Do Early Phase Oncology Trials Predict Clinical Efficacy in Subsequent Biomarker-Enriched Phase III Randomized Trials?
Journal
Targeted oncology
ISSN: 1776-260X
Titre abrégé: Target Oncol
Pays: France
ID NLM: 101270595
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
accepted:
16
09
2022
pubmed:
6
10
2022
medline:
26
11
2022
entrez:
5
10
2022
Statut:
ppublish
Résumé
Promising early phase trial results of biomarker-targeted therapies have occasionally led to regulatory approval. We examined if early phase trials were predictive of efficacy in randomized controlled trials (RCTs) with matching treatment settings. Cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Biomarker-enriched RCTs and associated matching early phase trials were included. Trial pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We examined whether early phase trials results were associated with RCT results using logistic regression. The search yielded 2157 unique RCTs and 27 RCTs pairing with early phase trials were included. Based on average difference of trial pairs, ORR was similar (1.6%; 95% confidence interval (CI) - 2.5 to 5.6, p = 0.50) and median PFS was higher in early phase trials (2.0 months; 95% CI 0.9-3.0, p < 0.05). On an individual pair basis, there was large variability in difference for ORR (range - 23.9 to 20.2%) and median PFS (range - 0.8 to 7.4 months). The probability of the RCT meeting its primary endpoint is 95% (95% prediction interval (PI) 72.8-99.3%) when the early phase trial ORR is 77.7%. Overall, in early phase trials, ORR has minimal bias and median PFS appears to be slightly overestimated. Substantial variability between trials suggests early phase trial results may be inconsistent with subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs.
Sections du résumé
BACKGROUND
Promising early phase trial results of biomarker-targeted therapies have occasionally led to regulatory approval.
OBJECTIVE
We examined if early phase trials were predictive of efficacy in randomized controlled trials (RCTs) with matching treatment settings.
PATIENTS AND METHODS
Cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Biomarker-enriched RCTs and associated matching early phase trials were included. Trial pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We examined whether early phase trials results were associated with RCT results using logistic regression.
RESULTS
The search yielded 2157 unique RCTs and 27 RCTs pairing with early phase trials were included. Based on average difference of trial pairs, ORR was similar (1.6%; 95% confidence interval (CI) - 2.5 to 5.6, p = 0.50) and median PFS was higher in early phase trials (2.0 months; 95% CI 0.9-3.0, p < 0.05). On an individual pair basis, there was large variability in difference for ORR (range - 23.9 to 20.2%) and median PFS (range - 0.8 to 7.4 months). The probability of the RCT meeting its primary endpoint is 95% (95% prediction interval (PI) 72.8-99.3%) when the early phase trial ORR is 77.7%.
CONCLUSIONS
Overall, in early phase trials, ORR has minimal bias and median PFS appears to be slightly overestimated. Substantial variability between trials suggests early phase trial results may be inconsistent with subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs.
Identifiants
pubmed: 36197635
doi: 10.1007/s11523-022-00920-y
pii: 10.1007/s11523-022-00920-y
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
665-674Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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