Dataset Information

Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

ABSTRACT: Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus 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).Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget 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.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.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.

SUBMITTER: Zabor EC

PROVIDER: S-EPMC5500836 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

Zabor Emily C EC Heller Glenn G Schwartz Lawrence H LH Chapman Paul B PB

Clinical cancer research : an official journal of the American Association for Cancer Research 20151021 6

<h4>Purpose</h4>Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus 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).<h4>Experimental design</h4>Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement dat ...[more]

PMID: 26490313

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Project description:BackgroundRecent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials.MethodsWe systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose.FindingsAfter screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0·71 (95% CI 0·29-0·90) with a random-effects assumption, 0·85 (0·59-0·95) with a fixed-effects assumption, and 0·89 (0·68-0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81-0·99), which decreased to 0·93 (0·74-0·98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0·55, 0·03-0·84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0·85 (0·51-0·96).InterpretationPFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials.FundingNone.

Project description:BackgroundSurrogate endpoints (SEs), such as progression-free survival (PFS) and objective response rate (ORR), are frequently used in clinical trials. The relationship between SEs and overall survival (OS) has not been well described in metastatic urothelial cancer (MUC).ObjectiveWe evaluated trial-level data to assess the relationship between SEs and OS. We hypothesize a moderate surrogacy relationship between both PFS and ORR with OS.Design setting and participantsWe systematically reviewed phase 2/3 trials in MUC with two or more treatment arms, and report PFS and/or ORR, and OS.Outcome measurements and statistical analysisLinear regression was performed, and the coefficient of determination (R2) and surrogate threshold effect (STE) estimate were determined between PFS/ORR and OS.Results and limitationsOf 3791 search results, 59 trials and 62 comparisons met the inclusion criteria. Of the 53 trials that reported PFS, 31 (58%) reported proportional hazard regression for PFS and OS. Linear regression across trials demonstrated an R2 of 0.60 between hazard ratio (HR) for PFS (HRPFS) and HR for OS (HROS), and an STE of 0.41. Linear regression of ΔPFS (median PFS in months of the treatment arm - that of the control arm) and ΔOS demonstrated an R2 of 0.12 and an STE of 14.1 mo. Thirty trials reported ORRs. Linear regression for ORRratio and HROS among all trials found an R2 of 0.08; an STE of 95% was not reached at any value and ΔORR and HROS similarly demonstrated a poor correlation with an R2 value of 0.03.ConclusionsPFS provides only a moderate level of surrogacy for OS; An HRPFS of ≤0.41 provides 95% confidence of OS improvement. ORR is weakly correlated with OS and should be de-emphasized in MUC clinical trials. When PFS is discussed, proportional hazard regression should be reported.Patient summaryWe examined the relationship between surrogate endpoints, common outcomes in clinical trials, with survival in urothelial cancer trials. Progression-free survival is moderately correlated, while objective response rate had a poor correlation with survival and should be de-emphasized as a primary endpoint.

Dataset Information

Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

Publications

Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

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