Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: A subanalysis from the SHARP trial

e14654 Background: SHARP was pivotal in determining the safety and efficacy of sorafenib in advanced hepatocellular carcinoma (HCC) in patients with predominately good liver function. In practice, many patients with advanced HCC receive radioembolization (RE). Investigators from the European Network on RE with yttrium-90 resin microspheres (ENRY) group conducted an analysis of safety and survival among consecutive patients who met the SHARP inclusion criteria. Methods: 58% of patients (189 of 325) who had received RE between 09/2003 and 12/2009 were considered SHARP-equivalents. Of these, 11.6% received sorafenib 4.7 months (median) after RE for a median duration of 2.8 months. Safety and tolerability analyses were conducted up to day 90 post RE; changes from baseline were recorded and transitions in CTCAE grades >3 tested. Statistical analyses used SAS (SAS, Cary NC) version 9.2 XP Pro. Results: Like the SHARP sorafenib cohort, most patients had advanced HCC (BCLC stage C: 72.5%), good liver function (Child–Pugh class A: 100%) and ECOG performance status (0–1: 90.5%). Macroscopic vascular invasion (MVI), extrahepatic spread (EHD) or both was present in 33.9%. 20.1% had received prior surgical procedures, 8.5% prior ablative procedures and 33.3% prior vascular [chemo]embolization. RE was predominantly a single whole-liver procedure (median activity 1.7 GBq). Median overall survival was 10.8 months (95% CI: 8.8–12.8) in the SHARP-equivalent cohort, 10.2 months (8.3–11.8) in patients with MVI/EHD, 9.7 months (7.6–10.9) in advanced HCC (BCLC stage C) and 16.6 months (11.2–22.8) in intermediate HCC (BCLC stage B). Treatment-related adverse events (all grades; grade >3) were: fatigue (50.3%; 2.1%), abdominal pain (25.9%; 2.1%), nausea/vomiting (31.2%; 0.5%) and GI ulcer (3.2%; 1.0%). At baseline, raised bilirubin (all grades) was present in 20.3%, increasing to 49.4% of patients evaluated up to day 90. Bilirubin grade was unchanged in 58.1% and increased in 37.8%; 4.0% had ≥grade 3 events. Conclusions: In patients matching the inclusion criteria for SHARP, RE was well tolerated with a median overall survival which compares favorably with sorafenib.

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KEYNOTE-224: Phase II study of pembrolizumab in patients with previously treated advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.tps504 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. TPS504-TPS504 ◽

Cited By ~ 7

Author(s):

Andrew X. Zhu ◽

Jennifer J. Knox ◽

Masatoshi Kudo ◽

Stephen L. Chan ◽

Richard S. Finn ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Disease Progression ◽

Kinase Inhibitor ◽

Performance Status ◽

Objective Response ◽

Progression Free Survival ◽

Locoregional Therapy ◽

Advanced Hepatocellular Carcinoma ◽

Ecog Performance Status ◽

Previously Treated

TPS504 Background: The tyrosine kinase inhibitor sorafenib is the standard of care for first-line hepatocellular carcinoma (HCC). For patients with HCC after disease progression on sorafenib or for those with intolerance to sorafenib, no approved therapies are available. Because HCC is often driven by inflammation and is also associated with a suppressed immunoenvironment, there is a strong rationale to evaluate immunotherapy in patients with this type of cancer. The single-arm, multisite, phase 2 KEYNOTE-224 study (ClinicalTrials.gov, NCT02702414) was designed to evaluate the efficacy and safety of the anti–PD-1 antibody pembrolizumab in patients with previously treated advanced HCC. Methods: Approximately 100 patients will be enrolled. Inclusion criteria include age ≥18 years, histologically or cytologically confirmed diagnosis of HCC Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease not amenable to or refractory to locoregional therapy, and disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation). Patients must also have measurable disease based on RECIST v1.1 as confirmed by central imaging vendor review, documented objective radiographic progression after stopping treatment with sorafenib or intolerance to sorafenib, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy > 3 months. Patients will be allocated to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision. Response will be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. The primary end point is objective response rate per RECIST v1.1 by central imaging vendor review. Secondary end points are overall survival; safety and tolerability; and duration of response, disease control rate, time to progression, and progression-free survival per RECIST v1.1 by central imaging vendor review. Enrollment in KEYNOTE-224 is ongoing. Clinical trial information: NCT02702414.

