Second-line treatment of advanced hepatocellular carcinoma: Time for more individualized treatment options?

Table 2 Randomized controlled trials in hepatocellular carcinoma: Subgroup analyses[37,40,42,17,48,49]

Ramucirumab (REACH, REACH-2 or AFP ≥ 400 ng/mL pooled population)
Patient Reported Outcomes	Pooled population REACH + REACH-2	Ramucirumab or placebo	542	AFP ≥ 400 ng/mL	Ramucirumab vs placebo. TtD in FHSI-8 Total Score: 3.3 mo vs 1.9 mo, HR = 0.725; P = 0.0152
Age	Pooled population REACH + REACH-2	Ramucirumab or placebo	542	AFP ≥ 400 ng/mL	Ramucirumab vs placebo. < 65 yr: 8.18 mo vs 4.76 mo, HR = 0.716 (95%CI: 0.556-0.922). ≥ 65 to < 75 yr: 7.62 mo vs 5.22 mo, HR = 0.593 (95%CI: 0.413-0.851). ≥ 75 yr: 8.87 mo vs 6.31 mo, HR = 0.641 (95%CI: 0.390-1.054)
AFP dynamics	REACH-2	Ramucirumab or placebo	292	AFP ≥ 400 ng/mL	Ramucirumab vs placebo. Time to AFP progression: 2.4 mo vs 1.4 mo, HR = 0.422 (95%CI: 0.309-0.576) P ≤ 0.0001. Time to radiographic progression: 3.0 mo vs 1.6 mo, HR = 0.427 (95%CI: 0.313-0.582) P ≤ 0.0001. AFP response: ≥ 20% decrease anytime post-baseline from baseline (% of patients): 42 vs 11 P ≤ 0.0001. ≥ 20% increase anytime post-baseline from baseline (% of patients): 62 vs 79, P = 0.0043
Regorafenib (RESORCE)
AFP response	RESORCE	Regorafenib or placebo	232	baseline AFP ≥ 20 ng/mL and an AFP measurement at the start of cycle 3	Regorafenib vs placebo. Median OS: 13.8 mo vs 8.9 mo, HR = 0.57 (95%CI: 0.40-0.82)
Cabozantinib (CELESTIAL)
Age subgroup	CELESTIAL	Cabozantinib or placebo	707	Subgroups based on age (< 65 yr and ≥ 65 yr)	Cabozatinib vs placebo. Median OS: < 65 yr: 9.6 mo vs 7.7 mo (HR = 0.81, 95%CI: 0.62-1.05); ≥ 65 yr: 11.1 mo vs 8.3 mo (HR = 0.74, 95%CI: 0.56-0.97). Median PFS: < 65 yr: 5.0 mo vs 1.9 mo (HR = 0.45, 95%CI: 0.35-0.57); ≥ 65 yr: 5.4 mo vs 2.0 mo (HR = 0.46, 95%CI: 0.35-0.59)
AFP	CELESTIAL	Cabozantinib or placebo		Baseline AFP < 400 ng/mL	Cabozatinib vs placebo. Median OS: 13.9 mo vs 10.3 mo (HR = 0.81, 95%CI: 0.62-1.04). Median PFS: 5.5 mo vs 1.9 mo (HR = 0.47, 95%CI: 0.37-0.60)
				Baseline AFP ≥ 400 ng/mL	Cabozatinib vs placebo. Median OS: 8.5 mo vs 5.2 mo (HR = 0.71, 95%CI: 0.54-0.94). Median PFS: 3.9 mo vs 1.9 mo (HR = 0.42, 95%CI: 0.32-0.55)

AFP: Alpha-fetoprotein; CI: Confidence interval; FHSI: Functional Hepatobiliary Symptom Index; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival.