Deborah Lehrer

PURPOSE: To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay. RESULTS: The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma. CONCLUSION: We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.

Abstract Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells. Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood. Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (<grade 2). In the patient with clinical benefit, IHC analysis of tumor showed increased CD4, CD8, PD1, and PD-L1 levels compared with patients with progressive disease. RNA-seq analysis of the same patient's tumor and peripheral blood mononuclear cells showed dramatic changes in response to poly-ICLC treatment, including upregulation of genes associated with chemokine activity, T-cell activation, and antigen presentation. Conclusions: Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). Clin Cancer Res; 24(20); 4937–48. ©2018 AACR.

4144 Background: HCC is a vascular tumor in which angiogenesis contributes to pathogenesis. VEGF-inhibition has not been previously attempted in cirrhosis or HCC. Methods: We enrolled patients with unresectable HCC to treatment with bevacizumab at 5 mg/kg or 10 mg/kg every 14 days to assess safety and preliminary efficacy. Inclusion criteria were BR < 3.0 mg/dl, transaminases 75K and PT within 4 seconds of normal. Additional criteria included no history of myocardial infarction, stroke, or condition requiring ongoing antiplatelet or antithrombotic therapy. Results: Initial safety assessments for patients treated for at least 8 weeks indicate that 10 of 11 patients treated at 5 mg/kg and 7 of 8 patients treated at 10mg/kg tolerated therapy with acceptable toxicity. Of the first 28 patients treated at either dose, four have had therapy discontinued because of adverse events (including one grade 3 transient ischemic attack). Three patients had serious esophageal bleeding which was likely secondary to progression of HCC and liver disease (although contribution of drug to these events cannot be excluded). The protocol has been modified to identify and treat esophageal varices prior to enrollment. Other toxicities have included grade 2 fatigue, abdominal pain, gastric ulcer, hypertension, hyperbilirubinemia, rash and proteinuria and grade 1 gingivitis, diarrhea, vomiting and epistaxis. Of the initial 25 patients evaluable for efficacy, 5 had progressive disease within 16 weeks. Two patients had PR and 18 had SD. Median time-to-progression was 6.5 months (range 3.9–24.2). Nineteen of 25 (76%) patients had HCC that progressed following transplant, surgery, RFA or embolization procedures. Conclusions: Bevacizumab can be given safely at both 5 mg/kg and 10 mg/kg in HCC patients with localized, unresectable HCC, preserved liver function and no significant esophageal varices. Preliminary results suggest significant disease-modifying effect (80% disease-control rate); median time-to-progression to-date has exceeded 6-months. [Table: see text]

Abstract Learning Objectives After completing this course, the reader will be able to: Identify the etiologic factors contributing to the increasing incidence of hepatocellular carcinoma in the U.S.Explain the rationale for antiangiogenic therapeutic strategies in the treatment of hepatocellular carcinoma.Describe the clinical features associated with a particularly poor prognosis in unresectable hepatocellular carcinoma. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Purpose. To evaluate thalidomide in advanced hepatocellular carcinoma (HCC) and to evaluate combined thalidomide and low-dose interferon-α2a (IFN-α2a) after tumor progression on thalidomide. Systemic therapy is minimally effective in HCC and tumor angiogenesis is a potential therapeutic target. Patients and Methods. Patients with unresectable HCC were eligible if they had preserved hepatic and renal function. The initial thalidomide dosage was 200 mg daily and was adjusted for toxicity. Upon progression, patients could continue thalidomide with additional low-dosage (one million units twice daily) IFN-α2a. Results. Thirty-eight enrolled patients were predominantly hepatitis C virus infected (53%), Child-Pugh class A (79%), and Eastern Cooperative Oncology Group performance status 0–1 (92%); 60% had extrahepatic metastasis. Confirmed disease control was seen in seven patients (18%) and included one complete and one partial response (5% response rate). The median progression-free survival was 2.1 months, and median overall survival was 5.5 months. Tumor invasion of the portal vein or vena cava, large (>10 cm) tumor, and younger age were associated with shorter overall survival. Toxicity included fatigue in 74% of patients. Six patients stopped therapy because of side effects, including two patients (5%) with grade 4 arteriothrombotic events. Five patients continued thalidomide upon progression with the addition of IFN-α2a; there was no disease control and 80% had grade 3 toxicity. Conclusions. Thalidomide is not well tolerated and confers limited disease control in advanced HCC. Combination thalidomide and low-dose IFN-α2a is neither safe nor efficacious in this population.

4122 Bevacizumab in hepatocellular carcinoma (HCC) in patients without metastasis and without invasion of the portal vein Background: HCC is a vascular tumor; angiogenesis contributes to pathogenesis. Bevacizumab (anti-VEGF) delays progression in colon cancer and its effect may be dose-dependent. VEGF-inhibition has not been previously attempted in cirrhosis. Methods: We enrolled patients with unresectable HCC to bevacizumab at 5mg/kg or 10mg/kg every 14 days to assess safety and preliminary efficacy. Inclusion criteria were BR < 3.0mg/dl, transaminases 75K and PT within 4 seconds of normal. Additional criteria included no history of gastrointestinal bleed, myocardial infarction, stroke, or condition requiring antiplatelet or antithrombotic therapy. Results: An initial safety assessment indicates that 10 of 11 patients treated for at least 8 weeks tolerated bevacizumab at 5mg/kg with minimal toxicity. Two patients had serious esophageal bleeding which was likely secondary to progression of HCC and liver disease (although contribution of drug to these events cannot be excluded). The protocol has been modified to identify and treat esophageal varices prior to enrollment. Three patients treated at 10mg/kg have undergone at least 8 weeks of therapy with minimal toxicity (grade 1 fatigue, abdominal pain and diarrhea). For the first 13 patients evaluable for efficacy, 11 have had confirmed response or stability. Two patients had disease progression at less than 4 months. Two patients had partial responses, one with eventual progression at 11.3 months. For the 9 patients with stable disease, 6 had eventual progression at 5.5, 6.5, 6.5, 6.7, 7.2, and 7.6 months. Three others have ongoing stability at 3.5+, 3.9+, and 12.7+ months. At least four of the patients with confirmed response/stability had documented rapidly-progressing disease in the months before receiving therapy. Conclusions: Bevacizumab can be given safely at both 5mg/kg and 10mg/kg in HCC patients with localized, unresectable HCC, preserved liver function and no significant esophageal varices. Preliminary results suggest significant disease-modifying effect, including 6+ month stability in patients with prior rapid growth. No significant financial relationships to disclose.