Validation of progression-free survival (PFS) as surrogate endpoint in randomised trials of immune checkpoint inhibitors in advanced solid cancers

Abstract

Abstract Background Combination of ICIs and chemotherapy (ICI-C) has become a more favourable design in recent trials. We have previously reported 6-month PFS rate (PFS6) is a good surrogate for 12-month overall survival rate (OS12) within treatment (ICI) arms, but had limited data to examine surrogate endpoints for treatment comparisons. We extend our work to validate prior findings by updating with data from more recent randomized controlled trials (RCTs), especially studies testing combination ICI-C. Methods We performed a literature search to identify eligible Phase (Ph) 2 and 3 RCTs of ICI. We excluded studies with sample size of\xa0 Results Forty-six RCTs (5 Ph2; 41 Ph3) with 51 treatment comparisons were identified. Associations between ORR RR with PFS HR, ORR RR with OS HR, and PFS HR with OS HR were r\xa0=\xa00.67, r\xa0=\xa00.42 and r\xa0=\xa00.52 respectively. For the 16 RCTs of ICI-C, these associations were r\xa0=\xa00.79, r\xa0=\xa00.58 and r\xa0=\xa00.64 respectively. For the 35 RCTs of ICI monotherapy, these associations were r\xa0=\xa00.71, r\xa0=\xa00.40 and r\xa0=\xa00.54. Within the ICI arms, associations between ORR and PFS6, ORR and OS12, and PFS6 and OS12 were r\xa0=\xa00.67, r\xa0=\xa00.54 and r\xa0=\xa00.79. Within ICI-C trials, these associations were r\xa0=\xa00.60, r\xa0=\xa00.56 and r\xa0=\xa00.60 respectively. Within ICI monotherapy trials, these associations were r\xa0=\xa00.51, r\xa0=\xa00.46 and r\xa0=\xa00.80 respectively. Conclusions In treatment comparison, the correlation between PFS and OS was modest, but stronger in ICI-C trials. Within ICI arms, PFS6 had stronger correlation with OS12 than ORR. PFS is recommended as a surrogate endpoint for ICI trials over ORR. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Friedlander: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Lecturer fees: AstraZeneca; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.