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BACKGROUND & AIMS: In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; durvalumab was noninferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or nonviral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan. METHODS: In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per Response Evaluation Criteria in Solid Tumors, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan. RESULTS: The Asian subgroup included 479 participants randomised to STRIDE (n=156), durvalumab (n=167), or sorafenib (n=156). OS was improved for STRIDE vs. sorafenib (HR 0.68; 95% CI 0.52-0.89]). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n=141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%). CONCLUSIONS: STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including the Asia-Pacific region. CLINICAL TRIAL NUMBER: NCT03298451 IMPACT AND IMPLICATIONS: The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS, vs. sorafenib, and that durvalumab monotherapy was noninferior to sorafenib in participants with unresectable hepatocellular carcinoma (uHCC). However, there are differences in the aetiology and clinical practices related to HCC in parts of Asia, compared to Western countries and Japan, which could lead to differences in treatment outcomes between these regions. The results of this analysis demonstrate the benefits of STRIDE for participants in the Asia-Pacific region, consistent with the full, global study population. Overall, these findings continue to support the use of STRIDE in a diverse population, reflective of uHCC globally.
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BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Sorafenib/uso terapéuticoRESUMEN
BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nivolumab/uso terapéutico , Sorafenib/uso terapéutico , Anciano , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/psicología , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/psicología , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Sorafenib/efectos adversosRESUMEN
BACKGROUND: This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). RESULTS: In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. CONCLUSIONS: Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. TRIAL REGISTRATION: ClinicalTrials.gov NCT01988493.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Piperidinas/administración & dosificación , Proteínas Proto-Oncogénicas c-met/genética , Piridazinas/administración & dosificación , Pirimidinas/administración & dosificación , Sorafenib/administración & dosificación , Regulación hacia Arriba , Administración Oral , Adulto , Anciano , Pueblo Asiatico/genética , Carcinoma Hepatocelular/genética , Esquema de Medicación , Femenino , Humanos , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Piridazinas/efectos adversos , Pirimidinas/efectos adversos , Sorafenib/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly. METHODS: In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models. RESULTS: Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib. CONCLUSIONS: Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
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Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/administración & dosificación , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Sorafenib/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Proton beam radiotherapy (PBT) has recently been applied to treat hepatocellular carcinoma (HCC); however, there is no randomized controlled trial-based evidence on its safety and efficacy. We compared the outcomes of PBT and radiofrequency ablation (RFA) in patients with recurrent/residual HCC (rHCC) in a phase III non-inferiority trial. METHODS: Patients with rHCC (size <3 cm, number ≤2) were randomly assigned to receive PBT or RFA according to Child-Pugh score and tumor stage. After randomization, if the assigned treatment was technically infeasible, crossover was allowed. The primary endpoint was 2-year local progression-free survival (LPFS), with a non-inferiority margin of 15% in the per-protocol (PP) population; a complementary analysis was performed in the intention-to-treat (ITT) population (NCT01963429). RESULTS: The ITT population comprised 144 patients receiving either PBT (n = 72) or RFA (n = 72). Six patients switched from the PBT arm to the RFA arm and 19 patients switched from the RFA arm to the PBT arm. In the PP population, the 2-year LPFS rate with PBT (n = 80) vs. RFA (n = 56) was 94.8% vs. 83.9%, a difference of 10.9 percentage points (90% CI 1.8-20.0; p <0.001); in the ITT population, the 2-year LPFS rate with PBT vs. RFA was 92.8% vs. 83.2%, a difference of 9.6 percentage points (90% CI 0.7-18.4; p <0.001), meeting the criteria for non-inferiority. The 3- and 4-year LPFS rates for PBT were also non-inferior to those for RFA. The most common adverse events were radiation pneumonitis (32.5%) and decreased leukocyte counts (23.8%) for PBT and increased alanine aminotransferase levels (96.4%) and abdominal pain (30.4%) for RFA. No Grade 4 adverse events or mortality were noted. CONCLUSIONS: PBT showed LPFS values that were non-inferior to those for RFA; in addition, PBT was tolerable and safe. CLINICAL TRIAL NUMBER: #NCT01963429 (ClinicalTrials.gov). LAY SUMMARY: Radiofrequency ablation is the standard of care for patients with small hepatocellular carcinoma in whom surgery is not feasible. This study is the first phase III randomized controlled trial to evaluate the clinical outcomes of proton beam radiotherapy vs. radiofrequency ablation in patients with recurrent small HCC. Our findings show that this new technique is not inferior and can be applied safely in patients with small recurrent hepatocellular carcinoma.
