Second-line Therapy For Hepatocellular Carcinoma Research Articles

OP14 Cost-Utility Analysis Of Regorafenib For Patients With Hepatocellular Carcinoma Who Progressed On Sorafenib Treatment

IntroductionIn the RESORCE trial, regorafenib was shown to provide overall survival (OS) benefit for patients with hepatocellular carcinoma (HCC) that has progressed on sorafenib treatment. Subsequently, it was approved by the Therapeutic Goods Administration for the treatment of patients with HCC who were previously treated with sorafenib; however, regorafenib is still not recommended by the Pharmaceutical Benefits Advisory Committee in Australia. We aimed to assess the cost effectiveness of regorafenib as a second-line therapy for patients with HCC who progressed on sorafenib from an Australian healthcare perspective.MethodsWe developed a Markov model to compare the cost effectiveness of regorafenib with best supportive care (BSC) as a second-line therapy for HCC after treatment with sorafenib. The health outcomes of life-years and quality-adjusted life-years (QALYs) were derived from the RESORCE trial. Survival benefits sourced from the RESORCE trial were fitted with the parametric model to estimate survival beyond the follow-up period. Drug costs and costs associated with adverse events (AEs) were sourced from published literature and the Independent Health and Aged Care Pricing Authority cost report. Model validity was verified using probabilistic sensitivity analyses.ResultsThe incremental monthly cost of treatment with regorafenib was AUD19,273 (USD13,374), with an incremental life-year gain of 0.38, compared with BSC. The incremental QALYs gained with regorafenib were 0.24, resulting in a base-case incremental cost-effectiveness ratio (ICER) of AUD80,511 (USD55,872) per QALY. In the probabilistic sensitivity analyses across scenarios, the ICER remained above the conventional threshold of AUD50,000 (USD34,698) per QALY, with a zero probability of being cost effective at this willingness-to-pay threshold.ConclusionsAt the current price, second-line treatment with regorafenib in patients with HCC that has progressed on sorafenib was not cost effective at the conventional willingness-to-pay threshold from an Australian health-system perspective.

A novel approach for the treatment of advanced hepatocellular carcinoma (HCC).

35 Background: No established treatments for patients with advanced HCC and moderate hepatic dysfunction (Child-Pugh B; CPB) are available. Namodenoson is an A3 adenosine-receptor agonist currently under clinical development as a treatment for advanced HCC with CPB. Methods: Wereport the results of a prospective placebo-controlled randomized (2:1) phase 2 trial investigating namodenoson (25 mg BID) as a second-line therapy in HCC with CPB and focus on a case of a long-term complete response (CR). Results: The study included 78 patients (50 namodenoson-treated, 28 placebo-treated). Namodenoson was well-tolerated and no treatment-related deaths were reported. Median overall survival (OS, the primary endpoint) was not statistically significantly different between the namodenoson and placebo arms (4.1 and 4.3 months, respectively, hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.49‒1.38; p=.46). The difference in 12-month OS was statistically significant (44% vs 18%, respectively, p=.028). Pre-planned analysis of patients with CPB7 (34 namodenoson-treated, 22 placebo-treated) showed nonsignificant improvements in OS and progression-free survival (PFS). OS: 6.9 vs 4.3 months; HR, 0.81; 95% CI: 0.45‒1.43; p=.46. PFS: 3.5 vs 1.9 months; HR, 0.89; 95% CI: 0.51‒1.55; p=.67. Of the patients with ≥1 assessment post-baseline, partial response (PR) was reported in 3 of 34 (8.8%) namodenoson-treated patients and none of the 21 placebo-treated patients. One of 3 the patients who achieved a PR (a 61-year old woman with CPB7, Barcelona Clinic Liver Cancer stage C, and Eastern Cooperative Oncology Group performance status 2) continued treatment with namodenoson under an open-label extension program (treatment is ongoing for >6 years). The patient achieved a CR (determined via CT scans) 4 years after treatment initiation. Furthermore, the patient's baseline ALT and AST levels which were elevated at baseline (68 U/L and 44 U/L, respectively) normalized after 4 weeks, and her serum α-fetoprotein level, which was 47 ng/ml at baseline, declined to normal levels after 20 weeks of treatment and reached 1.3 ng/mL at time of CR. The patient experienced no treatment-related adverse events. At present (6 years from treatment initiation), the response is ongoing as shown by liver function evaluation and imaging studies. Conclusions: Treatment with namodenoson can result in a complete and long-term response. The findings support the clinical development of namodenoson as a treatment for HCC with CPB7. Clinical trial information: NCT02128958 .

