Discontinuation Of Sorafenib Research Articles

Repeated Previous Transarterial Treatments Negatively Affect Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib

Background: Transarterial chemoembolisation (TACE) and radioembolisation (TARE) can lead to the deterioration of liver function, especially in cases of a high tumour burden, potentially lessening the benefits of subsequent systemic treatments. We aimed to verify whether a high number of previous transarterial treatments modified the outcomes of patients who received sorafenib as a frontline systemic treatment. Methods: A retrospective analysis of a large multicenter dataset containing prospectively collected data of sorafenib-treated patients was conducted. Results: Data from 696 patients were analysed, with 139 patients having received >two transarterial procedures before starting sorafenib. A propensity score matched 139 identified pairs of patients. Having received >two locoregional treatments was independently associated with a shorter survival (hazard ratio 1.325, 95% confidence interval 1.018–1.725, p = 0.039). This pattern was confirmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%, p = 0.089) and a lower rate of eligibility for second-line treatments (24.5 vs. 17.3%, p = 0.184) was observed in patients who had received >two transarterial procedures. Conclusions: Repeated endovascular treatments negatively impacted the survival of HCC patients, especially sorafenib-responders. An early switch to systemic therapies should be considered in cases that are unlikely to respond.

Real-world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption.

Sorafenib significantly improves survival of FLT3-ITD mutated AML patients when used as a post-allogeneic HSCT maintenance. Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation. The aim of our analysis was to evaluate the real-world experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. We conducted a single-center retrospective study on 30 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2017 and 2020 and who received sorafenib maintenance. 26 patients (87%) experienced toxicities leading to dose reduction (n=9) or direct interruption (n=17). Average time on sorafenib was 125 days (range 1-765). Most common toxicities were skin, gastrointestinal, and hematologic. Among patients who had a dose reduction, 4 eventually interrupted the drug and 5 were able to continue. Among patients who interrupted sorafenib because of toxicities, 7 were re-challenged with good tolerance in 3 cases. Overall, 18 patients (60% of the entire cohort) definitively discontinued sorafenib because of toxicities. 14 patients were thereafter switched to midostaurin. Importantly, with a median follow-up of 12 months, the median overall survival was not reached suggesting a positive impact of sorafenib maintenance despite the high rates of treatment interruption. In conclusion, our real-world analysis reveals high rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT. Interestingly, our results suggest the feasibility of re-challenging with sorafenib and/or of switching to other maintenance approaches in case of intolerance.

ALBI grade predicts suitability for further systemic therapy following sorafenib in patients with advanced hepatocellular carcinoma

AbstractBackground & AimsPreserved performance status (PS) and liver function are required for systemic therapy in patients with advanced hepatocellular carcinoma (aHCC). We investigated the frequency of suitability for further systemic therapies following sorafenib in aHCC.MethodsDemographic, tumour and therapy‐related data were collected retrospectively for patients with aHCC who received sorafenib at a UK tertiary referral centre (training cohort), and an independent French centre (validation cohort). The primary endpoint was percentage of patients with Child‐Pugh class A (CP‐A) liver disease and PS 0–1 after sorafenib discontinuation.ResultsSorafenib was received by 182 patients. After sorafenib discontinuation, 93 patients (51%) were CP‐A and 60 patients (33%) were PS 0–1; 43 patients (24%) were both CP‐A and PS 0–1. On multivariable analysis, patients with Albumin‐Bilirubin (ALBI) score of 1 at time of sorafenib commencement were more likely to be suitable for post‐sorafenib therapy, (44% grade 1 vs 15% grade 2) (OR 3.76, 95%CI 1.72–8.25, P = .0009). In the validation cohort of 216 patients baseline ALBI grade was also significantly associated with suitability for further systemic therapy (P = .008).ConclusionsMost patients with aHCC are not suitable for further systemic therapy after sorafenib, but those with ALBI grade 1 have a greater likelihood of suitability.