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Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Terapia de Protones/efectos adversos , Ablación por Radiofrecuencia/efectos adversos , Dolor Abdominal/etiología , Anciano , Alanina Transaminasa/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/epidemiología , Femenino , Humanos , Recuento de Leucocitos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Neumonitis por Radiación/etiología , República de Corea/epidemiologíaRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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 .).
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/efectos adversos , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Piridinas/efectos adversosRESUMEN
BACKGROUND AND AIM: The aim of this study was to evaluate whether presence of varices on computed tomography (CT) could predict treatment outcome for hepatocellular carcinoma patients. METHODS: We enrolled 241 patients with single hepatocellular carcinoma ≤ 5 cm treated by surgery. With the use of preoperative CT/endoscopy, patients were classified into the following: presence of standard clinically significant portal hypertension (CSPH) surrogate, defined as varices on esophagogastroduodenoscopy and/or thrombocytopenia with splenomegaly (group 1, n = 47); varices on CT without standard CSPH surrogate (group 2, n = 45); and none of both (group 3, n = 149). Development of posthepatectomy liver failure and overall survival (OS) were evaluated for each patient group, and patients were re-classified into two groups according to presence of CT-enhanced CSPH surrogate, defined as standard surrogate and/or varices on CT. Predictive power of each survival model was compared using Harrell's C-index. RESULTS: Posthepatectomy liver failure rate in group 2 was similar to that in group 1 (53.3% [24/45] vs. 55.3% [26/47]; P = 1.000) but significantly higher than that in group 3 (53.3% [24/45] vs. 28.2% [42/149], P = 0.002). Seven-year OS rates in group 2 were similar to those in group 1 (55.6% vs. 60.8%, P = 0.988) but significantly lower than those in group 3 (55.6% vs. 83.3%, P = 0.001). Presence of standard CSPH surrogate (hazard ratio = 1.89 [1.08-3.30], P = 0.025) and CT-enhanced CSPH surrogate (hazard ratio = 2.60 [1.56-4.39], P < 0.001) were significant predicting factor for OS. However, CT-enhanced CSPH surrogate had significantly higher Harrell's C-index than standard surrogate (0.619 vs. 0.553, P = 0.034). CONCLUSION: The presence of CT-enhanced CSPH surrogate including varices on CT was the significant predictive of poor OS, providing better predictive power than standard surrogate.
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Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Várices Esofágicas y Gástricas/diagnóstico por imagen , Hepatectomía/mortalidad , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Tomografía Computarizada por Rayos X/métodos , Anciano , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER: NCT01658878.
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Biomarcadores Farmacológicos/análisis , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nivolumab , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígenos CD/análisis , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Antígenos CD8/análisis , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Monitoreo de Drogas/métodos , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunohistoquímica , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Factor de Transcripción STAT1/análisis , Análisis de Supervivencia , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
2-Aryl/alkylbenzofurans, which constitute an important subclass of naturally occurring lignans and neolignans, have attracted extensive synthetic efforts due to their useful biological activities and significant pharmacological potential. Herein, we report a general and efficient approach to divergent 2-arylbenzofurans through a one-pot synthesis of versatile 2-bromobenzofurans as key intermediates. Using this approach, the first total synthesis of a series of trisubstituted and tetrasubstituted benzofurans bearing the hydroxyethyl unit, including the natural compounds isolated from Lavandula agustifolia (1-3) and their non-natural derivatives (4-8), was accomplished. We also report a modified synthesis of ailanthoidol, homoegonol, and egonol that enables the divergent synthesis of their derivatives for future exploration. Among these, the representative phenolic natural compound 2 and its derivatives 7 and 5 induced apoptotic cell death related poly(ADP-ribose) polymerase (PARP) cleavage in MCF74, A549, PC3, HepG2, and Hep3B cancer cell lines. Additionally, the tumor suppressor protein p53 was also induced in p53 wild type cancer cells.