Efficacy and Safety of TACE Combined with Regorafenib Plus PD-1 Inhibitor in the Treatment of Hepatocellular Carcinoma After Sorafenib Resistance.

To evaluate the efficacy and safety of TACE combined with regorafenib plus PD-1 inhibitor as a second-line therapy for hepatocellular carcinoma after sorafenib resistance. The clinical data of 76 patients with hepatocellular carcinoma who were drug-resistant to sorafenib from September 2018 to May 2022 in the tumor intervention department were collected. Among them, 35 patients used TACE combined with regorafenib plus PD-1 inhibitor (TACE-R-P) as second-line treatment, and the remaining 41 patients used TACE combined with regorafenib (TACE-R) as second-line treatment. The mRECIST (modified Response Evaluation Criteria in Solid Tumors) standard was used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes in biochemical indicators, and the adverse events (AEs) related to treatment were recorded. A total of 76 patients were included in the study, including 35 patients receiving TACE-R-P treatment and 41 patients receiving TACE-R treatment. Patients in the TACE-R-P group had longer median OS (19.7months vs 15.2months, HR:0.7716, 95% CI:0.4767-1.2490, P=0.03), longer median PFS (6.3months vs 3.8months, HR:0.6032, 95% CI:0.3727-0.9763, P=0.0029), higher objective response rate (37.14% vs 19.51%, P=0.001) and higher disease control rate (71.43% vs 48.78%, P=0.001) than those in the TACE-R group. Multivariate analysis showed that Child-Pugh grade (B/A; HR=1.283, 95% CI: 0.623-1.707, P=0.014), PVTT (Yes/No, HR=1.455, 95% CI: 0.977-2.038, P=0.018), extrahepatic metastasis (Yes/No, HR=1.766, 95% CI: 1.135-2.302, P=0.022) and treatment option (TACE-R/TACE-R-P, HR=1.930, 95% CI: 1.461-2.850, P=0.017) were independent prognostic factors for OS. There was no significant difference in the incidence and severity of AEs between the two groups. TACE-R-P treatment can be more effective than TACE-R treatment for HCC after sorafenib resistance and can be given priority as a second-line treatment for HCC.

Regorafenib combined with transarterial chemoembolization and PD-1 antibody as a second-line therapy for hepatocellular carcinoma: A real-world study.

e16167 Background: The benefits and tolerability of regorafenib combined with transarterial chemoembolization (TACE) and programmed death-1 (PD-1) antibody as a second-line therapy for advanced hepatocellular carcinoma (HCC) is unclear. We aimed to determine the efficacy and safety of regorafenib combined with TACE and PD-1 antibody as second-line treatment for advanced HCC. Methods: This study was approved by our institutional review board. In this retrospective study, a total of 55 consecutive advanced HCC patients who had tumor progression after first-line sorafenib treatment, and then treated with regorafenib plus TACE and programmed death-1 (PD-1) antibody between January 2017 and December 2020 were evaluated. The overall survival (OS), tumor response and adverse events (AEs) were analyzed. Statistical analysis was performed with the Kaplan-Meier method using the log-rank test and Cox regression models. Results: The median follow-up period was 35.5 months (range 6.0-52.0 months). The median age was 50 (range 18, 72) years. There were 49 (89.0%) males. The initial doses of regorafenib were 80 mg/d (n = 18, 32.7%) and 120 mg/d (n = 37, 67.3%). The patients underwent a median of two TACE sessions (range 1–5). The median OS after second-line treatment was 16.0 months (range 3.6-33.5 months), and the median PFS was 9.0 months (95%CI 6.1-11.7 months). According to modified RECIST criteria, complete response and partial response were found in 3 (5.5%) and 29 (45.5%) patients. The incidence of all grade 3/4 AEs was 29.6%, and the three main AEs were abdominal pain (10.9%), hypertension (7.3%) and hand-foot-skin reaction (5.5%). Two patients stopped PD-1 antibody and one stopped regorafenib due to AEs. Conclusions: Regorafenib combined with TACE and PD-1 antibody were tolerable and resulted in a promising OS and ORR in the second-line treatment of advanced HCC.

