A Detailed Review of a Second-Line Treatment Option for Hepatocellular Carcinoma

Including a Retrospective Exploratory Subgroup Analysis of HCC Patients with Child-Pugh B Cirrhosis
Written by Saurin Chokshi, MD
Sponsored by Exelixis, Inc.

The treatment of hepatocellular carcinoma (HCC) has seen much progress. The advent of immunotherapy and targeted therapies has helped to improve survival for these patients.¹ However, concurrent cirrhosis remains a complicating factor. Cirrhosis is often a competing cause of death and can be a significant hindrance to receiving therapy for HCC beyond the first line. Moreover, there is a paucity of data from large clinical trials involving patients with Child-Pugh B cirrhosis.^2,3 However, what I find compelling for the second-line treatment of patients with HCC are the CELESTIAL data for cabozantinib, indicated for patients who have been previously treated with sorafenib. Cabozantinib demonstrated superior efficacy and proven safety data as a second-line therapy in a clinically relevant and representative patient population.⁴ The trial included patients with tumor characteristics classically associated with worsening disease.^5,6 It also included a small subgroup of patients whose cirrhosis progressed from Child-Pugh A to Child-Pugh B.² Additionally, cabozantinib is the only TKI in HCC that has Phase 3 trial data on patients previously treated with VEGF and immune checkpoint inhibitor (ICI) therapies.^5,7 The National Comprehensive Cancer Network^® (NCCN^®) has given cabozantinib an NCCN Category 1 recommendation as a subsequent-line systemic therapy for advanced HCC.⁸

CELESTIAL trial design
The CELESTIAL trial was a randomized (2:1), double-blind, Phase 3 trial vs placebo in 707 HCC patients (Child-Pugh Class A). All patients received prior sorafenib, and 27% of patients received more than one prior systemic regimen.^4,7 The primary efficacy outcome measure was OS. Additional outcome measures were PFS and ORR, as assessed by investigators per RECIST v1.1.⁴

• CELESTIAL did not exclude patients with certain types of characteristics seen in advanced HCC^5,6
  • Bile duct invasion
  • Main portal vein invasion
  • >50% liver involvement
  • Prior immunotherapy
• Within the first 8 weeks of treatment, 11% of patients in the trial (73/707) progressed from Child-Pugh A to Child-Pugh B and remained in the trial until disease progression or unacceptable toxicity^2,4
• Cabozantinib is the only TKI in HCC that has Phase 3 trial data on patients who were previously treated with VEGF inhibitors (707/707) and immune checkpoint inhibitors (17/707)^5,7

Superior OS and PFS results in the treatment of second-line HCC
• Primary endpoint: Median OS was 10.2 months with cabozantinib (n=470) vs 8.0 months with placebo (n=237) in the ITT population of patients who received at least one prior therapy, including sorafenib (HR=0.76; 95% CI: 0.63-0.92, P=0.0049)⁴
• Secondary endpoint: Median PFS was 5.2 months with cabozantinib (n=470) vs 1.9 months for placebo (n=237) in the ITT population who received at least one prior therapy, including sorafenib (HR=0.44; 95% CI: 0.36-0.52; P<0.0001)⁴

In a prespecified exploratory subgroup analysis of patients who received only one prior systemic therapy⁸
• Median OS was 11.4 months with cabozantinib (n=335) vs 7.7 months for placebo (n=174; HR=0.74, 95% CI: 0.59-0.92)⁶
• Median PFS was 5.5 months with cabozantinib (n=335) vs 1.9 months for placebo (n=174; HR=0.43, 95% CI: 0.35-0.52)⁶

*No statistical procedure was employed for controlling type 1 error. Results should be considered hypothesis generating.⁷

CELESTIAL: safety results
ARs occurring at a higher incidence in patients treated with cabozantinib (between-arm difference of ≥ 5% [All Grades*] or ≥2 [Grades 3-4]) vs placebo: diarrhea (54% vs 19%), nausea (31% vs 18%), vomiting (26% vs 12%), stomatitis (13% vs 2%), dyspepsia (10% vs 3%), fatigue (45% vs 30%), asthenia (22% vs 8%), mucosal inflammation (14% vs 2%), decreased appetite (48% vs 18%), PPE (46% vs 5%), rash (21% vs 9%),† hypertension (30% vs 6%),‡ weight decreased (17% vs 6%), dysgeusia (12% vs 2%), hyperthyroidism (8% vs <1%), dysphonia (19% vs 2%), dyspnea (12% vs 10%), pain in extremity (9% vs 4%), muscle spasms (8% vs 2%).⁴

*NCI-CTCAE v4.0.⁴
†Includes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected.⁴
‡Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased.⁴

CELESTIAL: Retrospective exploratory subgroup analysis in patients whose liver cirrhosis progressed from Child-Pugh A to Child-Pugh B by week 8²
• Median OS was 8.5 months with cabozantinib (n=51) compared with 3.8 months for placebo (n=22; HR=0.32, 95% CI: 0.18-0.58)^2,4
• Median PFS was 3.7 months for cabozantinib (n=51) compared with 1.9 months with placebo (n=22, 95% CI: 0.25-.076)^2,4

