Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression.

BACKGROUND: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2). RESULTS: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%). CONCLUSIONS: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenib pretreated aHCC with MET overexpression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02115373.

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer.

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.

Lay abstract Many patients with metastatic colorectal cancer need a sequence of different treatments over time. Regorafenib and trifluridine/tipiracil (also called TAS-102) are two drugs which are both used late in this sequence of treatments, but there is no rule as to which should be used first. Both drugs have very different mechanisms of action, and it might be beneficial to patients to administer them both at the same time as a combination treatment, instead of sequential treatment. We therefore conducted a Phase Ib study with a small number of patients to investigate whether this combined treatment would be feasible and safe. The study was designed to test the drug combination at different doses, and we found that treatment with trifluridine/tipiracil at 25 mg/m² twice daily combined with regorafenib at 120 mg daily had acceptable side effects and is likely to be safe for use in future clinical trials. Efficacy results suggest that combined treatment with both drugs may extend patient's life span. However, these observations are preliminary and need testing in further clinical trials. Clinical trial registration: EudraCT 2016-001968-11; NCT03305913 (ClinicalTrials.gov).

Poor Prognosis of Advanced Cholangiocarcinoma: Real-World Data from a Tertiary Referral Center.

BACKGROUND: Incidence of cholangiocarcinoma (CCA) in western countries is rising. In the palliative setting, chemotherapy is the only established treatment. The evidence for other treatments including locoregional therapy is low. However, such individual treatments are offered in a real-world setting. The aim of this study is to document the offered treatments and to analyze the survival of patients with unresectable CCA treated at a tertiary referral center. PATIENTS AND METHODS: Data from 220 consecutive patients with CCA treated at a German university cancer center from January 1, 2008, until December 31, 2012. Of those, 105 patients were unresectable. Survival curves were calculated according to the Kaplan-Meier method; log-rank test was applied for survival analysis. RESULTS: Any palliative treatment was beneficial for patients with unresectable CCA when compared to best supportive care (BSC) alone; median OS with BSC was 10 weeks (BSC vs. transarterial chemoembolization [TACE] p = 0.017, HR 0.36; BSC vs. TACE/chemotherapy p < 0.001, HR 0.24; BSC vs. chemotherapy p < 0.001, HR 0.31). Combination of TACE and chemotherapy prolonged overall survival as compared to TACE alone (105 vs. 43 weeks, p = 0.045). CONCLUSION: Prognosis in advanced stage CCA is still very poor. However, multimodal treatment in palliative patients significantly prolong survival.

Established and Potential Predictive Biomarkers in Gastrointestinal Cancer--c-Kit, Her2, Ras and Beyond.

BACKGROUND: Gastrointestinal cancers are among the leading causes of cancer-related deaths worldwide. In different tumor types, personalized systemic treatment strategies based upon biomarker-selection were established over the last years. Although there is a flood of targeted agents in clinical development, only a few targeted agents with a predictive biomarker could be established for the treatment of patients with gastrointestinal cancer patients so far. SUMMARY: Currently, predictive biomarkers for gastrointestinal cancers include Her2 overexpression or amplification (gastroesophageal adenocarcinoma), c-Kit overexpression (gastrointestinal stromal tumors) and RAS wild-type (colorectal cancer). Selection of patients based on these biomarkers allows the efficient use of targeted agents. The presence of a BRAF mutation and/or high microsatellite instability is prognostic and rather a predictive marker in CRC. Promising candidate markers in advanced clinical development are MET amplification in gastroesophageal adenocarcinoma, Met overexpression and high AFP serum levels in hepatocellular carcinoma. KEY MESSAGE: Biomarker-guided systemic treatment is established in a subset of patients with gastrointestinal cancer. Ongoing clinical trials and further advances in high-throughput technologies will hopefully result in more personalized systemic treatment strategies for these patients in the near future.

Capnographic monitoring of propofol-based sedation during colonoscopy.