Treatment Patterns and Health Resource Utilization in Patients With Hepatocellular Carcinoma After Failure of Sorafenib in Real-World Setting in Taiwan

ObjectivesThis study aimed to characterize current treatment patterns and healthcare resource utilization (HRU) observed among patients with hepatocellular carcinoma (HCC) after the failure of sorafenib in real-world setting in Taiwan. MethodsA chart review was conducted in 130 patients; the inclusion criteria were patients with HCC who were aged 20 years or older and had received systemic therapy or best supportive care after failure of first-line systemic treatment with sorafenib between 2016 and 2018. Anonymized data on patient characteristics, treatment pathways, and survival were abstracted. ResultsThe mean age of patients was 61.7 years (range 27-84); of these 130 patients, 103 (79%) were male, 81 (62%) had high alpha-fetoprotein (AFP) levels (≥400 ng/mL), and 96 (78.0%) were deceased at the time of data abstraction. After sorafenib therapy, 60 patients (46%) received systemic therapy, including nivolumab monotherapy (42%) and chemotherapy (25%). Oncologist visits at a semiannual per-patient rate of 3.7 (95% confidence interval [CI] 3.4-4.0) and hospitalizations at rate of 1.1 (95% CI 1.0-1.3) were the key contributors to HRU. Semiannual per-patient hospitalization rate was 1.3 (95% CI 1.1-1.5) in the high-AFP group. Median survival from discontinuation of sorafenib was 6.9 months (95% CI 5.9-9.0). ConclusionsThis real-world evidence research on treatment patterns reflected substantial HRU consistent with the severity of HCC, particularly in the high-AFP group. Findings highlighted continuing high mortality in HCC, underlying a need for new treatments that can lengthen survival. Results can inform future evaluations of new HCC treatments that estimate the health economic impact of their adoption in Taiwan.

Real-World Treatment Patterns and Health-Resource Utilization in Patients with Hepatocellular Carcinoma (HCC) Following Failure of Sorafenib: A Retrospective Chart Review of 127 Patients in South Korea.

BackgroundEuropean, US, Asian and Korean treatment guidelines all recommend sorafenib as first-line systemic therapy in patients with hepatocellular carcinoma (HCC). However, due to the emergence of several new treatments, post-sorafenib treatment patterns in real-world clinical practice are less well understood.ObjectiveThis study aimed to characterize current treatment patterns and healthcare resource utilization (HRU) in patients with HCC following the failure of first-line sorafenib in a real-world setting in Korea.Patients and methodsA chart review was conducted in 127 HCC patients who received systemic therapy or best supportive care following failure of first-line systemic treatment with sorafenib (2016–2018). Anonymized data on patient characteristics, treatment patterns, and survival were abstracted by 37 physicians in Korea.ResultsThe mean (range) age of patients was 60 (37–79) years; 63 patients had low alpha-fetoprotein (AFP < 400 ng/mL), 64 patients had high alpha-fetoprotein (AFP ≥ 400 ng/mL). Post-sorafenib, 64 (50%) patients had systemic therapy. Regorafenib, used by 54 (84%) patients in second-line, and nivolumab monotherapy, by ten (56%) patients in third-line, were the most common therapies. Hepatologist visits and hospitalizations, at an average rate of 6.89 (95% CI 6.37–7.45) and 2.24 (95% CI 1.95–2.57) per patient-year, respectively, were the key contributors of HRU. The median overall survival (95% CI) from discontinuation of sorafenib was 13.0 (9.8–20.7), 6.5 (5.0–9.5) and 9.5 (6.7–12.3) months in the low AFP, high AFP and overall group, respectively.ConclusionThis real-world evidence research on treatment patterns reflected current clinical guidelines and highlighted fast progressing nature and continuing high mortality in HCC, especially among the high AFP group, underlying a need for new treatments that can lengthen survival. Results from this real-world chart review, together with existing clinical trial data, can inform future evaluations of new HCC treatments that estimate their health economic impact in Korea.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00286-z.

