Presentation (CTI)

OBJECTIVES: European Joint Clinical Assessment documentation specifies criteria for establishing surrogate relationships: level 1) evidence of corresponding treatment effects; level 2) association between outcomes; and level 3) biological plausibility. To support decision-making for repotrectinib, we aimed to estimate the relationship between overall survival (OS) and response-based endpoints (progression-free survival [PFS] or objective response rate [ORR]) among patients with ROS1+ locally advanced or metastatic non-small cell lung cancer (aNSCLC) who are ROS1 tyrosine kinase inhibitor (TKI)-naïve or -experienced.
METHODS: A systematic literature review was conducted, capturing clinical trials among patients with ROS1+ aNSCLC, treated with TKIs, and reporting OS and either PFS or ORR. No randomized controlled trials (RCTs) were identified, precluding comparison of treatment effects. Aggregate arm-level correlations were conducted using weighted linear regression to compare median OS versus: median PFS; and percent ORR. TKI-naïve and -experienced populations were analyzed separately. R2 was calculated along with 95% confidence intervals (CIs) using a bootstrapping method.
RESULTS: Twelve cohorts from non-randomized clinical trials involving treatment with crizotinib, entrectinib, lorlatinib, brigatinib or ceritinib were identified; repotrectinib cohorts were excluded. Nine cohorts consisting of 540 patients contributed to the analysis. Median OS ranged from 12.2 to 51.4 months. Among TKI-naïve patients, a strong correlation was observed between median OS and median PFS (6 cohorts; R2 = 0.97, 95% CI: 0.84, 1.00), but low correlation was observed versus percent ORR (5 cohorts; R2 = 0.22: 0.00, 1.00). The evidence base among TKI-experienced patients (3 cohorts) was considered insufficiently robust for formal analysis.
CONCLUSIONS: The current analysis demonstrated a strong association between OS and PFS among TKI-treated patients with ROS1+ aNSCLC, lending support to previous real world evidence evaluating surrogacy of PFS. However, OS and ORR demonstrated a weak association with substantial uncertainty. The lack of head-to-head evidence precluded assessment of the correlation between treatment effects.