BACKGROUND AND STUDY AIMS: Capnography enables the measurement of end-tidal CO2 and thereby the early detection of apnea, prompting immediate intervention to restore ventilation. Studies have shown that capnographic monitoring is associated with a reduction of hypoxemia during sedation for endoscopy and early detection of apnea during sedation for colonoscopy. The primary aim of this prospective randomized study was to evaluate whether capnographic monitoring without tracheal intubation reduces hypoxemia during propofol-based sedation in patients undergoing colonoscopy. PATIENTS AND METHODS: A total of 533 patients presenting for colonoscopy at two study sites were randomized to either standard monitoring (n = 266) or to standard monitoring with capnography (n = 267). The incidence of hypoxemia (SO2 < 90 %) and severe hypoxemia (SO2 < 85 %) were compared between the groups. Furthermore, risk factors for hypoxemia were evaluated, and sedation performed by anesthesiologists was compared with nurse-administered propofol sedation (NAPS) or endoscopist-directed sedation (EDS). RESULTS: The incidence of hypoxemia was significantly lower in patients with capnography monitoring compared with those receiving standard monitoring (18 % vs. 32 %; P  = 0.00091). Independent risk factors for hypoxemia were age (P = 0.00015), high body mass index (P = 0.0044), history of sleep apnea (P = 0.025), standard monitoring group (P = 0.000069), total dose of propofol (P = 0.031), and dose of ketamine (P < 0.000001). Patients receiving anesthesiologist-administered sedation developed hypoxemic events more often than those receiving NAPS or EDS. In patients with anesthesiologist-administered sedation, sedation was deeper, a combination of sedative medication (propofol, midazolam and/or ketamine) was administered significantly more often, and sedative doses were significantly higher compared with patients receiving NAPS or EDS.  CONCLUSIONS: In patients undergoing colonoscopy during propofol-based sedation capnography monitoring with a simple and inexpensive device reduced the incidence of hypoxemia.

Recurrent hepatocellular carcinoma after liver transplantation - an emerging clinical challenge.

In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.

An interstitial deletion at 3p21.3 results in the genetic fusion of MLH1 and ITGA9 in a Lynch syndrome family.

PURPOSE: Germline mutations in DNA mismatch repair genes, mainly MLH1 or MSH2, have been shown to predispose with high penetrance for the development of the clinical phenotype of hereditary nonpolyposis colorectal cancer (Lynch syndrome). Here, we describe the discovery and first functional characterization of a novel germline MLH1 mutant allele. EXPERIMENTAL DESIGN: A large kindred including 54 potential carriers was investigated at the molecular level by using different types of PCR experiments, gene cloning, transfection studies, Western blot experiments, and mismatch repair assays to identify and characterize a novel MLH1 mutant allele. Twenty-two of 54 putative carriers developed colon cancer or other tumors, including breast cancer. RESULTS: The identified MLH1 mutant allele emerged from an interstitial deletion on chromosome 3p21.3, leading to an in-frame fusion of MLH1 (exons 1-11) with ITGA9 (integrin alpha 9; exons 17-28). The deleted area has a size of about 400 kb; codes for LRRFIP2 (leucine-rich repeat in flightless interaction protein 2), GOLGA4 (Golgi autoantigen, golgin subfamily a, 4), and C3orf35/APRG1 (chromosome 3 open reading frame 35/AP20 region protein 1); and partly disrupts the AP20 region implicated in major epithelial malignancies. Tumor cells lost their second MLH1 allele. The MLH1*ITGA9 fusion protein provides no capability for DNA mismatch repair. Murine fibroblasts, expressing a doxycycline-inducible MLH1*ITGA9 fusion gene, exhibit a loss-of-contact inhibition phenotype. CONCLUSIONS: This is the first description of a functional gene fusion of the human MLH1 gene, resulting in the loss of mismatch repair capabilities. The MLH1*ITGA9 fusion allele, together with deletions of the AP20 region, presumably defines a novel subclass of Lynch syndrome patients, which results in an extended tumor spectrum known from hereditary nonpolyposis colorectal cancer and Muir-Torre syndrome patients.

Adenoma development in a patient with MUTYH-associated polyposis (MAP): new insights into the natural course of polyp development.

PURPOSE: Biallelic germ-line mutations in MUTYH have recently been found to predispose for MUTYH-associated polyposis (MAP). Affected patients present with a wide range of clinical phenotypes at the time of diagnosis, but there is little precise information about the natural course of this disease. RESULTS: Fourteen years of colonoscopic surveillance of an MAP patient (compound heterozygous p.Y165C/p.G382D) showed that adenoma development was slow after initial diagnosis of a single colorectal carcinoma at the age of 44, but then the annual number of new adenomas increased substantially in the patient's early fifties. CONCLUSION: This course of the disease, with a strong subsequent acceleration of polyp development, may explain the wide range of polyp numbers counted in newly diagnosed MAP patients as a result of the time of observation. Therefore, MAP should also be considered in younger patients (35-55 years) with only few adenomas or colorectal cancer. The high frequency of medium and severe dysplasia in the patient's preferential small adenomas suggests accelerated progression from adenoma to carcinoma in MAP, but this observation must be confirmed by further studies.

