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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:
Outcomes in the second line treatment of metastatic colorectal cancer (mCRC): Findings from 6,462 patients (pts) in the ARCAD database.Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 757
Rectal versus left-sided colon cancers: Clinicopathological differences observed in a pooled analysis of 4,182 patients enrolled to 8 clinical trials from the ARCAD database.Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 675
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