At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment
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This document serves as a practice aid summarizing recent clinical trials and key findings in the management of hepatocellular carcinoma (HCC). It reviews the effectiveness and safety of various systemic therapies, including lenvatinib, regorafenib, nivolumab, and cabozantinib, alongside their adverse event profiles. Additionally, it highlights recommended locoregional therapies for intermediate-stage HCC and provides information about current clinical trials for further reference.
![Access the activity,“At the Intersection of Local and Systemic Therapy in the
Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in
Multimodal Treatment,”at www.peerview.com/ZCA40.
Recent Key Clinical Trials
in the Treatment of
Hepatocellular Carcinoma
PRACTICE AID
a
P ≤ .021 for second interim analysis.
AEs: adverse events; AST: aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; CR: complete response; DCR: disease control rate; DOR: duration of response;
ECOG PS: Eastern Cooperative Oncology Group performance status; HCC: hepatocellular carcinoma; HFSR: hand-foot skin reaction; HR: hazard ratio; ITT: intention to treat; mRECIST: modified
Response Evaluation Criteria in Solid Tumors; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetic; QOL: quality of life; RR: response rate;
TTP: time to progression; TTR: time to recurrence.
1. Kudo M et al. Lancet. 2017 Feb 9 [Epub ahead of print].
2. Bruix J et al. Lancet. 2017;389:56-66.
3. El-Khoueiry AB et al. Lancet. 2017;389:2492-2502.
4. Abou-Alfa G et al. 2018 Gastrointestinal Cancers Symposium (ASCO GI 2018). Abstract 207.
CELESTIAL4
Efficacy
Cabozantinib Placebo
OS, months 10.2 8.0
HR (95% CI)a
0.76 (0.63-0.92); P = .0049
PFS, months 5.2 1.9
HR (95% CI) 0.44 (0.36-0.52); P .0001
Patients
o Advanced HCC
o Child-Pugh A
o ECOG PS 0-1
o Prior sorafenib
o Progression on at least 1
prior therapy
o ≤2 prior therapies
Safety
Grade 3 or 4 AEs (cabozantinib vs placebo)
o HFSR (17% vs 0%)
o Hypertension (16% vs 2%)
o Increased AST (12% vs 7%)
o Fatigue (10% vs 4%)
o Diarrhea (10% vs 2%)
Endpoints
Primary
o OS
Secondary
o PFS
o ORR
Cabozantinib
n = 470
Placebo
n = 237](https://image.slidesharecdn.com/pvipracticeaidszca-180507204115/85/At-the-Intersection-of-Local-and-Systemic-Therapy-in-the-Management-of-Hepatocellular-Carcinoma-Preparing-for-the-Next-Evolution-in-Multimodal-Treatment-4-320.jpg)
![Access the activity,“At the Intersection of Local and Systemic Therapy in the
Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in
Multimodal Treatment,”at www.peerview.com/ZCA40.
Understanding Locoregional
Therapy for Intermediate
Hepatocellular Carcinoma
PRACTICE AID
HCC: hepatocellular carcinoma; cTACE: conventional transarterial chemoembolization; DEB-TACE: drug-eluting bead transarterial chemoembolization; ECOG: Eastern Cooperative Oncology
Group; mRECIST: modified Response Evaluation Criteria in Solid Tumors; TACE: transarterial chemoembolization; TARE: transarterial radioembolization; Y90: yttrium 90.
1. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed February 21, 2018.