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5months; P<0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P=0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n=28). The median OS calculated from sorafenib start was 28.8months (95% CI, 17.6-40.1) in group 1 versus 15.3months (95% CI, 8.8-21.7) in group 2 (P<0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.

CaboRISE: A phase II study evaluating reduced starting dose and dose escalation of cabozantinib as second-line therapy for advanced HCC in patients with compensated liver cirrhosis.

TPS4163 Background: The multi-targeted tyrosine kinase inhibitor cabozantinib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in adults, who have previously been treated with sorafenib. In the pivotal phase 3 CELESTIAL trial a significant improvement for OS and PFS was shown for cabozantinib in comparison to placebo treated patients (Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63). However, in 62% of patients a dose reduction of cabozantinib was necessary and the median average daily dose was 35.8 mg. The discontinuation rate due to treatment-related adverse events (TRAEs) was 16% and grade 3-4 TRAEs occurred in 68% of patients. For HCC patients treated with sorafenib in first-line, a reduced starting dose of 200 mg BID was not inferior in terms of OS but showed a trend toward a decreased rate of sorafenib discontinuation(Reiss KA et al. J Clin Oncol 2017; 35:3575-3581). The aim of the CaboRISE trial is to study the effect of a reduced starting dose of cabozantinib on tolerability, safety, and efficacy. Methods: The CaboRISE trial is an open-label, single arm, multicenter phase II trial, including patients with advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis (Child-Pugh A) in second line treatment, after first line treatment with sorafenib or lenvatinib. Forty evaluable patients will be enrolled in the study to receive a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. The objective of the trial is to assess the tolerability of a reduced starting dose of cabozantinib, in order to reduce the treatment discontinuation rates due to treatment-related adverse events below 10%. Primary endpoint is the treatment discontinuation rate due to TRAEs. Secondary endpoints are overall survival, progression free survival at 10 weeks, objective response rate, time on treatment, treatment exposure, toxicity, and quality of life. Study start of the CaboRISE trial was in October 2020. By February 2021, 7 centers across Germany have been initiated and a total of 4 out of 40 planned patients have been enrolled. The study is currently ongoing. This study is financially supported by Ipsen. ClinicalTrials.gov: NCT04522908 EudraCT: 2020-000775-20. Clinical trial information: NCT04522908.

Regorafenib improves survival after sorafenib in patients with recurrent HCC after liver transplantation

Background and aim: Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit in patients treated with regorafenib compared to best supportive care (BSC) after sorafenib discontinuation.

Real-Life Experience of Sorafenib Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-ITD AML Reveals High Rates of Toxicity-Related Treatment Interruption

