Intermediate endpoints as surrogates for outcomes in cancer immunotherapy: a systematic review and meta-analysis of phase 3 trials

BACKGROUND: Cancer immunotherapy shows unique efficacy kinetics that differs from conventional treatment. These characteristics may lead to the prolongation of trial duration, hence reliable surrogate endpoints are urgently needed. We aimed to systematically evaluate the study-level performance of commonly reported intermediate clinical endpoints for surrogacy in cancer immunotherapy. METHODS: We searched the Embase, PubMed, and Cochrane databases, between database inception and October 18, 2022, for phase 3 randomised trials investigating the efficacy of immunotherapy in patients with advanced solid tumours. An updated search was done on July, 15, 2023. No language restrictions were used. Eligible trials had to set overall survival (OS) as the primary or co-primary endpoint and report at least one intermediate clinical endpoint including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and 1-year overall survival. Other key inclusion and exclusion criteria included: (1) adult patients (>18 years old) with advanced solid tumour; (2) no immunotherapy conducted in the control arms; (3) follow-up is long enough to achieve OS; (4) data should be public available. A two-stage meta-analytic approach was conducted to evaluate the magnitude of the association between these intermediate endpoints and OS. A surrogate was identified if the coefficient of determination (R(2)) was 0.7 or greater. Leave-one-out cross-validation and pre-defined subgroup analysis were conducted to examine the heterogeneity. Potential publication bias was evaluated using the Egger's and Begg's tests. This trial was registered with PROSPERO, number CRD42022381648. FINDINGS: 52,342 patients with 15 types of tumours from 77 phase 3 studies were included. ORR (R(2) = 0.11; 95% CI, 0.00–0.24), DCR (R(2) = 0.01; 95% CI, 0.00–0.01), and PFS (R(2) = 0.40; 95% CI, 0.23–0.56) showed weak associations with OS. However, a strong correlation was observed between 1-year survival and clinical outcome (R(2) = 0.74; 95% CI, 0.64–0.83). These associations remained relatively consistent across pre-defined subgroups stratified based on tumour types, masking methods, line of treatments, drug targets, treatment strategies, and follow-up durations. No significant heterogeneities or publication bias were identified. INTERPRETATION: 1-year milestone survival was the only identified surrogacy endpoint for outcomes in cancer immunotherapy. Ongoing investigations and development of new endpoints and incorporation of biomarkers are needed to identify potential surrogate markers that can be more robust than 1-year survival. This work may provide important references in assisting the design and interpretation of future clinical trials, and constitute complementary information in drafting clinical practice guidelines. FUNDING: None.