The effect of circadian rhythm on clinical outcome in patients receiving pembrolizumab in the INSPIRE pan-cancer trial.
Notice bibliographique
Résumé
2589 Background: The molecular networks comprising circadian rhythm are expressed in immune cells where they affect immune-related processes. Within the emerging field of chrono-immunotherapy, it has been proposed that immunotherapies should be applied at certain times of day to optimize efficacy. Two recent reports have suggested that earlier administration of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer and melanoma may offer improved survival outcomes (Karaboué et al. ASCO 2021, PMID 34780711). Whether this observation applies to other tumour types, or occurs in geographic regions with differing seasonality, is not known. Methods: We retrospectively analyzed the time of administration data from the INSPIRE single-centre, phase II, multi-cohort study of pembrolizumab (200 mg IV over 1 hour, q3w to maximum 35 cycles) in patients with advanced solid tumours (NCT02644369). Kaplan-Meier methods were used to estimate PFS and OS. Cox proportional hazards models were fitted to assess the association between time of administration and PFS or OS, adjusting for cohort. Fisher’s exact test was used to test for association with immune-related adverse events (irAEs). Results: A total of 106 patients (19 head and neck squamous cell, 22 triple negative breast, 21 epithelial ovarian, 12 melanoma, 32 other solid tumours) were accrued between March 21, 2016, and May 9, 2018. Median time of follow-up was 11.5 months. Start of infusion times were obtained for 806 total doses. The median time of administration was 15h06 for the first dose and 15h11 for all doses (range 09h19 – 18h34). No differences in PFS or OS were observed between patients who received their first dose before or after noon, or before or after 15h06. Furthermore, no differences in PFS or OS were observed between patients who received ≥ 50% of their doses before or after noon, or before or after 15h11. There was also no difference in PFS or OS between patients who did or did not have a significant proportion of doses (≥ 20%) after 16h30 (“evening” in previous reports). There were no differences in the frequency of grade ≥ 2 irAEs amongst the various groups. No differences in efficacy were found when individual cohorts were evaluated separately. Finally, no differences in PFS or OS were observed when participants were grouped by season of first dose. Conclusions: Despite previous reports of improved survival with earlier ICI dosing, we did not identify any association of time of pembrolizumab administration with clinical outcomes. Our analysis is limited by small sample size and patient heterogeneity which may hinder identification of smaller associations. It is also unclear whether lower response rates in a pan-cancer population (relative to prior reports in lung cancer and melanoma) might impact correlation analysis. Further studies will be necessary to interrogate this phenomenon and ensure that ICI are optimally applied.
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 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 | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».