Updates in the Management of Hepatocellular Carcinoma

Jeff Engle, PharmD MS
Hematology/Oncology Clinical Pharmacist
University of Minnesota Masonic Cancer Clinic
Fairview Specialty Pharmacy
Minneapolis, MN

Kirollos S. Hanna, PharmD BCOP BCPS
Assistant Professor of Pharmacy
Mayo Clinic College of Medicine
Rochester, MN
Hematology/Oncology Clinical Pharmacist
University of Minnesota Medical Center
Minneapolis, MN

Overview of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is associated with a high mortality rate and limited treatment options. The American Cancer Society estimates that in 2019, more than 42,000 individuals will be diagnosed with HCC, and nearly 32,000 individuals will succumb to the disease.¹ Despite an overall decline in cancer-related deaths in the United States, mortality rates due to liver cancer have increased and rank as the fifth leading cause of cancer-related death.² Chronic hepatitis B and C infections and alcohol consumption are the leading risk factors for the development of HCC in the United States.^3,4 Screening is recommended for individuals at high risk of developing HCC, and patients with early-stage disease may undergo surgical resection, ablation, transarterial chemoembolization, radiation therapy, or liver transplantation.^5,6 Patients diagnosed with late-stage or metastatic disease have limited treatment options. Prior to 2018, sorafenib was the only U.S. Food and Drug Administration (FDA)-approved targeted therapy for the initial treatment of unresectable HCC; nivolumab and regorafenib were approved in 2017 as second-line options following treatment with sorafenib.^7-9 The unmet need to improve outcomes for patients with advanced and metastatic HCC is clear. For this reason it is important to review recent FDA approvals and ongoing clinical trials of unique combination therapies for HCC.

Cabozantinib (Cabometyx)
On January 14, 2019, the FDA approved cabozantinib (Cabometyx) as second-line therapy for advanced HCC following initial sorafenib therapy.10 Cabozantinib is a multitargeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptors 1-3, FLT-3, KIT, MET, RET, and others. The approval followed the results of the randomized double-blind placebo-controlled phase 3 CELESTIAL trial.¹¹ Eligible patients were required to have had prior treatment with sorafenib, progressive disease after one or two prior therapies, Child-Pugh Class A liver function, Eastern Cooperative Oncology Group performance score (ECOG PS) of 1 or less, and adequate hematologic and renal function measures. Patients were randomized (2:1) to receive either cabozantinib 60 mg once daily or matching placebo until the disease progressed or an intolerable level of adverse effects was reached. The primary endpoint of the study was overall survival (OS); secondary endpoints were progression-free survival (PFS) and objective response rate (ORR).

Cabozantinib was given to 467 patients, and 237 patients received placebo; baseline demographic and clinical characteristics between the groups were balanced.¹¹ Among patients treated with cabozantinib, the median OS was 10.2 months, and the median OS with placebo was 8 months (hazard ratio [HR] 0.76; p = .005). The median PFS was significantly longer with cabozantinib (5.2 months; 95% confidence interval [CI]: 4–5.5) compared to placebo (1.9 months) with an HR for disease progression or death of 0.44 (95% CI: 0.36–0.52; p < .001). The ORR was also significantly higher with cabozantinib (4% vs. <1%; p = .009). The most common side effects (20% or more) in the cabozantinib arm were diarrhea (54%), decreased appetite (48%), palmar-plantar erythrodysesthesia (46%), fatigue (45%), nausea (31%), hypertension (29%), vomiting (26%), asthenia (22%), and elevated values in liver function tests (17%–22%). Grade 3–4 adverse effects occurred in 68% of cabozantinib-treated patients, with 62% of patients requiring dose reductions because of adverse effects.^10,11

The FDA-recommended starting dose of cabozantinib for HCC is 60 mg once daily taken on an empty stomach (1 hour before or 2 hours after a meal).¹⁰

Lenvatinib (Lenvima)
On August 16, 2018, the FDA approved lenvatinib (Lenvima), a multitargeted tyrosine kinase inhibitor of VEGF, as first-line treatment of patients with HCC.¹² Approval was based on the international multicenter randomized open-label phase 3 noninferiority REFLECT trial conducted with 954 patients who had previously untreated metastatic or unresectable HCC.¹³ Adult patients with Child-Pugh Class A and Barcelona Clinic Liver Cancer Stage C or B HCC who were ineligible for local liver-directed therapy, had an ECOG PS of 1 or lower, had received no prior systemic therapy for HCC, and had at least one measurable target lesion according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessment of HCC were randomized (1:1) to receive lenvatinib (12 mg for baseline body weight of 60 kg or greater or 8 mg for baseline body weight less than 60 kg) orally once daily or sorafenib 400 mg orally twice daily until radiological disease progression or unacceptable toxicity levels.

