A Pooled Analysis of Phase 2 Clinical Trials in Advanced Chordoma

AIM: 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. METHODS: 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. RESULTS: 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]). CONCLUSION: 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.