Objective: The ongoing Phase III randomized POLARIX study (GO39942; NCT03274492) demonstrated significantly improved progression-free survival (PFS) with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We compared statistical methodologies to extrapolate long-term PFS data from POLARIX.
Materials and methods: This analysis explored four different approaches to extrapolate the POLARIX data: standard parametric survival, mixture-cure, landmark, and spline models. The resulting extrapolation curves were validated via comparison with the corresponding Kaplan-Meier (KM) curves from POLARIX and the POLARIX-like population of the Phase III GOYA study (NCT01287741; R-CHOP arm).
Results: The R-CHOP PFS KM curve from the GOYA validation set was well aligned with the POLARIX KM curve. As we anticipated that PFS in POLARIX would evolve similarly to that of GOYA, the data from GOYA were used to externally validate the extrapolated modelling results. While all four statistical methods were able to fit the data to the POLARIX KM curve, the mixture-cure model was the most accurate in predicting long-term PFS in the GOYA external validation set. In the mixture-cure model, generalized gamma distribution estimated 64% (95% confidence intervals [CI]: 56-71%) of patients to have long-term remission in the R-CHOP arm of POLARIX and GOYA, and 75% (95% CI: 70-79%) in the Pola-R-CHP arm of POLARIX. A limitation of this study was the comparison of the statistical models only in the PFS KM curves, since it was not possible to determine which statistical method was more appropriate to extrapolate the overall survival KM curves.
Conclusions: Within this analysis, the mixture-cure model provided the best prediction of long-term outcomes from the primary PFS analysis of the POLARIX study.
Keywords: Diffuse large B-cell lymphoma; Landmark model; Mixture-cure model; Polatuzumab vedotin; Spline model; Standard parametric survival model.