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Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15630 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15630-e15630 ◽

Cited By ~ 1

Author(s):

J. Wu ◽

F. Muggia ◽

C. Henderson ◽

L. Feun ◽

P. V. Veldhuizen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Confidence Interval ◽

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Inorganic Arsenic ◽

Advanced Hepatocellular Carcinoma ◽

Ecog Performance Status ◽

Class A ◽

Pugh Class

e15630 Background: Inorganic arsenic has reported activity in advanced hepatocellular carcinoma (HCC) in Asia, yet its efficacy is limited by liver toxicity. Darinaparsin is a novel organic arsenic that is capable of reaching higher intracellular concentration in cells with decreased toxicity compared to inorganic arsenic. It is highly active as a single agent in HCC cell lines and animal tumor models. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC. Methods: Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status ≤2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was given at 420 mg/m2 intravenously administered over 60 minutes through a central line, twice weekly at least 72 hours apart for three weeks followed by one-week rest in a four-week cycle. The primary end point of the study was response rate. A Simon two-stage design was used to assess the efficacy of darinaparsin and the study would be terminated if no responses were observed after the first stage. Results: The planned 15 patients of the first stage were enrolled: median age = 60 (35 - 79). M/F = 14/1, ECOG performance status 0/1= 4/11, Child Pugh class A/B = 11/4. Seven patients received prior systemic chemotherapies. No objective responses were observed. Three patients had stable disease. The median number of cycles on study per patient was 2 (1–6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50 - 59) and 190 days (95% confidence interval: 93–227), respectively. Treatment was well tolerated. No treatment related hospitalizations or deaths occurred. Treatment related grade 1–2 toxicities included nausea/vomiting (31%), fatigue (23%), anorexia (15%) and diarrhea (15%). Grade 3 anorexia, wheezing, agitation, right upper quadrant pain and SGPT were observed in 1 patient each (8%), 1 patient experienced grade 4 hypoglycemia (8%). Conclusions: Darinaparsin was safely administered with tolerable toxicity profiles in HCC patients. However, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis. [Table: see text]

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A multicenter phase II study of sorafenib in Japanese patients with hepatocellular carcinoma and Child Pugh A or B cirrhosis.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.354 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 354-354

Author(s):

Eiichiro Suzuki ◽

Shuichi Kaneko ◽

Takuji Okusaka ◽

Masafumi Ikeda ◽

Kensei Yamaguchi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Performance Status ◽

Objective Response ◽

Japanese Patients ◽

Advanced Hepatocellular Carcinoma ◽

Efficacy And Safety ◽

Class A ◽

Pugh Class ◽

Grade 3

354 Background: Sorafenib has been used as the first-line treatment for advanced hepatocellular carcinoma (HCC), however, its efficacy and safety in Japanese patients (pts), especially those with Child-Pugh (CP) B cirrhosis, have not yet been fully examined. This study was conducted to evaluate the efficacy and safety of sorafenib in Japanese pts with HCC and CP B or CP A cirrhosis. Methods: The eligibility criteria were patients 1) with pathologically or clinically proven HCC, 2) with an ECOG performance status 0 to 2, 3) aged 20 to 79 years, 4) with measurable lesions, 5) with adequate hematological, renal and Child Pugh class A or B liver functions. Sorafenib was administered orally at the dose of 400 mg twice daily. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints included objective response, overall survival (OS), and toxicity. Results: Forty CP A pts and 12 CP B pts were enrolled between April 2010 and January 2012. The median PFS in the CP A pts was 3.3 months (M) and that in the CP B pts was 3.2 M. Among the pts with CP A, there was one patient with confirmed complete response (2.5%), 3 pts with partial response (7.5%), and 19 pts (47.5%) with stable disease (SD). Among the pts with CP B, there were no treatment responses, and 8 (66.7%) pts had SD. The median overall survival in the CP A pts was 13.4 M and that in the CP B pts was 7.4 M. With regard to toxicities, fewer CP A pts experienced grade 3/4 toxicities than CP B pts (77.5% vs. 91.6%). The grade 3/4 toxicities in the CP A and B pts, respectively, included thrombocytopenia (10% and 25%), hand foot skin reaction (27.5% and 16.7%), Erythema multiforme (0% and 16.7%), and upper gastrointestinal bleeding (0% and 16.7%). There were no treatment-related deaths in either group of patients. Conclusions: This study shows that sorafenib is effective and well-tolerated in Japanese patients with HCC and Child Pugh class A liver cirrhosis, consistent with previous reports. The outcome was poorer and severe toxicities were more frequent in patients with Child Pugh B cirrhosis than in those with Child Pugh A cirrhosis. Clinical trial information: 000002972.

