Systemic Therapy for Hepatocellular Carcinoma

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Abbreviations

AFP

alpha‐fetoprotein

AIH

autoimmune hepatitis

BCLC

Barcelona Clinic Liver Cancer

CI

confidence interval

CTP

Child‐Turcotte‐Pugh

ECOG

Eastern Cooperative Oncology Group

FDA

US Food and Drug Administration

HCC

hepatocellular carcinoma

HR

hazard ratio

ORR

objective response rate

OS

overall survival

PD‐L1

programmed cell death‐ligand 1

PFS

progression‐free survival

TACE

transarterial chemoembolization

TKI

tyrosine kinase inhibitor

The field of systemic therapy for hepatocellular carcinoma (HCC) has experienced revolutionary changes in recent years. Patients with advanced‐stage (Barcelona Clinic Liver Cancer [BCLC] stage C) or intermediate‐stage HCC (BCLC stage B) progressing on locoregional therapy should be considered for systemic therapy when curative therapy is not feasible. ¹ , ² Currently, six agents have been approved by the US Food and Drug Administration (FDA) and adopted into national and international liver society guidelines since 2016, ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ marking an end to nearly a decade of negative phase 3 trials (Table 1).

TABLE 1.

Approved Systematic Therapies for Advanced HCC

Trial/Year Published	Arms	Patients (n)	Stage of HCC	Outcomes
First Line
IMBrave150/phase III/2020	Atezolizumab + bevacizumab versus sorafenib	336 versus 165	Locally advanced or unresectable HCC, ECOG ≤ 1, CTP class A	12‐month OS: 67.2% (95% CI: 61.3‐73.1) versus 54.6% (95% CI: 45.2‐64)
			Excluded AIH, hepatitis B/C, and untreated esophageal or gastric varices
Alternate First Line
SHARP/phase III/2008	Sorafenib versus placebo	299 versus 303	Advanced HCC, ECOG ≤ 2, CTP class A	Median OS: 10.7 versus 7.9 months (HR 0.69; 95% CI: 0.55‐0.87, P < 0.001)
REFLECT/phase III/2018	Lenvatinib versus sorafenib	478 versus 476	Unresectable HCC, ECOG ≤ 1, CTP class A, no invasion of main portal vein	Median OS: 13.6 versus 12.3 months (HR 0.92, 95% CI: 0.79‐1.06)
Second Line
RESORCE/phase III/2016	Regorafenib versus placebo	379 versus 194	Advanced HCC, ECOG ≤ 1, CTP class A, radiological progression on sorafenib	Median OS: 10.6 versus 7.8 months (HR 0.63; 95% CI: 0.50‐0.79, P = 0.0001)
CELESTIAL/phase III/2018	Cabozantinib versus placebo	470 versus 237	Advanced HCC, ECOG ≤ 1, CTP class A, had disease progression after at least one systemic treatment	Median OS: 10.2 versus 8.0 months (HR 0.76; 95% CI: 0.63‐0.92, P = 0.0049)
				Median PFS: 5.2 versus 1.9 months (HR 0.44; 95% CI: 0.36‐0.52, P < 0.001)
REACH‐2/phase III/2019	Ramucirumab versus placebo	197 versus 95	BCLC stage B/C, CTP class A, ECOG ≤ 1, AFP ≥ 400 ng/mL, previously received sorafenib	Median OS: 8.5 versus 7.3 months (HR 0.710; 95% CI: 0.531‐0.949, P = 0.0199)
CheckMate 040/phase II/2017	Nivolumab	262	Advanced HCC, CTP class A/B7, ECOG ≤ 1, with or without prior exposure to sorafenib	ORR: 20%; median OS: 15.6 months
	Nivolumab + ipilimumab	49	As above	ORR 33% (95% CI: 20‐48)
CheckMate 459/phase III/2019	Nivolumab versus sorafenib	371 versus 372	Advanced HCC, CTP class A, ECOG ≤ 1, no prior systemic therapy	Primary endpoint not reached; median OS: 16.4 versus 14.7 months (HR 0.85; 95% CI: 0.72‐1.02; P = 0.075)
KEYNOTE‐224/phase II/2018	Pembrolizumab	104	Advanced HCC, CTP class A, ECOG ≤ 1, intolerant or progressed on sorafenib	ORR 17% (95% CI: 11‐26)
KEYNOTE‐240/phase III/2020	Pembrolizumab versus placebo	278 versus 135	Advanced HCC, CTP class A, ECOG ≤ 1	Primary endpoint of OS and PFS not reached

