Correlation between progression‐free and overall survival in patients with classical hodgkin lymphoma: a comprehensive analysis of individual patient data from ghsg trials

Introduction: Progression-free survival (PFS) and overall survival (OS) are predominant measures of treatment efficacy in classical Hodgkin lymphoma (HL). Despite the preference for OS from many regulatory authorities, PFS is most relevant to patients and frequently serves as primary endpoint in clinical trials. The relationship between PFS and OS in HL is of immediate interest but remains unknown to date. We aimed to evaluate correlation of PFS with OS after first-line treatment of HL and its potential to serve as a surrogate parameter. Methods: We analyzed individual patient data obtained during and after polychemotherapy-based treatment in nine randomized phase III GHSG first line trials (HD7-HD15) between 01/93 and 08/18. PFS was defined as time from randomization until progression, relapse, or death; OS was defined as time from randomization until death. Effects of 16 experimental treatments on PFS and OS on trial level were evaluated by estimation of the treatment effects with Cox proportional hazards (PH) regression and a linear weighted least squares (WLS) regression. On patient level, marginal Cox PH models for multiple endpoints were applied according to the Wei-Lin-Weissfeld method (WLW). Additionally, we correlated risk factor effects with marginal Cox PH models at patient level (WLW) and applied copula models to correlate PFS and OS directly at patient level. Results: At least one PFS and OS event was recorded in 1682 and 1064 of 10,605 HL patients, respectively. The statistical analysis at trial level revealed a high and significant correlation of treatment effects on PFS and OS (r = 0.72, r2 = 0.54, p < 0.001, Figure 1). A multiple regression model accounting for different effectiveness of experimental treatments and historical progress over trial generations reached almost perfect fit (r2 = 0.93). The statistical analysis at patient level confirmed a high correlation of treatment effects on PFS and OS. Within the trials, Pearson r was ranging between 0.61 and 0.85 (each p < 0.001) and with two exceptions all correlations were r > 0.70. In total, Pearson r was 0.74, r being higher in advanced stages of HL (r = 0.78) than in limited stages (r = 0.72). At patient level, we found similar high correlations between effects of risk factors on PFS and OS (Pearson r = 0.74–0.85, each p < 0.001, WLW analysis) and when correlating PFS and OS with copula (Pearson r = 0.72–0.83, each p < 0.001). Sixteen separately estimated treatment effects on PFS and OS at trial level with resulting linear regression line (r = 0.721, 95% CI = 0.350–0.896). Conclusions: In first-line trials of HL, PFS and OS as well as treatment effects and prognostic effects of risk factors on PFS and OS are highly correlated. PFS thereby predicts treatment effects on OS to a high degree and many years before OS can be reliably evaluated. Encore Abstract—previously submitted to EHA 2023 The research was funded by: Merck & Co., Inc Keyword: Hodgkin lymphoma Conflicts of interests pertinent to the abstract P. J. Bröckelmann Consultant or advisory role: Takeda Honoraria: BeiGene, Bristol-Myers Squibb, MSD Sharp & Dohme, Stemline, Takeda Research funding: BeiGene, Bristol-Myers Squibb, MSD Sharp & Dohme, Takeda Educational grants: Celgene X. Yang Employment or leadership position: Merck & Co., Inc B. von Tresckow Consultant or advisory role: Allogene, BMS/Celgene, Cerus, Incyte, IQVIA, Gilead Kite, Miltenyi, Novartis, Noscendo, Pentixapharm, Roche, Amgen, Pfizer, Takeda, Merck Sharp & Dohme, and Gilead Kite Honoraria: AstraZeneca, BMS, Incyte, Novartis, Roche Pharma AG, Takeda, and Merck Sharp & Dohme Research funding: Novartis (Inst), Merck Sharp & Dohme (Inst), and Takeda (Inst) Educational grants: AbbVie, AstraZeneca, Gilead Kite, Merck Sharp & Dohme, Roche, Takeda, and Novartis