Systemic Drugs for Hepatocellular Carcinoma: What Do Recent Clinical Trials Reveal About Sequencing and the Emerging Complexities of Clinical Decisions?

Figures & data

Table 1 Results of Published Phase 3 Trials of Approved Systemic Therapy for Advanced Hepatocellular Carcinoma

	Median OS [Months]	Median PFS [Months]	ORR [%]	Adverse Events
				AE Grade 3–4 [%]	TRAE [%]	Most Common AEs
Approval for first-line treatment
SHARP, phase 3 NEJM 2008 sorafenib vs placebo	10.7 vs 7.9 (HR 0.69)	5.5 vs 2.8 (HR0.58) Median TTP	2.3 vs 0.7		80 vs 52	Diarrhea Hand-foot syndrome Fatigue
REFLECT, phase 3 Lancet 2018 lenvatinib vs sorafenib	13.6 vs 12.3 (HR 0.92)	7.4 vs 3.7 (HR 0.66)	24.1 vs 9.2	75 vs 67	94 vs 95	Arterial hypertension Weight loss Bilirubin increase
IMbrave 150, phase 3 NEJM 2020 atezolizumab/bevacizumab vs sorafenib	19.2^a vs 13.2 (HR 0.58)	6.8 vs 4.3 (HR 0.59)	27.3 vs 11.9	57 vs 55		Arterial hypertension GOT elevation Proteinuria
HIMALAYA, phase 3 NEJM 2022 STRIDE vs sorafenib	16.4 vs 13.8 (HR 0.78)	3.8 vs 4.1 (HR 0.90)	20.1 vs 5.1		97 vs 96	Diarrhea Pruritus Immune-mediated AEs
HIMALAYA, phase 3 NEJM 2022 durvalumab vs sorafenib	16.6 vs 13.8 (HR 0.86)	3.7 vs 4.1 (HR 1.02)	17.0 vs 5.1		89 vs 96	Diarrhea Pruritus GOT elevation
Approval for second-line treatment
RESORCE 28, phase 3 Lancet 2017 regorafenib vs placebo	10.6 vs 7.8 (HR 0.63)	3.1 vs 1.5 (HR 0.46)	10.6 vs 4.1		93 vs 52	Arterial hypertension Hand-foot syndrome Fatigue
CELESTIAL, phase 3 NEJM 2018 cabozantinib vs placebo	10.2 vs 8.0 (HR 0.76)	5.2 vs 1.9 (HR 0.44)	3.8 vs 0.4	68 vs 36		Hand-foot syndrome Arterial hypertension GOT elevation
REACH 2, phase 3 Lancet 2019 ramucirumab vs placebo	8.5 vs 7.3 (HR 0.71)	2.8 vs 1.6 (HR 0.45)	4.6 vs 1.1	35 vs 29		Arterial hypertension Liver dysfunction Proteinuria
KEYNOTE-240, phase 3 Journal of Clinical Oncology 2020 pembrolizumab vs placebo^b	13.9 vs 10.6 (HR 0.78)	3.0 vs 2.8 (HR 0.72)	18.3 vs 4.4	52 vs 46		GOT elevation Bilirubin increase Fatigue

Notes: ^aAt the time of the data analysis published in NEJM in 2020, median overall survival in the atezolizumab/bevacizumab arm had not been reached. This updated overall survival was reported later (Finn RS, Qin S, Ikeda M, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). Journal of Clinical Oncology. 2021;39(3_suppl):267. doi:10.1200/JCO.2021.39.3_suppl.267). ^bNivolumab an pembrolizumab were granted accelerated approval by the FDA for second-line therapy of HCC, pretreated with sorafenib, based on phase II trials CheckMate-040 and KEYNOTE-224, respectively.

Abbreviations: OS, Overall Survival; PFS, Progression-Free Survival; ORR, Objective Response Rate; AE, Adverse Events; TRAE, Treatment Related Adverse Events; vs, versus; HR, Hazard Ratio; TTP, time to progression; GOT, Glutamate Oxaloacetate Transaminase; AST, Aspartate Aminotransferase.

Figure 1 Algorithm for systemic therapy of hepatocellular carcinoma.

Abbreviations: ICI, immune checkpoint inhibitor; Ipi + Nivo, ipilimumab plus nivolumab; AFP, Alpha fetoprotein; FDA, Food and Drug Administration.