Systemic Therapy Options

First‐Line Therapy

Atezolizumab + Bevacizumab (IMbrave 150 Trial)

For more than a decade, sorafenib was the standard of care for advanced HCC until the pivotal IMbrave 150 trial, which proved that atezolizumab and bevacizumab provided significant overall survival (OS) benefit over sorafenib as first‐line therapy. ⁹ Atezolizumab is a fully humanized monoclonal antibody against programmed cell death‐ligand 1 (PD‐L1), and bevacizumab is an angiogenesis inhibitor that blocks the binding of vascular endothelial growth factor A. In this phase 3 trial, 501 treatment‐naive patients with unresectable HCC were randomized in a 2:1 fashion to receive either a combination of 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks or 400 mg sorafenib orally twice daily, respectively. The coprimary endpoints were OS and progression‐free survival (PFS) according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Atezolizumab + bevacizumab demonstrated statistically significant improvement in both OS at 12 months (67.2% [95% confidence interval (CI): 61.3‐73.1] versus 54.6% [95% CI: 45.2‐64]) and PFS (6.8 months [95% CI: 5.7‐8.3] versus 4.3 months [95% CI: 4‐5.6]) compared with sorafenib. The objective response rate (ORR) was doubled with the combination group over sorafenib. Grade 3 or 4 events occurred in 38% of the atezolizumab + bevacizumab arm, with hypertension being the most common, followed by proteinuria and fatigue. Bleeding is a known side effect of bevacizumab, and patients in this trial were required to have an upper endoscopy for evaluation and treatment of varices 6 months before enrollment. The positive results of this trial led to FDA approval of atezolizumab + bevacizumab as first‐line therapy for unresectable or metastatic HCC in 2020.

Alternate First‐Line Therapy

Sorafenib (SHARP Trial)

Sorafenib was the first approved oral tyrosine kinase inhibitor (TKI) for treatment of advanced HCC in 2007. ¹⁰ The pivotal SHARP trial confirmed a median OS of 10.7 months for sorafenib versus 7.9 months in placebo‐treated patients and has been the standard of care for more than a decade. This survival benefit was confirmed in the Asia‐Pacific trial as well. ¹¹

Lenvatinib (REFLECT Trial)

Subsequently, there have been multiple negative trials until the approval of lenvatinib, another multitargeted TKI, in 2018. In a phase 3 trial, oral lenvatinib was found to be noninferior to sorafenib (median OS, 13.6 versus 12.3 months). ³ However, lenvatinib had statistically significant improvement in PFS (7.3 versus 3.6 months) and time to progression (7.4 versus 3.7 months). Furthermore, better quality of life and improved tolerability were observed in the lenvatinib arm. The most common adverse events associated with lenvatinib were hypertension, diarrhea, and decreased weight.

Second‐Line Therapy

Regorafenib (RESORCE Trial)

Regorafenib, another TKI, was the first therapy to show survival benefit in patients progressing on sorafenib and was approved as a second‐line therapy for HCC in 2017. ⁴ Patients in the regorafenib arm had extended median OS by 10.6 months compared with 7.8 months in the placebo group. In addition, regorafenib after sorafenib failure led to a median survival of 21 months from initiation of sorafenib therapy.

Cabozantinib (CELESTIAL Trial)

In January 2019, the FDA approved cabozantinib (combination TKI and c‐MET inhibitor), for patients previously treated with sorafenib. ⁶ In the CELESTIAL trial, patients in the cabozantinib arm had a median OS of 10.2 months compared with 8.0 months in the placebo arm. The most frequently observed high‐grade adverse event in the cabozantinib group was hand‐foot‐skin reaction.