2. Lencioni R et al. Hepatology. 2016;64:106-116.
3. Lencioni R et al. Cardiovasc Intervent Radiol. 2012;35:980-985.
4. Salem R et al. Hepatology. 2018 Dec 1 [Epub ahead of print].
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Locoregional treatment is the guideline recommended therapy of choice for patients
with intermediate-stage disease1
cTACE DEB-TACE Y90 microspheres
Patient selection
• Standard of care for intermediate HCC
• Child-Pugh B7 or better
• ECOG ≤1
Main contraindications
• Portal vein thrombosis
• Bilirubin 3 mg/dL
• Extensive tumor burden in both lobes
• Tumor size ≥10 cm
Main side effects
• Elevated liver enzymes, nausea,
vomiting, and abdominal pain
Patient selection
• May be used in selected patients
with segmental/branch portal vein
thrombosis
• Child-Pugh B7 or better
• ECOG ≤2
Main contraindications
• Hepatopulmonary shunting
• Bilirubin 3 mg/dL
Main side effects
• Abdominal pain, nausea, vomiting
TACE2,3
TARE4
TRANSITIONING TO SYSTEMIC THERAPY
• If tumor responds by mRECIST, then additional TACE may be given
• If no response after 2-3 TACE to the same tumor region, consider systemic therapy
• Distinguish between failure of treated tumor to respond and recurrence with new tumor](https://image.slidesharecdn.com/pvipracticeaidszca-180507204115/85/At-the-Intersection-of-Local-and-Systemic-Therapy-in-the-Management-of-Hepatocellular-Carcinoma-Preparing-for-the-Next-Evolution-in-Multimodal-Treatment-7-320.jpg)
At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment
- 1. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Recent Key Clinical Trials in the Treatment of Hepatocellular Carcinoma PRACTICE AID This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients. REFLECT1 Efficacy Lenvatinib Sorafenib OS, months 13.6 12.3 HR (95% CI) 0.92 (0.79-1.06) PFS, months 7.4 3.7 HR (95% CI) 0.66 (0.57-0.77); P < .00001 ORR, % 24.1 9.2 Odds ratio (95% CI) 3.13 (2.15-4.56); P < .00001 Patients o Unresectable HCC o No prior systemic therapy for unresectable HCC o BCLC stage B or C o Child-Pugh A o ECOG PS ≤1 o ≥1 measurable target lesion per mRECIST o Adequate organ function Safety Most frequent AEs with lenvatinib (≥20% of patients) o Hypertension o Diarrhea o Decreased appetite o Decreased weight o Fatigue Serious grades 3-4 AEs o Hypertension (23% lenvatinib vs 14% sorafenib) o HFSR (3% lenvatinib vs 11% sorafenib) o HFSR o Proteinuria o Dysphoria o Nausea Endpoints Primary o OS: noninferiority Secondary o PFS o TTP o ORR o QOL o PK Lenvatinib n = 478 Sorafenib n = 476
- 2. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Recent Key Clinical Trials in the Treatment of Hepatocellular Carcinoma PRACTICE AID RESORCE2 Efficacy Regorafenib Placebo OS, months 10.6 7.8 HR (95% CI) 0.63 (0.50-0.79); P .0001 PFS, months 3.1 1.5 HR (95% CI) 0.46 (0.37-0.51); P .0001 Patients o Advanced HCC o Documented radiologic progression during sorafenib treatment o BCLC stage B or C o Child-Pugh A o ECOG PS ≤1 Safety Most frequent AEs with regorafenib (≥20% of patients) o HFSR o Diarrhea o Fatigue o Hypertension o Anorexia Serious grades 3-4 AEs o HFSR (13% regorafenib, 1% placebo) o Hypertension (13% regorafenib, 3% placebo) Endpoints Primary o OS in ITT population Secondary o PFS o TTP o RR o DCR Regorafenib n = 379 Placebo n = 194 APPROVED
- 3. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Recent Key Clinical Trials in the Treatment of Hepatocellular Carcinoma PRACTICE AID CheckMate-0403 (Dose escalation/expansion cohorts) Efficacy (Dose expansion) Nivolumab N = 214 ORR 20% DOR 9.9 months DCR 75% Patients o HCC not amenable to curative resection o Child-Pugh ≤6; ≤7 for dose escalation o Progression on at least 1 prior line of systemic therapy, intolerant to sorafenib, or refused sorafenib Safety (Dose expansion) Common any-grade AEs o Fatigue (21%) o Pruritus (15%) Primary o Safety Secondary o CR o DCR o DOR Nivolumab Dose escalation (n = 48) Dose expansion (n = 214) o PFS o OS o OS rate o TTR o TTP o TTP rate o Biomarkers o PK Endpoints o Tolerability o ORR o Rash (12%) o Diarrhea (9%) ACCELERATED APPROVAL