*The observed outcomes of cabozantinib treatment in patients with reduced liver function should be interpreted with caution because of the retrospective nature of the analyses and relatively small size of the Child-Pugh B subgroup.² No statistical procedure was employed for controlling type I error. Results should be considered hypothesis generating.⁶
†At the time of the first Child-Pugh assessment at Week 8 after randomization by the investigator, 51/470 patients in the CABOMETYX arm and 22/237 patients in the placebo arm had Child-Pugh B cirrhosis (ie, Child-Pugh B subgroup).²

The most frequent ARs leading to permanent discontinuation were (1%): decreased appetite, diarrhea, and nausea; (2%): PPE and fatigue.⁶ ARs occurring in >30% of patients who received cabozantinib included fatigue, ascites, decreased appetite, diarrhea, nausea, and hypoalbuminemia.²

CABOMETYX dosing
The recommended dose of cabozantinib is 60 mg once daily until disease progression or unacceptable toxicity.⁴ It is recommended to reduce the starting dose of cabozantinib to 40 mg once daily in patients with moderate hepatic impairment (Child-Pugh B) and to avoid the drug in those individuals with severe hepatic impairment (Child-Pugh C).⁴

The overall efficacy results of the CELESTIAL trial were achieved in the context of dose modifications.⁴ The median average daily dose was 35.8 mg for those receiving cabozantinib in the overall population and 36.9 mg for patients receiving cabozantinib in the Child-Pugh B subgroup.^2,4 For patients receiving cabozantinib, the rates of dose reduction and discontinuation were 62% and 16% for the overall population and 61% and 18% for the Child-Pugh B subgroup, respectively.² The rates of dose reduction and discontinuation in the placebo group were 13% and 3% for the overall population and 14% and 5% for the Child-Pugh B subgroup, respectively.^2,6,7

Guideline recommendations
NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) recommend cabozantinib as a Category 1 subsequent-line treatment option for HCC⁸*

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
NCCN Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
*For certain patients, following disease progression on or after systemic treatment.

In summary, the CELESTIAL data indicate that:

• Cabozantinib is the only TKI in HCC that has Phase 3 trial data on patients who were previously treated with VEGF inhibitors (707/707) and immune checkpoint inhibitors (17/707)^5,7
• Cabozantinib improved OS and PFS outcomes vs placebo in the treatment of second-line HCC^4*
  *Vs placebo in post-sorafenib-treated patients who had progressed on at least one prior systemic therapy.⁴

• Patients who progressed from Child-Pugh A to Child-Pugh B within the first 8 weeks of treatment remained in the trial until disease progression or unacceptable toxicity (73/707).^2,4
  • In this small, retrospective, exploratory subgroup analysis, patients treated with cabozantinib showed a median OS of 8.5 months vs 3.8 months with placebo and median PFS of 3.7 months vs 1.9 months. No new safety signals were identified.^2,4*

  *Results should be hypothesis generating.^2,6

• NCCN Guidelines^® recommend cabozantinib as a Category 1 subsequent-line treatment option for HCC^8*

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
NCCN Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
*For certain patients, following disease progression on or after systemic treatment.

In conclusion, I am confident in cabozantinib as a second-line therapy for post-sorafenib-treated patients as it is supported by a balance of data that demonstrated superior efficacy and tolerability vs placebo in a clinically representative patient population and carries an NCCN Category 1 recommendation in the subsequent-line setting.^2,4,6,8

Please take time to review the additional safety information, including warnings and precautions, in the following section.

Please see accompanying full Prescribing Information for Important Safety Information.

INDICATION

CABOMETYX^® (cabozantinib) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, occurred in CABOMETYX patients. Monitor for signs and symptoms and discontinue in patients with Grade 4 fistulas or GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension including hypertensive crisis. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea may be severe. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to fetus. Verify pregnancy status and advise use of effective contraception during treatment and for 4 months after last dose.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800 FDA-1088.

Dr. Chokshi received a fee for participating in the development of this article, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

AR=adverse reaction; CI=confidence interval; CTCAE=Common Terminology Criteria for Adverse Events; HR=hazard ratio; ITT=intent to treat; NCI=National Cancer Institute; ORR=objective response rate; OS=overall survival; PFS=progression‐free survival; PPE=palmar-plantar erythrodysesthesia; RECIST=Response Evaluation Criteria in Solid Tumors; VEGF=vascular endothelial growth factor.

References
1. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525-543.
2. El-Khoueiry AB, Meyer T, Cheng A-L, et al. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child-Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomized controlled trial. BMC Cancer. 2022;22(1):377.
3. Costa F, Wiedenmann B, Roderburg C, Mohr R, Abou-Alfa GK. Systemic treatment in patients with Child-Pugh B liver dysfunction and advanced hepatocellular carcinoma. Cancer Med. 2023;12(13):13978-13990.
4. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
5. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma [supplementary appendix]. N Engl J Med. 2018;379(1):54-63.
6. Data on file. Exelixis, Inc.
7. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63.
8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatocellular Carcinoma V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed April 10, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.

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