Contrast-enhanced ultrasound in the diagnosis of malignant mesenchymal liver tumors.

PURPOSE: Contrast-enhanced ultrasound can differentiate malignant from benign hepatic tumors, but has not been studied in malignant mesenchymal liver tumors. METHODS: We describe the findings of contrast-enhanced ultrasound in a cohort of five patients with histological-proven malignant hepatic mesenchymal tumors. RESULTS: The presence of imaging features such as peripheral (nodular) enhancement, chaotic central vascularization, and absence of contrast enhancement in the late phase allowed differentiation from hemangiomas. CONCLUSIONS: If these findings are demonstrated in large hepatic tumors, then the diagnosis of hemangioma is unlikely and further workup is necessary.

Photochemical internalization and gemcitabine combined with first-line chemotherapy in perihilar cholangiocarcinoma: observations in three patients.

Photochemical internalization (PCI) is a technology to induce a localized, intracellular enhancement of therapeutics that are processed through endosomal pathways, including gemcitabine in malignant cells. In addition to a direct phototoxic and tumoricidal effect, PCI specifically disrupts endosomal membranes and, thereby, the compartmentalization of certain cytotoxic compounds to enhance a drug's intended intracellular target reach within the tissue treated. Non-resectable extrahepatic cholangiocarcinoma (eCCA) is a common primary tumor and gemcitabine/cisplatin chemotherapy is widely considered standard of care for it. PCI is well suited as an endoscopic intervention, and clinical observations in three subjects participating in a phase I/IIa dose escalation safety trial are described. The trial included patients with perihilar, non-resectable CCA suitable for standard-of-care chemotherapy. Per protocol, a single endoscopic PCI procedure with gemcitabine was conducted at the initiation of standard gemcitabine/cisplatin therapy. Sixteen patients enrolled in the initial dose escalation phase of the trial, which later was extended to explore the safety of a second PCI procedure during chemotherapy. While limited to a case series, the various clinical observations described here serve to illustrate the effects of localized, perihilar tumor targeting in appropriate patients by any safe methodology, including PCI. As previously indicated by clinical data using other localized treatment modalities, adding a directed, tumor-targeting treatment to systemic therapy to ameliorate the progressively expanding extrahepatic tumor burden can have important effects on the overall outcome of systemic treatment in many patients who have incurable eCCA.

First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7-not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.

Nivolumab for the treatment of hepatocellular carcinoma.

INTRODUCTION: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.

Bevacizumab-based first-line chemotherapy in elderly patients with metastatic colorectal cancer: an individual patient data based meta-analysis.

BACKGROUND: The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients (≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials. RESULTS: Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70-88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials. MATERIALS AND METHODS: PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age. CONCLUSIONS: This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.

Thymosin beta 4 expression and nuclear transport are regulated by hMLH1.

For hMLH1, a key enzyme of DNA mismatch repair and frequently mutated in human cancers, several additional functions have been suggested. We now identified Thymosin beta4 (Tbeta4), an actin-binding and cell motility regulating protein, by bacterial two-hybrid screening. Interaction was confirmed by coimmunoprecipitation. Tbeta4 was weakly expressed in the hMLH1-deficient cell lines 293T and HCT-116. Reconstitution of hMLH1 resulted in strong expression of Tbeta4. Confocal laser microscopy revealed nuclear colocalization of both proteins. Reconstitution with hMLH1 mutants lacking a functional nuclear localization sequence resulted in cytoplasmatic retention of both proteins. After Tbeta4- or hMLH1-siRNA treatment, cell migration of hMLH1-proficient cells was markedly decreased. Our results show that hMLH1 interacts with Tbeta4 and regulates its expression and nuclear transport. Moreover, loss of hMLH1 causes Tbeta4 deprivation and results in reduced migratory activity in vitro. These data give insight into novel functions of hMLH1 and probably disease related dysregulated mechanisms.