A phase I/II trial to evaluate cabozantinib in patients with advanced hepatocellular carcinoma with Child-Pugh class B cirrhosis after first-line therapy.

TPS357 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.

Cost-effectiveness of Pembrolizumab as a Second-Line Therapy for Hepatocellular Carcinoma

Immune checkpoint inhibitors have been approved for use as a second-line therapy for hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has shown substantial antitumor activity and a favorable toxicity profile as a second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both the clinical efficacy and cost. To evaluate the cost-effectiveness of pembrolizumab vs placebo as second-line therapy in patients with HCC from the US payer perspective. A Markov model was developed to compare the lifetime cost and efficacy of pembrolizumab as a second-line treatment of HCC with those of placebo using outcome data from the KEYNOTE-240 randomized placebo-controlled trial, which included 413 patients with advanced HCC previously treated with sorafenib and randomized patients to receive pembrolizumab plus best supportive care or placebo plus best supportive care in a 2:1 ratio. Life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were estimated at a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed to account for the parameter of uncertainty. A cost-threshold analysis was also performed. The study was conducted from January 31 to July 29, 2020. The base-case model found that treatment with pembrolizumab was associated with increased overall cost by $47 057 and improved effectiveness by 0.138 QALYs compared with placebo, leading to an ICER of $340 409 per QALY. The model was most sensitive to the hazard ratio of overall survival (range, 0.61-1.00), health utility of placebo (range, 0.59-0.93), price of pembrolizumab (range, $5531-$8297), and price of postprogression therapies (range, $5596-$7944 for pembrolizumab and $4770-$7156 for placebo). The ICER of pembrolizumab was larger than $150 000 per QALY in most of the sensitivity and subgroup analyses. The price of pembrolizumab needed to be reduced by 57.7% to $2925 per cycle to achieve cost-effectiveness. The findings of this cost-effectiveness analysis suggest that, at its current price, pembrolizumab is not a cost-effective second-line therapy for HCC in the US, with a willingness-to-pay threshold of $150 000 per QALY.

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

P-259 Pembrolizumab as second-line therapy of hepatocellular carcinoma: A cost-effectiveness analysis

Recently, checkpoint inhibitors have been approved for the second-line therapy of hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has demonstrated substantial anti-tumor activity and favorable toxicity profile as second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both efficacy and cost. We aimed to evaluate the cost-effectiveness of pembrolizumab vs. placebo as second-line therapy in hepatocellular carcinoma (HCC) patients from the US payer perspective.

FGF19 and Met co‐activation in murine liver induces HCC: Biological and clinical relevance

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths worldwide. While several tyrosine kinase inhibitors (TKIs) have been approved as first or second line therapy for HCC, the overall efficacy of these agents is limited. Thus, developing useful animal models may shed light on the biology of HCC tumor and provide a platform to evaluate the potential therapeutic agents. In the current study, we found about 37% HCC patients have c‐Met and FGF19 up‐regulation together in about 110 HCC patient samples from China. Concomitant expression of FGF19 and c‐Met worked synergistically to induce tumor after 13 weeks post co‐delivery of the sleeping beauty plasmids and transposase via hydrodynamic tail vein injection. H&E staining showed the tumor histology to be reminiscent of HCC. Immunochemistry staining showed that these tumors had upregulation of glycogen synthetase and cell cycle protein cyclin‐D1. Ki‐67 staining was also increased in the tumor nodule. pERK and pmTOR were also activated in the tumor areas by IHC staining. The HCC tissue was assessed by RNA‐seq and compared to normal FVB mice. Such analysis revealed alterations in about 15 KEGG pathways including MAPK, RAS, RAP1, PI3K/AKT and others. Thus, we have generated a highly relevant animal model of a subset of human HCC, which can be used to address molecular mechanisms and test targeted therapy.Support or Funding Information1R01DK62277, 1R01DK100287,1R01CA204586 and Endowed Chair for Experimental Pathology (S.P.M.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prognostic factors and disease course in patients enrolled onto clinical trials of second-line therapy for hepatocellular carcinoma.

