A pooled analysis of phase 2 clinical trials in advanced chordoma

Chordoma is an ultra-rare malignancy with no approved therapies. In this study, we analyzed individual patient-level data (IPD) for patients with chordoma reconstructed from previously completed clinical trials. Our primary objectives were to synthesize the historical objective response rate (ORR) and to generate a pooled Kaplan-Meier progression-free survival (PFS) curve. Our overarching goal is that these data will inform future trial design and interpretation of results.

A literature review was conducted to identify prospective chordoma systemic therapy clinical trials. Eligible studies were required to be prospective; to include locally advanced/metastatic conventional chordoma; to report a PFS Kaplan-Meier curve; and to assess PFS/ORR by RECIST (1.0/1.1). IPD were reconstructed from the PFS curves and data were synthesized to estimate the pooled PFS and ORR.

Twelve studies met eligibility, contributing 328 patients (320 response evaluable). The combined ORR was 4.7% and median PFS was 10.8 months (95% CI 9, 12). Sensitivity analyses revealed no significant differences in PFS between studies partitioned by study-level variables. In "leave-one-out" analyses of each study alone versus pooled data, only everolimus/imatinib showed a significantly longer PFS (p = 0.0014), with a median PFS of 14.0 months (95% CI 11.5, NA) compared to 10.0 months (95% CI 8.3,11.2) for the remaining pooled cohort (estimated hazard ratio: 0.50 [95% CI 0.33, 0.77]).

IPD from 12 trials were reconstructed and analyzed, consolidating outcomes for 328 trial-eligible patients with chordoma. The estimated overall response rate (ORR) is 4.7% and median PFS 10.8 months, providing a historical benchmark useful for future trial design. Notably, everolimus/imatinib was the only study treatment associated with a statistically significant improvement in PFS, which may warrant further investigation.