Lenvatinib was noninferior but not statistically superior to sorafenib for OS (HR 0.92; 95% CI: 0.79–1.06).¹³ Median OS was 13.6 months in the lenvatinib arm and 12.3 months in the sorafenib arm. Lenvatinib resulted in a statistically significant improvement in PFS of 7.3 months versus 3.6 months in the sorafenib arm (HR 0.64; 95% CI: 0.55–0.75; p < .001) per mRECIST and RECIST v1.1 for HCC. The ORR was higher for the lenvatinib arm compared to the sorafenib arm (41% vs. 12% per mRECIST and 19% vs. 7% per RECIST v1.1). The most common grade 1–4 adverse reactions observed in the lenvatinib arm (20% or more) were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia or myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%), compared with palmar-plantar erythrodysesthesia (52%), diarrhea (46%), fatigue (36%), hypertension (31%), abdominal pain (28%), decreased appetite (27%), rash (24%), decreased weight (22%), and arthralgia or myalgia (20%) for sorafenib^.12

The recommended lenvatinib dose for patients with HCC is based on actual body weight and is 12 mg orally once daily in patients 60 kg or greater or 8 mg orally once daily in patients less than 60 kg.¹²

Pembrolizumab (Keytruda)
On November 9, 2018, the FDA granted accelerated approval to pembrolizumab (Keytruda) for patients with HCC following disease progression on or after sorafenib therapy.¹⁴ The KEYNOTE-224 trial, a single-arm phase 2 multicenter trial, enrolled 104 patients with HCC who were required to have disease progression on or after sorafenib or to be intolerant to sorafenib, have measurable disease, an ECOG PS of 1 or lower, and Child-Pugh Class A liver impairment. Participants received 200 mg pembrolizumab intravenously (IV) every 3 weeks for 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision.¹⁵

Pembrolizumab resulted in a confirmed independent central review–assessed ORR of 17% (95% CI: 11–26), with one complete response (CR) and 17 partial responses (PRs).¹⁵ Response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of 6 months or longer, and 56% had response durations of 12 months or longer. Forty-six patients (44%) had stable disease, 34 patients (33%) had progressive disease, and 6 patients (6%) did not have a postbaseline assessment on the cutoff date and were considered not to be assessable. Adverse reactions occurring in patients with HCC were similar to those described previously with pembrolizumab; however, there were increased incidences of grade 3 or 4 ascites (8%), immune-mediated hepatitis (2.9%), elevated aspartate aminotransferase (AST) (20%), alanine aminotransferase (ALT) (9%), and hyperbilirubinemia (10%).^14,15

In contrast to these findings, the results of the confirmatory trial, KeynotE-240, showed that the combination of pembrolizumab plus best supportive care for the treatment of patients with advanced HCC who had been previously treated with systemic therapy did not improve PFS or OS compared to the combination placebo plus best supportive care alone, missing the coprimary endpoints. In a press release on February 19, 2019, Merck stated that “the drug’s continued approval for this indication may be contingent upon the results of confirmatory trials.”¹⁶

The HCC dosing for pembrolizumab is 200 mg IV every 3 weeks administered over 30 minutes.¹⁴

The future of HCC management is extremely bright, and several therapeutic targets are in trial phases. COSMIC-312 (NCT03755791) is an ongoing phase 3 trial evaluating the safety and efficacy of cabozantinib in combination with atezolizumab versus sorafenib in adults with advanced HCC who have not received previous systemic anticancer therapy.²⁰ Other phase 3 trials are evaluating checkpoint inhibition such as BGB-A317 versus sorafenib as front-line treatment in unresectable HCC (NCT03412773) and SHR-1210 in combination with FOLFOX4 (5-fluorouracil, oxaliplatin, leucovorin) versus sorafenib or FOLFOX4 as first-line treatment in advanced HCC (NCT03605706).^21,22

Conclusion
HCC is associated with poor outcomes and limited treatment options. Recent FDA approvals of lenvatinib in the first-line treatment setting and cabozantinib and pembrolizumab following treatment with sorafenib provide more treatment options for patients with advanced HCC. Ongoing clinical trials of unique agents and combinations aim to shed light on improving outcomes in HCC.

References

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