- 4. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Recent Key Clinical Trials in the Treatment of Hepatocellular Carcinoma PRACTICE AID a P ≤ .021 for second interim analysis. AEs: adverse events; AST: aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; CR: complete response; DCR: disease control rate; DOR: duration of response; ECOG PS: Eastern Cooperative Oncology Group performance status; HCC: hepatocellular carcinoma; HFSR: hand-foot skin reaction; HR: hazard ratio; ITT: intention to treat; mRECIST: modified Response Evaluation Criteria in Solid Tumors; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetic; QOL: quality of life; RR: response rate; TTP: time to progression; TTR: time to recurrence. 1. Kudo M et al. Lancet. 2017 Feb 9 [Epub ahead of print]. 2. Bruix J et al. Lancet. 2017;389:56-66. 3. El-Khoueiry AB et al. Lancet. 2017;389:2492-2502. 4. Abou-Alfa G et al. 2018 Gastrointestinal Cancers Symposium (ASCO GI 2018). Abstract 207. CELESTIAL4 Efficacy Cabozantinib Placebo OS, months 10.2 8.0 HR (95% CI)a 0.76 (0.63-0.92); P = .0049 PFS, months 5.2 1.9 HR (95% CI) 0.44 (0.36-0.52); P .0001 Patients o Advanced HCC o Child-Pugh A o ECOG PS 0-1 o Prior sorafenib o Progression on at least 1 prior therapy o ≤2 prior therapies Safety Grade 3 or 4 AEs (cabozantinib vs placebo) o HFSR (17% vs 0%) o Hypertension (16% vs 2%) o Increased AST (12% vs 7%) o Fatigue (10% vs 4%) o Diarrhea (10% vs 2%) Endpoints Primary o OS Secondary o PFS o ORR Cabozantinib n = 470 Placebo n = 237
- 5. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Selected Phase 3 Trials in Intermediate and Advanced Hepatocellular Carcinomaa PRACTICE AID This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients. LocallyAdvanced Disease First-LineSystemicTherapy TACE vs SBRT in patients with residual or recurrent disease after TACE (NCT02762266) HIMALAYA: Durvalumab +/- tremelimumab vs sorafenib (NCT03298451) OPTIMA: Liposomal doxorubicin + RFA vs placebo + RFA (NCT02112656) IMbrave150: Atezolizumab + bevacizumab vs sorafenib (NCT03434379) CheckMate-9DX: Nivolumab in patients with high risk of recurrence (NCT03383458) CheckMate-459: Nivolumab vs sorafenib (NCT02576509) STOP-HCC: Y90 glass microspheres + sorafenib vs sorafenib (NCT01556490) PHOCUS: Pexa-Vec + sorafenib vs sorafenib (NCT02562755) Sorafenib + SBRT vs sorafenib (NCT01730937)
- 6. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Selected Phase 3 Trials in Intermediate and Advanced Hepatocellular Carcinomaa PRACTICE AID a More information and current enrollment status for the clinical trials listed here can be found at www.clinicaltrials.gov. AFP: alpha-fetoprotein; BSC: best supportive care; Pexa-Vec: pexastimogene devacirepvec; RFA: radiofrequency ablation; SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; Y90: yttrium 90. Second-LineTherapy orBeyond KEYNOTE-394: Pembrolizumab vs placebo in Asian patients (NCT03062358) REACH-2: Ramucirumab vs placebo in patients with elevated AFP (NCT02435433) KEYNOTE-240: Pembrolizumab vs BSC (NCT02702401)
- 7. Access the activity,“At the Intersection of Local and Systemic Therapy in the Management of Hepatocellular Carcinoma: Preparing for the Next Evolution in Multimodal Treatment,”at www.peerview.com/ZCA40. Understanding Locoregional Therapy for Intermediate Hepatocellular Carcinoma PRACTICE AID HCC: hepatocellular carcinoma; cTACE: conventional transarterial chemoembolization; DEB-TACE: drug-eluting bead transarterial chemoembolization; ECOG: Eastern Cooperative Oncology Group; mRECIST: modified Response Evaluation Criteria in Solid Tumors; TACE: transarterial chemoembolization; TARE: transarterial radioembolization; Y90: yttrium 90. 1. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed February 21, 2018. 2. Lencioni R et al. Hepatology. 2016;64:106-116. 3. Lencioni R et al. Cardiovasc Intervent Radiol. 2012;35:980-985. 4. Salem R et al. Hepatology. 2018 Dec 1 [Epub ahead of print]. This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients. Locoregional treatment is the guideline recommended therapy of choice for patients with intermediate-stage disease1 cTACE DEB-TACE Y90 microspheres Patient selection • Standard of care for intermediate HCC • Child-Pugh B7 or better • ECOG ≤1 Main contraindications • Portal vein thrombosis • Bilirubin 3 mg/dL • Extensive tumor burden in both lobes • Tumor size ≥10 cm Main side effects • Elevated liver enzymes, nausea, vomiting, and abdominal pain Patient selection • May be used in selected patients with segmental/branch portal vein thrombosis • Child-Pugh B7 or better • ECOG ≤2 Main contraindications • Hepatopulmonary shunting • Bilirubin 3 mg/dL Main side effects • Abdominal pain, nausea, vomiting TACE2,3 TARE4 TRANSITIONING TO SYSTEMIC THERAPY • If tumor responds by mRECIST, then additional TACE may be given • If no response after 2-3 TACE to the same tumor region, consider systemic therapy • Distinguish between failure of treated tumor to respond and recurrence with new tumor