlation of 0.73(0.66-0.78). On the 6-month OS landmark analysis (Table), patients who discontinued their 1L regimen had poor OS (adjusted HR: 2.77 (95%CI: 2.16-3.55)). Additionally, those who transitioned to a 2L therapy within the first 6 months showed worse OS, reflected by an HR of 2.82 (2.22-3.59). Patients who did not have an objective response also had worse OS (adjusted HR: 2.74 (95%CI: 2.15-3.49)). On the other hand, patients with an objective response had an 18-month OS rate (equivalent of 12-month OS post the 6-month landmark) of 91% (95%CI: 88%-93%) vs 74% (95%CI: 70%-78%) for those with no response at 6 months. Table. Landmark analysis of OS from 6 months of post therapy initiation, according to OR, TTF and TTNT event status at 6 months, in whole cohort and by IMDC and treatment groups. Conclusions Our study explored TTF, TTNT and OR as clinical IEs for OS. TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating treatment efficacy in ICI-based regimens.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».