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Systematic literature review of trials assessing recommended systemic treatments in hepatocellular carcinoma

Hepatic Oncology ◽

10.2217/hep-2021-0003 ◽

2021 ◽

pp. HEP41

Author(s):

Sarah Ronnebaum ◽

Abdalla Aly ◽

Dipen Patel ◽

Fernando Benavente ◽

Juan-David Rueda

Keyword(s):

Hepatocellular Carcinoma ◽

Literature Review ◽

Randomized Trials ◽

Severe Disease ◽

Performance Status ◽

Advanced Hepatocellular Carcinoma ◽

Second Line ◽

Efficacy And Safety ◽

First Line ◽

Systemic Treatments

Aim: To identify and evaluate the similarity of all trials assessing recommended treatments for advanced hepatocellular carcinoma. Materials & methods: Single arm and randomized trials from any phase and published any time up to February 2021 were systematically searched. Results: From 5677 records reviewed, 50 trials were included in the review, and 24 for assessed for similarity. In the first-line (1L) setting, several trials assessing sorafenib were noted for enrolling patients with more severe disease and/or performance status than other 1L trials; trials within the second-line (2L) setting were generally similar. Median survival was <2 years in all trial arms. Conclusions: Trials assessing recommended treatments are largely similar and appropriate for quantitative comparisons of several efficacy and safety outcomes.

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A retrospective study on the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16127 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16127-e16127

Author(s):

Zhen Zeng ◽

Linzhi Zhang ◽

Tong Wu ◽

Jiamin Cheng ◽

Yan Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Retrospective Study ◽

Adverse Events ◽

Controlled Trial ◽

Performance Status ◽

Objective Response ◽

Advanced Hepatocellular Carcinoma ◽

Efficacy And Safety ◽

Significant Difference ◽

Grade 3

e16127 Background: To evaluate the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma. Methods: This retrospective study included patients with advanced/metastatic hepatocellular carcinoma who received sintilimab (iv. 200 mg, Q3W) combined with sorafenib (oral, 400 mg twice-daily) (cohort A) or lenvatinib (oral, 12 mg/day for bodyweight≥60 kg or 8 mg/day for bodyweight < 60 kg) (cohort B) as first line therapy between March 2019 to December 2020 in the 5th medical center of the PLA general hospital of China. The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), Time to Progression (TTP) and safety. Results: 45 patients were enrolled, of which 29 were in the cohort A and 16 were in the cohort B. Except for the extrahepatic metastasis (62.1% vs 25.0%, P= 0.029), there were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous treatment regimens between the two cohorts. The mean (±SD) exposure cycles in the two cohorts were 7.2±6.7 vs 7.1±4.7 ( P= 0.584). The median PFS of cohort A (8.2 months, 95%CI 3.1-19.5) was longer than that of cohort B (5.2 months, 95%CI 2.0-10.8), but there was no significant difference (HR 0.55, 95%CI 0.24-1.29, P = 0.161). However, there was no significant difference between the two cohorts in ORR (24.1% vs 6.3%, P= 0.226), DCR (82.8% vs 75.0%, P= 0.700) and median TTF (8.2 vs 4.6months, HR 0.49, 95%CI 0.21- 1.10, P= 0.074). OS data were not yet mature. There was no significant difference in the incidence of all grades and grade 3-4 adverse events between the two cohorts. The most common grade 3-4 adverse events in the two cohorts were hand-foot syndrome (17.2%, 5/29) and lung infection (12.5%, 2/16). There was 1 patient (immune hepatitis) in cohort A and 2 patients (pulmonary infection) in cohort B leading to treatment interruption due to adverse events, and no deaths due to treatment. Conclusions: Sorafenib or lenvatinib combined with sintilimab showed a good efficacy and safety in patients with advanced hepatocellular carcinoma, the safety and tolerability profiles were consistent with those previously observed. Sorafenib plus sintilimab provided an improved PFS versus lenvatinib, which requires a large sample of randomized controlled trial to confirm.[Table: see text]