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Anisoles/química , Benzofuranos/síntesis química , Benzofuranos/farmacología , Lavandula/química , Anisoles/farmacología , Benzofuranos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclización , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Oxidación-Reducción , Análisis Espectral/métodosRESUMEN
OBJECTIVE: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN: Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION: In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER: NCT00692770.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/patología , Sorafenib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Adhesión del Tejido , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. METHODS: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, nâ¯=â¯169) or in combination with cTACE on demand (Arm C, nâ¯=â¯170). Sorafenib was started within 3â¯days and cTACE within 7-21â¯days of randomization. The primary endpoint was overall survival (OS). RESULTS: For Arms C and S, the median OS was 12.8 vs. 10.8â¯months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; pâ¯=â¯0.290); median time to progression, 5.3 vs. 3.5â¯months (HR 0.67; 90% CI 0.53-0.85; pâ¯=â¯0.003); median progression-free survival, 5.2 vs. 3.6â¯months (HR 0.73; 90% CI 0.59-0.91; pâ¯=â¯0.01); and tumor response rate, 60.6% vs. 47.3% (pâ¯=â¯0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (pâ¯=â¯0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8â¯months; HR 0.58; 95% CI 0.40-0.82; pâ¯=â¯0.006). CONCLUSION: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. LAY SUMMARY: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , Anciano , Alanina Transaminasa/sangre , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ascitis/etiología , Quimioembolización Terapéutica/efectos adversos , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hiperbilirrubinemia/etiología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Sorafenib/administración & dosificación , Sorafenib/efectos adversos , Trombocitopenia/etiologíaRESUMEN
BACKGROUND: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING: Eisai Inc.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Anciano , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Sorafenib , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Background The pivotal RESORCE trial showed that regorafenib was effective as second-line therapy for patients with advanced HCC who progressed on first-line sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Methods Between April 2017 and August 2017, the Named Patient Program (NPP) was activated to provide controlled, pre-approval access of regorafenib in Korea. This analysis is a multicenter retrospective study of patients who received regorafenib under the NPP. Results A total of 49 patients entered into this NPP, and 40 patients received regorafenib in five Korean institutions. All but one patient received regorafenib as second-line therapy after progression on sorafenib, and 36 (90%) and 34 (85%) patients were classified as Child-Pugh A and BCLC stage C, respectively. The response rate was 10% (n = 4). The median progression-free survival (PFS) was 3.7 months (95% CI, 2.5-4.9 months), and the median overall survival (OS) was not reached. The 1 year OS rate was 54.6%. The time-to-progression (TTP) on prior sorafenib was significantly associated with PFS and OS. The most common grade 3-4 toxicities were hand-foot skin reaction (n = 3, 8%), hypertension (n = 2, 5%), and increased aspartate aminotransferase (n = 2, 5%). Conclusion Regorafenib was well-tolerated and effective in patients with advanced HCC who progressed on first-line sorafenib, with efficacy and safety outcomes consistent with those of the previous RESORCE trial. TTP on first-line sorafenib may predict the efficacy of subsequent regorafenib.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Peritoneales/secundario , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , República de Corea , Estudios Retrospectivos , Sorafenib/administración & dosificación , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
CpG-DNA activates the host immune system to resist bacterial infections. In this study, we examined the protective effect of CpG-DNA in mice against Escherichia coli (E. coli) K1 infection. Administration of CpG-DNA increased the survival of mice after E. coli K1 infection, which reduces the numbers of bacteria in the organs. Pre-injection of mice with CpG-DNA before E. coli K1 infection increased the levels of the complement C3 but not C3a and C3b. The survival of the mice after E. coli K1 infection was significantly decreased when the mice were pre-injected with the cobra venom factor (CVF) removing the complement compared to the non-CVF-treated mice group. It suggests that the complement has protective roles against E. coli K1 infection. In addition, the survival of complement-depleted mice was increased by CpG-DNA pre-administration before E. coli K1 infection. Therefore, we suggest that CpG-DNA enhances the anti-bacterial activity of the immune system by augmenting the levels of complement systems after E. coli K1 infection and triggering other factors as well. Further studies are required to investigate the functional roles of the CpG-DNA-induced complement regulation and other factors against urgent bacterial infection.
