Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein ≥ 400 ng/mL: A Matching-Adjusted Indirect Comparison

Jörg Trojan, Patrick Mollon, Bruno Daniele, Florence Marteau, Lidia Martín, Yuxin Li, Qing Xu, Fabio Piscaglia, Renata Zaucha, Debashis Sarker, Ho Yeong Lim, Marino Venerito, Jörg Trojan, Patrick Mollon, Bruno Daniele, Florence Marteau, Lidia Martín, Yuxin Li, Qing Xu, Fabio Piscaglia, Renata Zaucha, Debashis Sarker, Ho Yeong Lim, Marino Venerito

Abstract

Introduction: Cabozantinib and ramucirumab are approved for the treatment of adults with hepatocellular carcinoma (HCC) following prior sorafenib treatment; ramucirumab is restricted to use in patients with serum alpha-fetoprotein (AFP) ≥ 400 ng/mL. This matching-adjusted indirect comparison evaluated the efficacy and safety of both drugs after sorafenib in patients with HCC and AFP ≥ 400 ng/mL.

Methods: Individual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.

Results: After matching and weighting, baseline characteristics were balanced between populations (REACH-2, N = 292; CELESTIAL, effective sample size = 105). Weighted KM estimates for OS (median [95% CI]) were not significantly different between cabozantinib and ramucirumab (10.6 [9.5-17.3] months versus 8.7 [7.3-10.8] months; p = 0.104), but PFS was significantly longer for cabozantinib than for ramucirumab (5.5 [4.6-7.4] months versus 2.8 [2.7-4.1] months; p = 0.016). Parametric modeling results were consistent with the weighted KM analysis. Rates of some grade 3 or 4 TRAEs were lower with ramucirumab than with cabozantinib; however, TRAE-related discontinuation rates were similar (p = 0.271).

Conclusion: In this MAIC, cabozantinib significantly prolonged median PFS compared with ramucirumab after prior sorafenib treatment in patients with HCC and AFP ≥ 400 ng/mL; rates of some grade 3 or 4 TRAEs were lower with ramucirumab than cabozantinib but related discontinuation rates were not significantly different between treatments.

Trial registration: Clinical trials.gov identifiers: CELESTIAL trial (NCT01908426) and REACH-2 trial (NCT02435433). These slides can be retrieved under Electronic Supplementary Material.

Keywords: Alpha-fetoprotein (AFP); Cabozantinib; Hepatocellular carcinoma (HCC); Indirect treatment comparison (ITC); Matching-adjusted indirect comparison (MAIC); Monoclonal antibody (mAb); Ramucirumab; Tyrosine kinase inhibitor (TKI); Vascular endothelial growth factor (VEGF); second-line treatment / 2L treatment.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves for a OS and b PFS of the matching-adjusted CELESTIAL population and the REACH-2 populations. a OS, b PFS. 2L second line, CI confidence interval, OS overall survival, PFS progression-free survival

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