Presentation (CTI)

OBJECTIVES: In the absence of long-term follow-up from a randomized controlled trial (RCT), NICE recommend trial-level surrogacy (level-1) to predict OS treatment effects. For targeted treatments, this may be challenging to establish given limited number of RCTs in the target population. This study describes the experience of a recent NICE appraisal using a novel patient-level approach to predict OS based on the association with progression-free survival (PFS) (level-2).
METHODS: Public NICE draft guidance (GID-TA11342) documents were reviewed, and drivers of decision-making were assessed. The manufacturer estimated individual-level PFS-OS surrogacy based on a single-arm Phase-I/IIb trial in the target population (KRASG12C-mutated second-line non-small cell lung cancer [NSCLC]). OS was predicted for the Phase-III RCT arms using progression status, the PFS-OS individual-level surrogacy, and observed deaths in the RCT.
RESULTS: Despite minimal methodological critiques, NICE considered the level-2 surrogacy-based OS predictions inappropriate for decision-making: “no evidence to suggest that PFS benefits translate to OS benefits, or that PFS is a reliable surrogate for OS in [the target population].” External validation in second-line KRAS-unselected NSCLC was not considered sufficient for the KRAS-mutated target population. Assessors assumed no OS benefit and the technology was not recommended for routine use or for the Cancer Drug Fund (CDF) despite PFS benefits versus standard of care from the RCT (hazard-ratio: 0.58, p<0.0001) and favorable efficacy versus another KRAS inhibitor in the CDF. The other KRAS inhibitor was recommended based on a single-arm trial; RCT OS results later became available. It is unclear whether trial-level surrogacy may have been inferred based on this one RCT.
CONCLUSIONS: This experience suggests that early evidence from a single-arm trial using unanchored comparisons may be preferable to evidence from an RCT leveraging OS predictions based on level-2 surrogacy. Data collection in the CDF may provide an opportunity for patient access and reduced clinical uncertainty.