Introduction: FLT3-Internal Tandem Duplication (FLT3-ITD) mutations of the gene encoding the FLT3 tyrosine kinase receptor are found in 25-30% of AML patients and are associated with a poor prognosis despite intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). FLT3 tyrosine kinase inhibitors (TKI) significantly improve survival of FLT3 mutated AML patients in large prospective trials (Stone, NEJM 2017; doi:10.1056/NEJMoa1614359). Post-HSCT maintenance with sorafenib - a broad-spectrum TKI with strong activity against FLT3 - was recently shown to reduce the risk of relapse and improve survival in the phase II SORMAIN trial (Burchert, JCO 2020; doi: 10.1200/JCO.19.03345). Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation (Chen et al, BBMT 2014;doi: 10.1016/j.bbmt.2014.09.007; Burchert et al., J Clin Oncol. 2020; doi: 10.1200/JCO.19.03345). The aim of our single-center retrospective analysis was to evaluate the real-life experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. Methods: We conducted a single-center retrospective study on 33 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2013 and 2020, including 20 patients who received sorafenib maintenance and 13 who did not. Sorafenib was started at hematologic reconstitution at 200 mg BID and increased at 400 mg BID after a week in case of good tolerance. Treatment was maintained until two years if tolerated. In case of toxicity, the drug was either reduced to 200mg BID, or stopped. Among the 13 patients in the untreated group, 8 were transplanted between 2013 and 2016 before we started to routinely use sorafenib maintenance, and 5 were transplanted in 2017 or later. Among the latter, sorafenib maintenance was not started because of aGVHD and insufficient hematologic reconstitution (n=3), low-allelic ratio of FLT3-ITD (n=1), early death due to PTLD (n=1). Results: In the sorafenib group (n=20), median time from transplant to sorafenib initiation was 68 days (range 40-213). Overall, 16 patients (80%) experienced toxicities leading to dose reduction (4 patients, 20%) or interruption (12 patients, 60%). In these patients, the average time on sorafenib before toxicity occurrence was 98 days (range 1-717; only one patient stopped treatment after 1 day because of severe diarrhea). Most common toxicities were skin (7, grade II), gastrointestinal (5, grade II), and hematologic (5, grade II and III). One patient experienced uveitis (grade III) and pneumonia (grade IV), both resolutive after sorafenib interruption. One patient experienced severe hypertension (grade III), 1 had hepatitis (grade III) and another one a PRESS syndrome (grade IV) possibly related to sorafenib. Other causes of sorafenib interruption included FLT3-ITD negative relapse in 1 patient, relapse in 1 patient, and end of scheduled maintenance in 1 patient. Among the 12 patients who interrupted sorafenib because of toxicities, 3 patients were re-challenged with good tolerance in 2 cases, while 7 were switched to midostaurine. Among these 7, 4 completed the 2-y treatment and 3 interrupted midostaurine because of toxicities (2 patients experienced digestive intolerance and 1 pneumonia). The average time of sorafenib exposure in the whole sorafenib group was 180 days (range 1-765). Importantly, the analysis of patients' outcome confirmed the previously reported positive impact of sorafenib maintenance on overall survival (Figure 1B) despite high rates of treatment interruption. Conclusion: Our real-life analysis reveals higher rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT than previously reported in clinical trials. Interestingly, our results confirm the favorable impact of sorafenib maintenance on clinical outcome despite a high rate of toxicity-related treatment interruption, suggesting the feasibility of switching to other maintenance approaches in case of low tolerability. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: sorafenib as a maintenance treatment to prevent FLT3-ITD mutated AML reccurence after allogeneic transplantation

Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma.

To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC). We retrospectively studied 154 patients with HCC who received sorafenib therapy. A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation. Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.

Sequential treatment with sorafenib (SOR) followed by regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (HCC): Interim analysis of the observational REFINE study.

e16680 Background: REG is approved for the treatment of pts with HCC who previously received SOR, based on results of the phase 3 RESORCE trial. The REFINE study was designed to evaluate the safety and effectiveness of REG in pts with HCC in real-world practice. Methods: This prospective, observational study aims to recruit 1000 pts with unresectable HCC for whom a decision to treat with REG was made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints include overall survival (OS) and progression-free survival (investigator assessed). This interim analysis includes the first 500 pts on study for ≥4 months. Results: Of 500 pts enrolled and observed for ≥4 months, 498 received REG and were evaluable (data cut-off: November 11, 2019). Pts were Child-Pugh A 67%, B 11%, C 1%, and missing/not evaluable 21%. Most pts (98%; n = 490) had received prior systemic therapy; 97% (n = 482) had received prior SOR. REG was second line treatment in 81% of pts (n = 403), third line or higher in 17% (n = 87), and first line in 2% (n = 8). Of the 403 pts who received REG second line, 398 (99%) received prior SOR. Among the 482 pts who received SOR in any prior line, the median duration of prior SOR was 4.8 months (interquartile range 2.5–9.6), 45% (n = 216) had a last daily SOR dose of 800 mg, and 8% (n = 40) had a TEAE leading to SOR discontinuation (SOR-intolerant). OS by treatment line is shown in the Table. Among all treated pts, the most frequent TEAEs (any grade) were hand–foot skin reaction (HFSR; 30%), diarrhea (21%), fatigue (16%), and decreased appetite (14%). In SOR-intolerant pts (n = 40), the most frequent TEAEs (any grade) were diarrhea (25%), HFSR (20%), abdominal pain (15%), and decreased appetite (13%). Conclusions: In this interim analysis of REFINE, most pts received REG second line after SOR versus other lines of therapy. Median OS in this subgroup was longer than OS in RESORCE, but the proportion of censored pts was high. The most common TEAEs were similar to those in RESORCE in both the overall cohort and in SOR-intolerant pts. Clinical trial information: NCT03289273 . [Table: see text]

