Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

PURPOSE: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS: Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.

Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy.

PURPOSE: Tumor hypoxia is associated with poor prognosis and a more malignant tumor phenotype. SR-4554, a fluorinated 2-nitroimidazole, is selectively bioreduced and bound in hypoxic cells. We present validation studies of SR-4554 as a noninvasive hypoxia marker detected by fluorine-19 magnetic resonance spectroscopy ((19)F MRS) in the P22 carcinosarcoma, a tumor with clinically relevant hypoxia levels. EXPERIMENTAL DESIGN: Tumor-bearing female severe combined immunodeficient mice received SR-4554 at 180 mg/kg. Pharmacokinetic studies of parent SR-4554 in plasma and tumors were performed using high-performance liquid chromatography-UV. Total SR-4554 (parent SR-4554 and bioreduction products) was monitored in tumor by (19)F MRS using a 4.7 T spectrometer, with continuous acquisition for up to 5 h. A parameter of total SR-4554 retention, the 3-h (19)F retention index ((19)FRI) was determined. Tumor pO(2), assessed polarographically, was decreased (5 mg/kg hydralazine or 100 mg/kg combretastatin A-4 phosphate) or increased [1 l/min carbogen (5% CO(2), 95% O(2)) plus 500 mg/kg nicotinamide], and the corresponding (19)FRI was measured. RESULTS: Comparative HPLC-UV- and MRS-derived assessments of parent and total SR-4554, respectively, indicated that concentrations of total SR-4554 consistently exceeded parent SR-4554, the differential increasing with time. This indicates formation and retention of SR-4554 bioreduction products in tumor, confirming the presence of hypoxia. The (19)FRI was higher in hydralazine- and combretastatin-treated animals compared with unmodulated animals (P = 0.004 and 0.15, respectively) and animals receiving carbogen and nicotinamide (P = 0.0001 and 0.005, respectively). Significant correlations were demonstrated between mean (19)FRI and polarographic pO(2) parameters (P < 0.002). CONCLUSIONS: Retention of hypoxia-related SR-4554 bioreduction products can be detected in the clinically relevant P22 tumor by (19)F MRS, and the (19)FRI correlates with polarographically measured pO(2). These findings support the use of SR 4554 as a noninvasive hypoxia marker.