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

Table 1 Summary of survival data from phase III randomized controlled trials of second- or later-line treatments in patients with advanced hepatocellular carcinoma

Ref.	Study design	Treatment arms	n	Patient population	Key findings
Zhu et al[20], REACH	Randomized, placebo-controlled, double-blind, multicenter, phase III trial	Ramucirumab or placebo	565	Patients with advanced HCC with previous progression or intolerance to sorafenib	Ramucirumab vs placebo. Median OS: 9.2 mo (95%CI: 8.0-10.6) vs 7.6 mo (95%CI: 6.0-9.3), HR = 0.87 (95%CI: 0.72-1.05) P = 0.14. Median PFS: 2.8 mo (95%CI: 2.7-3.9) vs 2.1 mo (95%CI: 1.6-2.7), HR = 0.63 (95%CI: 0.52-0.75) P < 0.0001
Zhu et al[44], REACH-2	Randomized, placebo-controlled, double-blind, multicenter, phase III trial	Ramucirumab or placebo	292	Patients with advanced HCC with previous progression or intolerance to sorafenib, AFP ≥ 400 ng/mL	Ramucirumab vs placebo. Median OS (7.6 mo follow-up): 8.5 mo (95%CI: 7.0-10.6) vs 7.3 mo (95%CI: 5.4-9.1), HR = 0.710 (95%CI: 0.531-0.949) P = 0.0199. Median PFS: 2.8 mo (95%CI: 2.8-4.1) vs 1.6 mo (95%CI: 1.5-2.7), HR = 0.452 (95%CI: 0.339-0.603) P < 0.0001
Bruix et al[33], RESORCE	Randomized, double-blind, parallel-group, phase III trial	BSC + regorafenib or placebo	573	Patients with advanced HCC with previous progression or intolerance to sorafenib	BSC + regorafenib vs placebo. Median OS: 10.6 mo (95%CI: 9.1-12.1) vs 7.8 mo (95%CI: 6.3-8.8), HR = 0.63 (95%CI: 0.50-0.79) one-sided P < 0.0001. Median PFS (RESIST 1.1): 3.4 mo (95%CI: 2.9-4.2) vs 1.5 mo (95%CI: 1.4-1.5), HR = 0.43 (95%CI: 0.35-0.52) P < 0.0001
Abou-Alfa et al[39], CELESTIAL	Randomized, double-blind, placebo-controlled, phase III trial	Cabozantinib or placebo	773	Patients with advanced HCC with previous progression or intolerance to sorafenib	Cabozantinib vs placebo. Median OS: 10.2 mo (95%CI: 9.1-12.0) vs 8.0 mo (95%CI: 6.8-9.4), HR = 0.76 (95%CI: 0.63-0.92) P = 0.005. Median PFS: 5.2 mo (95%CI: 4.0-5.5) vs 1.9 mo (95%CI: 1.9-1.9), HR = 0.44 (95%CI: 0.36-0.52) P < 0.001

AFP: Alpha-fetoprotein; BSC: Best supportive care; CI: Confidence interval; HCC: Hepatocellular carcinoma; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival.

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.