Effect of Urea Cream on Sorafenib-Associated Hand-Foot Skin Reaction in Patients with Hepatocellular Carcinoma: A Multicenter, Randomized, Double-Blind Controlled Study

Background: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment, which is the main reason for dose de-escalation or discontinuation of sorafenib in hepatocellular carcinoma (HCC) patients. Here, we aimed to investigate the role of urea cream in the prevention or amelioration of HFSR severity. Methods: HCC patients at 13 hospitals in Korea were recruited from May 2016 to May 2018. Patients were treated with placebo cream and urea cream for 12 weeks concomitantly with sorafenib treatment. Development of HFSR, score for Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire, and adverse event were assessed at 2, 4, 8, and 12 weeks. Findings: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analyzed. The urea cream group showed lower cumulative incidence of any grade of HFSR (Log-rank, p=0.247) and severe HFSR of grade 2 or higher (Log-rank, p = 0.394) without statistical significance. In the incidence by time point, the development of severe HFSR of grade 2 or higher was significantly lower in the urea cream group than in the placebo control group at two weeks (13.8% vs. 23.9%, p=0.042). The urea cream group showed a significantly improved questionnaire score compared to the placebo control group (11.8 vs. 19.7, p=0.014) at 12 weeks. Interpretation: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream could be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. Trial Registration: This study was registered at ClinicalTrial.gov (NCT03212625). Funding Statement: The Korea Liver Cancer Association and Hanmi Pharmacy (IIT-CAV-004). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written informed consent. This study was approved by the institutional review board of each participating institute (2016GR0350).

An Analysis for Survival Predictors for Patients with Hepatocellular Carcinoma Who Failed to Sorafenib Treatment in Pre-regorafenib Era

Background/Aims: Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to investigate the prognosis predictors and the role of second-line cytotoxic systemic chemotherapy (CSC) in patients with advanced HCC after sorafenib discontinuation in the pre-regorafenib era. Methods: From 2007 to 2015 in the pre-regorafenib era, the medical records of 166 HCC patients, who had permanently discontinued sorafenib, were retrospectively reviewed. For further analysis of survival factors after sorafenib treatment failure, we compared the survival of patients who had maintained liver function after second-line treatment with the best supportive care (BSC) group and selective BSC (SBSC) group. Results: After discontinuation of sorafenib, median overall survival (OS) was 2.8 (1.9-3.7) months. The OS in patients who discontinued sorafenib due to adverse effect, progression, and poor clinical condition were 5.5 (2.4-8.6), 5.5 (2.2-8.9), and 0.9 (0.5-1.3) months, respectively (P<0.001). The independent predictive factors of survival after sorafenib failure were serum level of bilirubin and albumin, α-fetoprotein, discontinuation cause, and second-line CSC. In comparison with survival between second-line CSC and BSC group, the CSC group showed better survival outcome compared to the BSC group (10.6 vs. 1.6 months, P<0.001) and SBSC group (10.6 vs. 4.2 months, P=0.023). Conclusions: The survival after sorafenib failure in patients who discontinued sorafenib due to progression and adverse effects was significantly better than in those who discontinued treatment due to clinical deterioration. In the pre-regorafenib era, patients who received second-line CSC showed better survival than those who received only supportive care after sorafenib failure. (J Liver Cancer 2019;19:117-127)