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Comparative effectiveness of sorafenib, lenvatinib, and nivolumab as first-line systemic therapy for patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis treated at VA Medical Centers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4102 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4102-4102

Author(s):

William Joseph Chapin ◽

Wei-Ting Hwang ◽

Thomas Benjamin Karasic ◽

Anne Marie McCarthy ◽

David Edward Kaplan

Keyword(s):

Hepatocellular Carcinoma ◽

Systemic Therapy ◽

Comparative Effectiveness ◽

Performance Status ◽

Decompensated Cirrhosis ◽

Advanced Hepatocellular Carcinoma ◽

Ecog Performance Status ◽

Medical Centers ◽

Class B ◽

Lower Hazard

4102 Background: Up to 90% of cases of hepatocellular carcinoma (HCC) in the U.S. occur in patients with cirrhosis. As prognosis in patients with decompensated cirrhosis may be more related to liver function than tumor stage, patients with Child-Pugh (CP) class B and C cirrhosis are often excluded from randomized trials despite representing up to 30% of patients treated with systemic therapy in clinical practice. While prospective data such as the GIDEON registry and CHECKMATE-040 have demonstrated safety of sorafenib and nivolumab in CP B cirrhosis, studies of comparative effectiveness of sorafenib, lenvatinib, and nivolumab are lacking. Methods: We performed a retrospective cohort study of patients with HCC and CP B cirrhosis at U.S. Veterans Affairs Medical Centers who initiated first systemic therapy with sorafenib, lenvatinib, or nivolumab between 9/22/2017 and 2/13/2021. Overall survival (OS) by first systemic therapy was assessed with Kaplan Meier analysis and Cox proportional hazards modeling with pre-specified candidate covariates and a backward elimination approach for variable selection. Missing data were imputed by multiple imputation with chained equations. Results: Among 401 CP B patients undergoing first systemic therapy, 98% were male, 29% had macrovascular invasion (MVI), 35% had extrahepatic spread (EHS), 57%/29%/13% had CP score 7/8/9, 5% had hepatic encephalopathy, 37% had ascites, 63%/2%/36% had HCV/HBV/non-viral cirrhosis, 63% had prior embolization or ablation, and 35% had ECOG performance status of > = 2. Of these patients, 320 received sorafenib, 33 received lenvatinib, and 48 received nivolumab. In univariate analysis, median OS was 4.8 months (95% CI 3.8 – 6.0; 1 year OS 21.8%) in the sorafenib cohort, 6.9 months (95% CI 4.4 – 8.4 months; 1 year OS 27.8%) in the lenvatinib cohort, and 7.7 months (95% CI 3.9 – 9.1 months; 1 year OS 31.7%) in the nivolumab cohort. Covariates with at least one category significantly associated with survival that were retained in the multivariate model included CP score, MELD-Na, BMI, log(AFP), time from diagnosis to systemic treatment, ECOG performance status, Cirrhosis Comorbidity index, and VA complexity level (all p < 0.05); MVI, EHS, and age were retained in the model as pre-specified despite lack of statistical significance. Compared with sorafenib, nivolumab was associated with significantly lower hazard of death (adjusted HR 0.63; 95% CI 0.43 – 0.91; p = 0.015) while hazard of death for lenvatinib treatment was not significantly different (adjusted HR 0.83; 95% CI 0.54 – 1.28, p = 0.41). Conclusions: Among patients with HCC and CP class B cirrhosis undergoing first systemic therapy, nivolumab was associated with significantly lower hazard of death compared to sorafenib after adjusting for important covariates.

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Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients Who Have Advanced Hepatocellular Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.3301 ◽

2009 ◽

Vol 27 (6) ◽

pp. 843-850 ◽

Cited By ~ 231

Author(s):

Melanie B. Thomas ◽

Jeffrey S. Morris ◽

Romil Chadha ◽

Michiko Iwasaki ◽

Harmeet Kaur ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Response Rate ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Advanced Hepatocellular Carcinoma ◽

Study Objective ◽

Advanced Hcc

Purpose The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. Patients and Methods Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. Results The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). Conclusion The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

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