Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man—PFS2: A Measure of Therapeutic Action-At-A-Distance

Abstract

Overall survival (OS) has emerged as the definitive regulatory “be-all, end-all” for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a “test of time,” OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials. Second, OS captures the impact of subsequent therapies, both beneficial (i.e., active) and detrimental, on survival but it does not take into account the contribution of subsequent therapies by treatment arm; the postprogression period is treated as an unknown black box (no information about the potential influence of next-line therapies on the outcome) under the implicit assumption that the clinical trial treatment is the only clinical variable that matters: what OS explicitly measures is the destination, that is, the elapsed time between the date of randomization (or intention to treat) and the date of death, not the journey, that is, what transpires in-between.In long-term maintenance strategies, patients receive treatment in temporally separated but mutually interdependent and causally linked sequences that exert a “field of influence” akin to action-at-a-distance forces like gravity, electricity, and magnetism on both the tumor and each other. Hence, in this setting, a new end point, PFS2, is required to measure this field of influence. This article reviews the definition and use in clinical trials of PFS2 and makes the case for its potential applicability as a preferred end point to measure the mutual influence of individual regimens in long-term maintenance strategies with resensitizing agents in particular.

Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

“…PFS was prolonged with PFS2 may serve as a surrogate endpoint for OS when survival data are not available [23]. The use of PFS2 has been suggested as a preferred endpoint, particularly for studies investigating long-term maintenance treatment [23][24][25]. The findings presented here demonstrate that D-Rd significantly prolongs the time to subsequent therapy and PFS2 versus Rd, conferring a 47% reduction in the risk of disease progression or death on the next line of therapy.…”

“…It is important to note that an updated next-generation sequencing assay with improved calibration rate was used to determine MRD negativity in the current study. PFS was prolonged with PFS2 may serve as a surrogate endpoint for OS when survival data are not available [23]. The use of PFS2 has been suggested as a preferred endpoint, particularly for studies investigating long-term maintenance treatment [23][24][25].…”

The low IGFBP-3 level is associated with esophageal cancer patients: a meta-analysis

“…Overall survival (OS), an easily appreciated parameter, remains the strongest trial endpoint in cancer clinical trials, which is independent of bias resulting from the definition of progression, approaches of evaluation, and clinical assessment [33]. Previous studies implied that for esophageal cancer patients, the elevated IGFPB-3 level was significantly associated with improved overall survival [15, 17], which was inconsistent with the related study published in 2004 [16].…”

Three-Year Follow up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma (RRMM)

“…16 PFS2 may serve as a surrogate endpoint for OS when survival data are not available. 23 The use of PFS2 has been suggested as a preferred endpoint, particularly for studies investigating long-term maintenance treatment. [23][24][25] The findings presented here demonstrate that D-Rd significantly Follow-up for OS in POLLUX is ongoing, with the final analysis planned after 330 deaths.…”