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Antibacterianos/farmacología , Proteínas del Sistema Complemento/efectos de los fármacos , Proteínas del Sistema Complemento/inmunología , Factores Inmunológicos/farmacología , Oligodesoxirribonucleótidos/farmacología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Activación de Complemento/efectos de los fármacos , Activación de Complemento/inmunología , Escherichia coli/efectos de los fármacos , Escherichia coli/inmunología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/química , Infusiones Parenterales , Ratones , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/química , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunologíaRESUMEN
Prophylactic antiviral therapy is recommended for hepatitis B virus (HBV)-infected patients with malignancies who are undergoing systemic chemotherapy. In the current study, we aimed to develop a risk scoring system to guide the selection of prophylactic antiviral agents. In this retrospective analysis, we included consecutive chronic hepatitis B patients who received antiviral prophylaxis for chemotherapy of solid or hematologic malignancies at three large-volume hospitals in Korea. The primary endpoint was HBV reactivation. The inverse probability treatment weighting method was used to minimize selection bias in terms of antiviral assignments. A total of 419 patients were enrolled: 129 patients received lamivudine (LAM), 216 received telbivudine (LdT), and 74 received entecavir (ETV), respectively. Of these, 36 patients developed on-treatment HBV reactivation (LAM, 17; LdT, 18; ETV, 1). Multivariate analysis identified three independent predictors for reactivation: hepatitis B e-antigen positivity, HBV DNA level, and type of malignancy. Accordingly, a risk scoring system was developed wherein one point was assigned for each of the risk factors. HBV reactivation occurred more frequently in the high-risk group (score ≥ 2) than in the low-risk group (hazards ratio, 14.17; P < 0.001). ETV exhibited superior prophylactic efficacy over LdT or LAM in the high-risk group, whereas no significant difference was noted in the low-risk group. The prognostic scoring system was useful for risk stratification of chemotherapy-related HBV reactivation. High genetic barrier agents appear to be vital for high-risk patients, whereas cost-effectiveness may be more relevant for low-risk patients.
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Antineoplásicos/uso terapéutico , Antivirales/administración & dosificación , Técnicas de Apoyo para la Decisión , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Activación Viral , Adulto , Anciano , Pueblo Asiatico , Quimioprevención/métodos , ADN Viral/sangre , Quimioterapia , Femenino , Antígenos e de la Hepatitis B/sangre , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , República de Corea , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS. METHODS: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. RESULTS: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months). CONCLUSIONS: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. LAY SUMMARY: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. CLINICAL TRIAL NUMBER: NCT00825955.
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Alanina/análogos & derivados , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alanina/uso terapéutico , Biomarcadores , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
BACKGROUND AND AIM: Most prognostic models for hepatocellular carcinoma are based on data at the time of diagnosis. However, the disease frequently recurs or progresses after initial treatment, with changes in tumor burden and clinical status. Therefore, we developed a risk score model to predict survival of hepatocellular carcinoma patients at the time of disease recurrence or progression. METHODS: Of 1972 patients newly diagnosed with hepatocellular carcinoma at the National Cancer Center, Korea, between January 2004 and December 2009, 1301 with recurrent or progressive disease were enrolled. They were randomly classified into a development (75%, n = 976) and a validation cohort (25%, n = 325). A survival prediction method was established in the development cohort using the multivariate Cox proportional hazards model, and its performance was evaluated on the validation cohort. RESULTS: A model predicting survival of patients with recurrent or progressive hepatocellular carcinoma was developed using some known independent prognostic factors for overall survival: age, albumin, Model for End-Stage Liver Disease score, tumor burden, serum alpha-fetoprotein level, and presence of ascites. In addition, initial treatment modality and best response after initial treatment were also independent prognostic factors and were incorporated in the model. The C-statistics and χ2 statistics of this novel score for the validation cohort were 0.808 (95% CI: 0.781-0.834) and 4.408 for 3-year survival. CONCLUSIONS: A new model to predict survival of patients with recurrent or progressive hepatocellular carcinoma was developed and validated. This model may be useful for planning subsequent treatments.
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Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/mortalidad , Modelos de Riesgos Proporcionales , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Predicción , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , República de Corea/epidemiología , Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND & AIMS: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).