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Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Incyte Corporation.

Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7–15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11–39]). Grade 3–4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. F Hoffmann-La Roche–Genentech.

The limited performance of guideline‐recommended abdominal ultrasound and serum alpha‐fetoprotein (AFP) highlights the urgent, unmet need for new biomarkers for more accurate detection of early hepatocellular carcinoma (HCC). To this end, we have conducted a prospective clinical validation study to evaluate the performance of the HelioLiver Test, a multi‐analyte blood test combining cell‐free DNA methylation patterns, clinical variables, and protein tumor markers. A blinded, multicenter validation study was performed with 247 subjects, including 122 subjects with HCC and 125 control subjects with chronic liver disease. The performance of the HelioLiver Test was compared with AFP and the GALAD score as established HCC surveillance blood tests. The performance of the HelioLiver Test (area under the receiver operating characteristic curve [AUROC] = 0.944) was superior to both AFP (AUROC = 0.851; p < 0.0001) and GALAD (AUROC = 0.899; p < 0.0001). Using a prespecified diagnostic algorithm, the HelioLiver Test showed sensitivities of 85% (95% confidence interval [CI], 78%–90%) for HCC of any stage and 76% (95% CI, 60%–87%) for early stage (American Joint Committee on Cancer [AJCC] I and II) HCC. In contrast, AFP (≥20 ng/mL) alone and the GALAD score (≥−0.63) showed lower sensitivities of 62% (95% CI, 54%–70%) and 75% (95% CI, 67%‐82%) for HCC overall, and 57% (95% CI, 40%–71%) and 65% (95% CI, 49%–79%) for early stage (AJCC I and II) HCC, respectively. The specificities of the HelioLiver Test (91%; 95% CI, 85%–95%), AFP (97%; 95% CI, 92%–99%), and the GALAD score (94%; 95% CI, 88%–97%) were similar for control subjects. The HelioLiver Test showed superior performance for HCC detection compared to with both AFP and the GALAD score and warrants further evaluation in HCC surveillance settings. The limited performance of guideline‐recommended abdominal ultrasound and serum alpha‐fetoprotein (AFP) highlights the urgent, unmet need for new biomarkers for more accurate detection of early hepatocellular carcinoma (HCC). To this end, we have conducted a prospective clinical validation study to evaluate the performance of the HelioLiver Test, a multi‐analyte blood test combining cell‐free DNA (cfDNA) methylation patterns, clinical variables, and protein tumor markers. The HelioLiver Test showed superior peformacne for HCC detection compared to both AFP and the GALAD score and warrants further evaluation in HCC surveillance settings.

Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno‐oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3–5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.

Background Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)‐β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF‐targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). Methods This is a multicenter, open‐label, phase 1b study of galunisertib, an inhibitor of TGF‐β receptor 1, and ramucirumab, an anti‐VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha‐fetoprotein and TGF‐β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1–14 of a 28‐day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. Results Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose‐limiting toxicities were observed. Treatment‐related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment‐related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose‐proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. Conclusion Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF‐targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab. The combination of galunisertib (up to 150 mg twice as day) and ramucirumab 8 mg/kg intravenously every 2 weeks (standard dose) was safe and tolerable and displayed favorable pharmacokinetics in patients with advanced hepatocellular carcinoma. The results do not support the preclinical hypothesis that blocking transforming growth factor‐beta signaling enhances efficacy of VEGF‐targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Agios Pharmaceuticals.

The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin. This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete. Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7–18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6–8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2–1·5; hazard ratio 0·56, 95% CI 0·39–0·81; p=0·0019). The most common grade 3–4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths. Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer. Servier and HK inno.N For the Korean translation of the abstract see Supplementary Materials section.

Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.

Background Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low‐energy electromagnetic fields (EMFs) can influence cell biological processes via non‐thermal effects and may represent a new treatment option. Methods This single‐site feasibility trial enrolled patients with advanced HCC, Child‐Pugh A and B, Eastern Cooperative Oncology Group 0–2. Patients underwent 90‐min amplitude‐modulated EMF exposure procedures every 2–4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health‐related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. Results Sixty‐six patients with advanced HCC received 539 AutEMdev procedures (median follow‐up, 30 months). No serious adverse events occurred during procedures. Self‐limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude‐modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). Conclusion AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti‐tumor efficacy. NCT01686412.

Cholangiocarcinoma is an aggressive malignancy with poor overall survival. Approximately 15% of intrahepatic cholangiocarcinomas contain FGFR alterations. Infigratinib is an oral FGFR 1–3 kinase inhibitor. Favorable results from a Phase II trial of infigratinib in advanced/metastatic FGFR-altered cholangiocarcinomas has led to its further investigation in the front-line setting. In this article we describe the design, objectives and rationale for PROOF 301, a Phase III multicenter, open label, randomized trial of infigratinib in comparison to standard of care gemcitabine and cisplatin in advanced/metastatic cholangiocarcinoma with FGFR2 translocations. The results of this study have the potential to define a new role for a chemotherapy-free, targeted therapy option in the front-line setting for these patients. Clinical Trial Registration: NCT03773302 (ClincalTrials.gov)