406 Background: Prognostic factors of survival and disease course in patients with hepatocellular carcinoma (HCC) and preserved liver reserves, enrolled onto clinical trials of second-line treatments after sorafenib, are unclear. Methods: This single-center database analysis included all patients with Child-Pugh A score and ECOG performance status (PS) 0 - 1 participating between 2012 and 2017 in clinical trials of second-line systemic treatments for advanced HCC. Patients received first-line sorafenib and experienced either disease progression (PD) to sorafenib or were sorafenib-intolerant. Their clinicopathologic characteristics were correlated with overall survival (OS, calculated from the first day of second-line treatment to death or last visit available), and post-treatment survival (PTS, calculated from the date of end-of-treatment to death or last follow-up). Results: Ninety-nine patients (21 sorafenib-intolerant, 78 progressors) were enrolled onto trials of checkpoint inhibitors (CPI, 23 patients), tyrosine kinase inhibitors (TKI, 44 patients) versus best supportive care (BSC, 24 patients), open-label TKI (8 patients). Overall, median OS was 9.4 months (9.6, 9.8, and 8.0 months for CPI, TKI and BSC, respectively; p = 0.493). Median time-to-treatment failure was 3.5, 4.4, 3.7 months for CPI, TKI and BSC, respectively (p = 0.561). In multivariable analyses, worse OS was linked to high neutrophil/lymphocyte ratio (Hazard Ratio, HR = 1.13; p = 0.005) and macrovascular invasion [(MVI), HR = 2.59; p < 0.001]. Second-line treatment discontinuation due to liver failure independently conferred worse PTS than adverse events (HR = 2.32; p = 0.111) or PD (HR = 3.44; p = 0.002), as did ECOG PS > 1 at EOT (HR = 3.05; p = 0.002). Death rate within 30 days of end-of-treatment was 4.2% on placebo versus 10.5% on IO versus 22.9% on TKI. Conclusions: In this homogeneous cohort of compensated HCC patients pre-treated with sorafenib, MVI and NLR at start of second-line clinical trial are prognostic factors of OS. Besides ECOG PS and liver failure, further predictors of subsequent PTS to inform treatment options beyond second-line were not identified.

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension.

Background and AimsAngiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC.MethodsFibrosis (in vivo and in vitro), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl4, partial portal vein ligation) after acute and chronic treatment with regorafenib.ResultsLong-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed.DiscussionRegorafenib might be especially suitable as therapy in patients with PHT and preserved liver function.

Liver cancer: Regorafenib as second-line therapy in hepatocellular carcinoma.

Drug development in hepatocellular carcinoma had essentially stalled since 2008 when sorafenib was established as the modest standard of care. Now, a positive result in a phase III study evaluating regorafenib challenges us to weigh its clinical significance as well as its real-world benefits and potential harms.

RAM Fails to Improve OS as Second-Line Treatment for Hepatocellular Cancer

As second-line therapy for hepatocellular carcinoma, ramucirumab did not improve overall survival compared with placebo in a phase 3 randomized study, but benefit was observed in a selected population with an elevated baseline level of alpha-fetoprotein. The results of the randomized, phase 3 Ramucirumab Second-Line Treatment in Patients With Hepatocellular Carcinoma After First-Line Therapy With Sorafenib study [REACH; NCT01140347] are discussed in this article.

O-0009 Second Line Therapy in Hepatocellular Carcinoma (HCC): A Randomized Controlled Phase 2 Trial (RCT) with Tivantinib (ARQ 197)