Sorafenib-induced Pancreatic Pseudocyst in a Patient with Advanced Hepatocellular Carcinoma: a Rare Adverse Event

A 54-year old man diagnosed with advanced hepatocellular carcinoma began treatment with sorafenib. After 3 weeks of treatment, he complained of abdominal pain and nausea. Abdominal sonography showed multiple hepatic lesions only. Serum amylase and lipase levels were 35 U/L and 191 U/L, respectively. The patient was diagnosed with sorafenib-induced acute pancreatitis. After 10 days of discontinuing sorafenib he still complained of nausea and loss of appetite. Esophagogastroduodenoscopy showed a large bulging lesion, which was suspected to cause extrinsic compression on the high body of the gastric anterior wall. Computed tomography scan revealed a cystic lesion, 8.3 cm in size, in the pancreatic tail, suggesting a pancreatic pseudocyst. After the withdrawal of sorafenib, systemic chemotherapy with Adriamycin and cisplatin was administered. Four months after the discontinuation of sorafenib, the size of the pancreatic pseudocyst decreased from 8.3 cm to 3 cm. The patient''s symptoms were also relieved. (J Liver Cancer 2019;19:154-158)

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5)years; median time on sorafenib was 11.3 (0.7-76.4)months and 14 (1-591)days from sorafenib discontinuation to regorafenib. During regorafenib (6.3months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n=7) and dermatological reaction (n=5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.

FRI-475-Experience impacts on reasons leading to sorafenib discontinuation and chance of long-term response tyrosine-kinase inhibitors, as these molecules share a common toxicity-profile.

FRI-475-Experience impacts on reasons leading to sorafenib discontinuation and chance of long-term response tyrosine-kinase inhibitors, as these molecules share a common toxicity-profile.

Doxorubicin-Loaded Nanoparticles for Patients with Advanced Hepatocellular Carcinoma after Failure of Sorafenib: RELIVE, a Phase-3 Trial

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma (HCC). We evaluated the intravenous perfusion of doxorubicin-loaded nanoparticles (DT) in HCC patients with prior failure of sorafenib therapy. Methods: We conducted a randomized, open label, 3 parallel groups, phase-3 trial at 70 sites in 11 countries. Patients with HCC with prior one or more systemic therapies including sorafenib were randomised 1:1:1 for DT-30 mg/m2 (DT-30), DT-20 mg/m2 (DT-20) or best standard of care (BSC); stratified by performance status, Child-Pugh score, DT dosage, macrovascular invasion, extrahepatic spread, alpha-fetoprotein level, number of prior systemic lines, reason of sorafenib discontinuation, and aetiology of HCC. The primary endpoint was overall survival. This trial is registered at ClinicalTrials.gov, number NCT01655693. Findings: Between June 2012 and January 2017, 541 patients were screened, 397 randomized (DT-30=133; DT-20=130; BSC=134; population for efficacy analysis), and 376 initiated treatments (DT-30=120; DT-20=122; BSC=134; population for safety analysis). After pooling the DT-30 and DT-20 arms in the analysis, pooled DT (pDT) did not improve overall survival with a hazard ratio of 1.00 (95% CI 0.78-1.28; p=0.99); median overall survival (95%CI) was 9.1 months (8.1-10.4) for pDT versus 9.0 months (7.1-11·8) for BSC. The hazard ratio for progression-free survival was 0.95 (95% CI 0.74-1.22; p=0.70) and for time to progression 0.96 (95%CI 0.74-1.23; p=0.74). Adverse events were reported in 94% (247/263) of pDT and 75% (100/134) of BSC. The most common grade 3 or 4 treatment-emergent adverse events included (pDT; BSC) neutropenia (8% [20/242]; 5% [6/134]), asthenia (3% [6/242]; 3% [4/134]), and thrombocytopenia (1% [3/242]; 7% [9/134]). Rates of drug-related death per investigators were 1% (3/242; pDT) and 1% (2/193; BSC). Interpretation: DT doesn't show benefit on survival in HCC patients with failure on prior sorafenib treatment, but it has a comforting safety profile. Trial Registration Number: ClinicalTrials.gov, number NCT01655693 Funding: ONXEO Conflict of Interest: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, BMS, and MSD. JFB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. JPB has received consultancy and advisory fees from Onxeo, and Bayer. GP has received consultancy and advisory fees from Bayer, AbbVie, Novartis, and Gilead. AA has received consultancy and advisory fees from AbbVie, MSD, and Gilead. IW has received consultancy and advisory fees from Janssen, AbbVie, MSD, Marcyrl, Pharco, and Gilead. NY has received consultancy and advisory fees from Halozyme, Boston Biomedical Inc., Pharmacyclics, EMD Serono, Merck, Onxeo, Regeneron, and Momenta. Ethical Approval: The trial was approved by each centre’s ethics committee or institutional review board and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws.

