Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage ...disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha‐fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro‐proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are the historical and current uses of AFP for screening and surveillance, diagnosis, its utility as a prognostic and predictive biomarker and its role as a tumour antigen in HCC. Taken together, these data demonstrate the relevance of AFP for patients with HCC and identify several remaining questions that will benefit from future research.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Summary Background Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that ...induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov , NCT00749502. Findings Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients 48%), nausea (42 42%), fatigue (42 42%), thrombocytopenia (35 35%), anorexia (26 26%), neutropenia (24 24%), constipation (23 23%), and vomiting (20 20%), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% 95% CI 19–64) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% 7–93) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding Merck Sharp and Dohme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly ...selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer.
We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine–tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine–tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting.
Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3–6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7–8·2) in the fruquintinib group versus 4·8 months (4·0–5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55–0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 14%), asthenia (n=35 8%), and hand-foot syndrome (n=29 6%). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group).
Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population.
HUTCHMED.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus ...TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer.
Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety.
Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation.
PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).
Introduction.
Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone ...deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo.
Patients and Methods.
Eight patients with low‐grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression.
Results.
Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40‐fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated.
Conclusion.
VPA activates Notch1 signaling in vivo and may have a role in treating low‐grade NETs.
摘要
引言.研究已证实Notch1对神经内分泌肿瘤（NET）具有肿瘤抑制作用。既往在NET细胞系中进行的体外研究已显示，组蛋白去乙酰化酶抑制剂丙戊酸（VPA）可激活Notch1，而Notch1的激活与NET的肿瘤标志物降低有关。因此，本研究旨在评价VPA在NET治疗中的作用，并确定在体内VPA是否诱发Notch信号通路传递信号。
患者与方法.8例低度恶性NET（类癌和胰腺）患者接受口服VPA500 mg一天2次治疗，调整剂量至VPA水平维持在50~ 100 μg/mL。对所有患者随访12个月或直至疾病进展。
结果.治疗前所有肿瘤均不存在Notch1信号传递，而VPA可上调Notch1信号传递。1例患者获得不确定的部分缓解，Notch1 mRNA水平增加40倍。4例患者获得的最佳反应是疾病稳定。7例患者中有5例肿瘤标志物改善。采用VPA治疗总体耐受良好。
结论. VPA在体内激活Notch1信号传递，可能在低度恶性的NET的治疗中发挥作用。
Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors. Previous in vitro studies in neuroendocrine tumor cell lines have also suggested that valproic acid, a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for neuroendocrine tumors. This study showed that valproic acid activates Notch1 signaling in vivo and may have a role in treating low‐grade neuroendocrine tumors.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background & Aims
Radiological progression patterns to first‐line sorafenib have been associated with post‐progression and overall survival in advanced hepatocellular carcinoma, but these ...associations remain unknown for therapies in second‐ and later‐line settings. This post hoc analysis of REACH and REACH‐2 examined outcomes by radiological progression patterns in the second‐line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo.
Methods
Patients with advanced hepatocellular carcinoma, Child‐Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion including new macrovascular invasion, new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH‐2 and REACH (alpha‐fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post‐progression survival.
Results
Post‐progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51‐3.60), REACH‐2 (HR 1.49, 95% CI 0.72‐3.08) and the pooled population (HR 1.75, 95% CI 1.12‐2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39‐0.80) in the pooled population.
Conclusions
The emergence of new extrahepatic lesions in the second‐line setting is a poor prognostic factor for post‐progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The cover image is based on the Review Article Biology and Significance of Alpha‐Fetoprotein in Hepatocellular Carcinoma by Peter Robert Galle, Masatoshi Kudo, Friedrich Foerster et al., ...https://doi.org/10.1111/liv.14223
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Purpose
GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation ...study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295.
Patients and methods
Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m
2
. GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.
Results
A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m
2
. Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (
n
= 2, 5%), increased AST (
n
= 1, 2.5%), hypokalemia (
n
= 1, 2.5%), and hypoxia (
n
= 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (
n
= 13; 33%). Gastrointestinal toxicities of diarrhea (
n
= 12, 31%), nausea (
n
= 8, 21%), and vomiting (
n
= 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m
2
and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9–11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m
2
dose level.
Conclusions
The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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