Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib
Menée à partir de données portant sur 675 patients atteints d'un mélanome métastatique avec mutation V600E du gène BRAF et inclus dans un essai de phase III évaluant l'efficacité du vémurafénib par rapport au dacarbazine, puis validée à partir de données portant sur 132 autres patients, cette étude évalue la corrélation entre différents critères de jugement de substitution, dont le délai avant progression tumorale, et la survie globale
Purpose:Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib vs. dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2). Experimental Design:De-identified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and non-target tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set.
Results:Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort.
Conclusions: TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early phase studies.
Clinical Cancer Research , résumé, 2015