ABSTRACT Introduction Tivantinib is a selective, oral inhibitor of c-MET, the tyrosine kinase receptor for hepatocyte growth factor involved in tumor cell migration, invasion, proliferation and angiogenesis. Tivantinib has shown promising results in HCC in phase 1 studies as monotherapy and in combination with sorafenib. Methods This multi-center RCT enrolled patients with: unresectable HCC, failure to 1 systemic therapy, ECOG PS Results Of 107 enrolled HCC patients, 71 received tivantinib (TA: 38 TB: 33), 36 placebo. Main characteristics of patients on tivantinib vs placebo were: 82% vs 78% male; median age 70 vs 68; PS 0 58% vs 58% VI 21% vs 36% Met+ 22 vs 15; Met- 27 vs 13; HCV+ 51% vs 39% HBV+ 23% vs 14% HBV-HCV- 34% vs 47%. TA was reduced to TB in all patients due to G > 3 neutropenia rate. Major advantage of tivantinib vs placebo was observed in Met+ patients, with median TTP: 2.7 vs 1.4 months (HR 0.43, 95% CI 0.19-0.97; P = 0.03); PFS: 2.2 vs 1.4 months (HR 0.45, 95%CI 0.21-0.95, P = 0.02); DCR (95%CI): 50% (28–72%) vs 20% (4–48%). A preliminary OS trend (HR 0.47) favoring tivantinib is being followed for updates. In ITT, tivantinib vs placebo results are: TTP: 1.6 vs 1.4 months (HR 0.64, 90%CI 0.43-0.94; P = 0.04); PFS: 1.5 vs 1.4 months (HR 0.67, 95%CI 0.44-1.04; P = 0.06); DCR (95% CI): 44% (31-56%) vs 31% (16-48%). In HCV+ patients, median TTP for patients on Tivantinib vs Placebo was: 2.7 vs 1.4 months (HR = 0.395, P = 0.012); in HBV+ patients median TTP was: 1.4 vs 1.4 (HR 1.24, P = 0.68). No relationship between cMet and viral status was observed. The most common AEs in tivantinib were asthenia (26.8%), neutropenia (25.4%), low appetite (25.4%); the most common drug-related AEs were neutropenia (25.4%), anemia (15.5%). The most frequent drug-related serious AE was neutropenic sepsis (4.2%). Efficacy was independent of dose, with less frequent G > 3 neutropenia in TB (21.1% vs 6.1%). Additional data on secondary endpoints will be presented. Conclusion Tivantinib was shown to be effective as second-line therapy in HCC when compared to placebo. This advantage is more evident in Met + patients. The safety profile of tivantinib at 240 mg BID was manageable.

Retrospective review of doxorubicin plus sorafenib as second-line therapy in hepatocellular carcinoma (HCC).

298 Background: Doxorubicin plus sorafenib has yielded an improved overall survival, progression-free-survival, and time-to-progression when compared to doxorubicin plus placebo, in the first line setting in patients with advanced HCC (Abou-Alfa, GK, et al. JAMA 2011). We explored the activity of doxorubicin and sorafenib following sorafenib failure. Methods: An IRB exemption was obtained to identify patients with HCC who were treated with doxorubicin and sorafenib after sorafenib failure. Demographic data, including age, gender, race, stage of disease, and risk factors were collected. Data were collected on treatment doses, duration, response, and adverse events including left ventricular ejection fractions (LVEF). Median progression-free survival (PFS) and overall survival (OS) were calculated from the start of combined therapy. Results: N=14 patients: Median age 60 years (range 43-70), median KPS 80%, 12 males (86%), 4 stage III (29%)/10 stage IV (71%), 8 HBV (57%) /3 HCV (21%). The median number of doxorubicin doses was 3 (range 1-11). Eight patients had grade 3-4 toxicities, including neutropenia, febrile neutropenia, thrombocytopenia, hepatitis B flare, dehydration, nausea, vomiting, mucositis, pain, and seizure. No >20% relative drops in LVEF from baseline were noted. There were no toxicity-related deaths. There were no objective responses. Of 14 evaluable patients, 5 (36%) had SD for ≥ 4 months, and 9 (64%) had POD. Median PFS was 3.4 months (95% CI 2.30-8.36), and OS 10.1 months (95% CI 4.34-11.45). Conclusions: In this small retrospective review of a select group of patients, doxorubicin plus sorafenib was tolerable, albeit with substantial toxicity. Doxorubicin and sorafenib may have activity after sorafenib failure however whether this is due to a synergy between the drugs, or to doxorubicin alone, cannot be determined from this review. A formal evaluation of doxorubicin plus sorafenib versus doxorubicin alone, versus best supportive care in the second line setting is warranted.