Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar–plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426.)

Purpose: This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients. Methods: Patients with inoperable HCC, no prior systemic treatment, and Child–Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients. Results: Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand–foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished “nonprogressors” from “progressors” with an estimated 100% accuracy. Conclusion: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

Purpose:: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Methods: Matched tumor/normal DNA from HCC patients (N=127) were analyzed using a hybridization capture-based, NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/β-catenin pathway (45%) and TP53 (35%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib treated patients (N=81), oncogenic PI3K-MTOR pathway alterations were associated with lower disease control rates (DCR, 8.3 vs. 40.2%), shorter median PFS (1.9 vs 5.3 months) and OS (10.4 vs 17.9 months). For patients treated with immune checkpoint inhibitors (N=31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0 vs 53%), shorter median PFS (2.0 vs 7.4 months) and OS (9.1 vs 15.2 months). 24% of patients harbored potentially actionable alterations including TSC1/2 (8.5%)inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). 6% of patients treated with systemic therapy were matched to targeted therapeutics. Conclusion: Linking NGS to routine clinical care has the potential to identify those HCC patients likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations. Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients. Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154–61. ©2018 AACR.

PURPOSE: To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population. RESULTS: Nine phase III randomized controlled trials met the inclusion criteria. RECOMMENDATIONS: Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .