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Evaluation of complete response rate at 30 months (CR30) as a surrogate for progression-free survival (PFS) in first-line follicular lymphoma (FL) studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data (IPD) of 3,837 patients (pts).
Background: Although PFS is the standard endpoint for new drug approvals in first-line FL, advances in efficacy (median PFS >7 y) coupled with the indolent nature of FL necessitate extended patient follow-up in clinical trials. The FLASH group conducted a meta-analysis to evaluate whether treatment effects on CR30, an earlier endpoint, could accurately predict treatment effects on PFS. Methods: Correlation of CR30 odds ratio (OR) with PFS hazard ratio (HR) was evaluated using both linear regression (R2WLS) and copula bivariate (R2Copula) models. Prespecified criteria for CR30 surrogacy required either R2WLS or R2Copula ≥ 0.80 with a lower bound of the 95% confidence interval (CI) > 0.60, with neither estimate < 0.70. The minimum CR30 difference to predict significant PFS difference was calculated. Results: Data from 13 randomized first-line trials (8 induction, 5 maintenance trials) with IPD for 3837 pts were included. The prespecified threshold for surrogacy was met: R2WLS of 0.88 (95% CI, 0.77-0.96) and R2Copula of 0.86 (95% CI, 0.72-1.00, Table), supporting the hypothesis that treatment effects on CR30 predict effects on PFS in pts with previously untreated FL. Multiple sensitivity and IPD surrogacy analyses supported the robustness of the primary analysis. A minimum 10% absolute improvement in CR30 over a control CR30 of 50% predicted significant improvement in PFS. Conclusions: This large IPD meta-analysis of chemo/immunotherapy trials establishes CR30 as a surrogate endpoint for PFS in first-line FL trials and supports its use to expedite therapeutic development.
|Trial type||Trials, N (pts)||R2WLS (95% CI)a||R2Copula (95% CI)a|
|Overall||13 (3837)||0.88 (0.77-0.96)||0.86 (0.72-1.00)|
|Rituximab included||9 (2851)||0.85 (0.62-0.97)||0.80 (0.56-1.00)|
|No rituximab||4 (986)||0.91 (0.05-1.00)||0.96 (0.90-1.00)|
|Induction||8 (2207)||0.89 (0.75-0.98)||0.89 (0.74-1.00)|
|Maintenance||5 (1630)||0.93 (0.84-1.00)||0.89 (0.71-1.00)|
a R2 values range from 0 (no association) to 1 (perfect prediction).
Abstracts by Daniel J. Sargent:
Prognostic value of isolated peritoneal versus other metastatic sites in colorectal cancer (CRC) patients treated by systemic chemotherapy: Findings from 9,265 pts in the ARCAD database.Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: 656
Prognostic value of primary tumor resection in synchronous metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of first-line randomized trials from the ARCAD database.Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: 658
Association of tumor infiltrating lymphocytes (TILs) with molecular subtype and prognosis in stage III colon cancers (CC) from a FOLFOX-based adjuvant chemotherapy trial.Meeting: 2016 ASCO Annual Meeting | Abstract No: 3518
Presentations by Daniel J. Sargent:
Meeting: 2012 ASCO Annual Meeting
Session: Endpoints for Cancer Trials in 2012: Statistical, Regulatory, and Clinical Perspectives (eQ&A) (Education Session)
Meeting: 2012 Gastrointestinal Cancers Symposium
Session: Clinical Trial Design Debate: Development of Biomarker-Driven Studies (Meet the Professor Session)