Ramucirumab (REACH‐2 Trial)

Ramucirumab is a recombinant anti–vascular endothelial growth factor receptor 2 monoclonal human antibody that showed negative results in the REACH trial of patients previously treated with sorafenib; however, survival benefit was observed in a subgroup of patients with a baseline serum alpha‐fetoprotein (AFP) level ≥ 400 ng/mL. ¹² In the REACH‐2 trial, patients with baseline AFP level ≥ 400 ng/mL receiving ramucirumab had median OS of 8.5 months compared with 7.3 months in the placebo arm. ⁵ Common adverse effects associated with ramucirumab included fatigue, peripheral edema, hypertension, and ascites.

Nivolumab (CheckMate 040 and 459 Trial) and Pembrolizumab (KEYNOTE 224 and 240 Trial)

Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that disrupts PD‐1 immune checkpoint signaling. It was the first approved immunotherapy for HCC, with an ORR of 20% and median survival of 16 months with acceptable safety profiles in patients who progressed on or were intolerant to sorafenib. It also showed promising results in treatment‐naive patients. ¹³ The results were independent of PD‐L1 expression. Unfortunately, the phase 3 study comparing nivolumab with sorafenib as first‐line therapy for advanced HCC reported negative results for primary endpoint of OS, although nivolumab had a more favorable safety profile (CheckMate 459). ⁸ Pembrolizumab, another PD‐1 antibody, showed promising results in a phase 2 trial (KEYNOTE 224), which led to accelerated approval by the FDA as a second‐line therapy. ¹⁴ However, in a subsequent phase 3 study, pembrolizumab failed to show statistically significant improvement in OS or PFS per the prespecified protocol criteria (KEYNOTE 240). ⁷

Combination Therapies

In March 2020, the FDA granted accelerated approval to the combination of nivolumab and ipilimumab as a second‐line agent for advanced HCC. The approval was based on a cohort analysis of the CheckMate 040 study showing patients who received 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab every 3 weeks for four doses, followed by single‐agent 240 mg nivolumab every 2 weeks, had an ORR of 33%, with 31% of responses lasting at least 24 months. ¹³

The combination of lenvatinib and pembrolizumab has also shown promise. In a phase 1b trial, 104 patients were enrolled with a median follow‐up of 10.6 months. ¹⁵ The median OS was 22 months, and median PFS was 8.6 months. The majority of patients experienced treatment‐emergent adverse events (grade ≥ 3, 85%; grade ≥ 4, 23%), and three patients died of treatment‐related adverse events. A phase 3 trial (LEAP‐002 trial) is currently ongoing to assess lenvatinib plus pembrolizumab compared with lenvatinib monotherapy as a first‐line treatment for patients with unresectable HCC.

Other promising phase 3 trials evaluating combination therapies, such as COSMIC‐312 (atezolizumab + cabozantinib versus sorafenib) and HIMALAYA (durvalumab + tremelimumab versus sorafenib), are currently underway.

With increasing clinical impact of systemic therapy, the appropriate timing to shift from locoregional to systemic or combination therapy remains unclear and is heavily influenced by how treatment failure is defined. The TACTICS trial ¹⁶ was able to show superior PFS in the TACE + sorafenib group compared with TACE alone by redefining progression as unTACEable as opposed to standard radiographic progression, which highlights the importance of trial design to guide clinical practice. Future studies on optimal trial design and endpoints are needed to determine the sequence of therapies to maximize survival.

Future Directions

The global disease burden of HCC is increasing, and patients who are not candidates for curative options will require systemic therapy. Ongoing trials on the benefits of combining locoregional with systemic therapy in select patients will undoubtedly expand future indications for systemic therapy. Major breakthroughs in therapy options have occurred in the past few years; however, long‐term OS remains dismal. The approval of atezolizumab + bevacizumab highlights the current trend favoring combination therapies as the next wave in systemic therapy options. It is important to note that the majority of studies included patients with preserved liver function (Child‐Turcotte‐Pugh [CTP] class A), and there are very limited data on the safety and efficacy of these therapies in patients with advanced cirrhosis. Improved understanding of molecular targets of HCC and development of predictive biomarkers will be invaluable to guide therapy and predict response to currently available treatment options.