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7)months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8)months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

Long-term follow-up of complete remission of advanced hepatocellular carcinoma following sorafenib therapy: A case report.

Sorafenib is a tyrosine kinase inhibitor that has been demonstrated to improve the overall survival time of patients with advanced hepatocellular carcinoma (HCC). Although there have been a number of reports of patients achieving complete remission (CR) following sorafenib therapy, the long-term clinical outcomes of these patients have yet to be ascertained. A 72-year-old male patient with chronic hepatitis C, diabetes, hypertension and an old cerebral infarction was referred for the evaluation of a liver mass identified on an abdominal ultrasound. Abdominal computed tomography (CT) demonstrated a 13-cm mass replacing the right lobe of the liver, with portal vein thrombosis. HCC was confirmed by a percutaneous needle biopsy and treated with sorafenib. At 4 months, a follow-up CT demonstrated no enhancing viable lesions in the tumor and recanalization of the portal vein. Sorafenib therapy was continued for 48 months until the patient experienced dyspnea due to congestive heart failure, with pleural effusion. Following the discontinuation of sorafenib, the patient's symptoms improved. The patient followed up without recurrence for 52 months. Subsequent to achieving CR through treatment with sorafenib, long-term sorafenib therapy may be an option and efforts should be made to monitor cardiac toxicity during sorafenib therapy, particularly in high-risk patients.

Survival Estimates after Stopping Sorafenib in Patients with Hepatocellular Carcinoma: NEXT Score Development and Validation.

Background/AimsLimited information is available regarding patient survival after sorafenib discontinuation in patients with hepatocellular carcinoma (HCC). Thus, we developed and validated a novel survival prediction model.MethodsClinical data from 409 patients with HCC who stopped taking sorafenib between September 2008 and February 2015 were reviewed.ResultsIn the training cohort, four factors were independent negative predictors of survival (p<0.05). Based on the β regression coefficient of each factor, we established the NEXT score (Survival after Stopping Nexavar Treatment), allocating 1 point each for an Eastern Cooperative Oncology Group score ≥2, Child-Pugh class B or C, serum sodium ≤135 mEq/L, and α-fetoprotein >400 ng/mL. Area under the receiver operating characteristic curve values to predict 1-, 3-, and 6-month survival rates were 0.805, 0.809, and 0.774, respectively, in the training cohort and 0.783, 0.728, and 0.673, respectively, in the validation cohort (n=137). When the training and validation cohorts were stratified into three risk groups (NEXT score 0 [low-risk] vs 1 to 2 [intermediate-risk] vs 3 to 4 [high-risk]), survival differed significantly between the groups (p<0.05, log-rank test).ConclusionsIn patients with HCC, survival after stopping sorafenib is poor. However, risk estimates based on a new “NEXT score” may help predict survival and prognosis even in patients who discontinue sorafenib treatment.