Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: An individual patient-level analysis of multiple randomized trials

Qian D Shi, Christopher R. Flowers, Wolfgang Hiddemann, Robert Marcus, Michael Herold, Anton Hagenbeek, Eva Kimby, Howard Hochster, Umberto Vitolo, Bruce A. Peterson, Emmanuel Gyan, Michele Ghielmini, Tina Nielsen, Sabine De Bedout, Tommy Fu, Nancy Valente, Nathan H. Fowler, Eva Hoster, Marco Ladetto, Franck MorschhauserEmanuele Zucca, Gilles Salles, Daniel J. Sargent

Research output: Contribution to journalArticle

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Abstract

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, . 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2 WLS) and bivariate copula (R2 Copula) models. Prespecified criteria for surrogacy required either R2 WLS or R2 Copula $ 0.80, with a lowerbound 95% CI . 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

Original languageEnglish (US)
Pages (from-to)552-560
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number5
DOIs
StatePublished - Feb 10 2017

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Follicular Lymphoma
Biomarkers
Disease-Free Survival
Therapeutics
Maintenance
Immunotherapy
Multicenter Studies
Linear Models
Odds Ratio
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy : An individual patient-level analysis of multiple randomized trials. / Shi, Qian D; Flowers, Christopher R.; Hiddemann, Wolfgang; Marcus, Robert; Herold, Michael; Hagenbeek, Anton; Kimby, Eva; Hochster, Howard; Vitolo, Umberto; Peterson, Bruce A.; Gyan, Emmanuel; Ghielmini, Michele; Nielsen, Tina; De Bedout, Sabine; Fu, Tommy; Valente, Nancy; Fowler, Nathan H.; Hoster, Eva; Ladetto, Marco; Morschhauser, Franck; Zucca, Emanuele; Salles, Gilles; Sargent, Daniel J.

In: Journal of Clinical Oncology, Vol. 35, No. 5, 10.02.2017, p. 552-560.

Research output: Contribution to journalArticle

Shi, QD, Flowers, CR, Hiddemann, W, Marcus, R, Herold, M, Hagenbeek, A, Kimby, E, Hochster, H, Vitolo, U, Peterson, BA, Gyan, E, Ghielmini, M, Nielsen, T, De Bedout, S, Fu, T, Valente, N, Fowler, NH, Hoster, E, Ladetto, M, Morschhauser, F, Zucca, E, Salles, G & Sargent, DJ 2017, 'Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: An individual patient-level analysis of multiple randomized trials', Journal of Clinical Oncology, vol. 35, no. 5, pp. 552-560. https://doi.org/10.1200/JCO.2016.70.8651
Shi, Qian D ; Flowers, Christopher R. ; Hiddemann, Wolfgang ; Marcus, Robert ; Herold, Michael ; Hagenbeek, Anton ; Kimby, Eva ; Hochster, Howard ; Vitolo, Umberto ; Peterson, Bruce A. ; Gyan, Emmanuel ; Ghielmini, Michele ; Nielsen, Tina ; De Bedout, Sabine ; Fu, Tommy ; Valente, Nancy ; Fowler, Nathan H. ; Hoster, Eva ; Ladetto, Marco ; Morschhauser, Franck ; Zucca, Emanuele ; Salles, Gilles ; Sargent, Daniel J. / Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy : An individual patient-level analysis of multiple randomized trials. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 5. pp. 552-560.
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abstract = "Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, . 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2 WLS) and bivariate copula (R2 Copula) models. Prespecified criteria for surrogacy required either R2 WLS or R2 Copula $ 0.80, with a lowerbound 95{\%} CI . 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2 WLS of 0.88 (95{\%} CI, 0.77 to 0.96) and an R2 Copula of 0.86 (95{\%} CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11{\%} absolute improvement in CR30 from a 50{\%} control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.",
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T1 - Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy

T2 - An individual patient-level analysis of multiple randomized trials

AU - Shi, Qian D

AU - Flowers, Christopher R.

AU - Hiddemann, Wolfgang

AU - Marcus, Robert

AU - Herold, Michael

AU - Hagenbeek, Anton

AU - Kimby, Eva

AU - Hochster, Howard

AU - Vitolo, Umberto

AU - Peterson, Bruce A.

AU - Gyan, Emmanuel

AU - Ghielmini, Michele

AU - Nielsen, Tina

AU - De Bedout, Sabine

AU - Fu, Tommy

AU - Valente, Nancy

AU - Fowler, Nathan H.

AU - Hoster, Eva

AU - Ladetto, Marco

AU - Morschhauser, Franck

AU - Zucca, Emanuele

AU - Salles, Gilles

AU - Sargent, Daniel J.

PY - 2017/2/10

Y1 - 2017/2/10

N2 - Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, . 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2 WLS) and bivariate copula (R2 Copula) models. Prespecified criteria for surrogacy required either R2 WLS or R2 Copula $ 0.80, with a lowerbound 95% CI . 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

AB - Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, . 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2 WLS) and bivariate copula (R2 Copula) models. Prespecified criteria for surrogacy required either R2 WLS or R2 Copula $ 0.80, with a lowerbound 95% CI . 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

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