Molecular therapies for HCC: Looking outside the box

Summary Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC

Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib.

BackgroundTransforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib.MethodsThis phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored.ResultsThe study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036).ConclusionsConsistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results

A phase II multicentre, open-label, proof-of-concept study of tasquinimod in hepatocellular, ovarian, renal cell, and gastric cancers

Background: Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors. Patients and Methods: This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment. Results: Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%). Conclusions: This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer. Trial registration: NCT01743469

Ten questions about antiangiogenic in hepatocellular carcinoma

La validation du sorafenib dans le carcinome hépatocellulaire (CHC) avancé a permis un progrès majeur dans la prise en charge des patients atteints de cette maladie et a entraîné un déferlement d’investigations portant sur des agents ciblés dans cette pathologie. Un concept important est que la tolérance et l’efficacité de cet agent reposent sur une sélection optimale des patients. Cependant, plusieurs questions pertinentes restent non résolues concernant l’utilisation du sorafenib en routine clinique. En effet, si le sorafenib a permis une amélioration significative de la survie globale des patients atteints d’un CHC avancé sur cirrhose Child A comparativement au placebo, ceci contraste avec de faibles taux de réponse obtenus par cette molécule selon les critères RECIST. Ainsi, de nouveaux paramètres intégrant des modifications de densité intratumorale pourraient être pris en compte en plus des critères dimensionnels pour juger de l’efficacité objective de cette drogue. Actuellement, les recherches en cours doivent définir la place des antiangiogéniques en association avec les autres approches thérapeutiques et identifier des biomarqueurs fiables prédictifs de réponse.The recent approval of sorafenib for advanced hepatocellular carcinoma (HCC) has been a breakthrough for patient care and has led to a flurry of clinical studies in HCC. Undeniably, patient selection is a crucial issue for treatment tolerance and efficacy. Routine clinical practice raised several important questions. Even if sorafenib showed a clear improvement in overall survival, minimal responses by traditional RECIST criteria were observed. Beside dimensional measurement, new parameters including intratumor density are requested for appropriate evaluation. Finally, future researches integrate antiangiogenic agents in combination with other approaches and identify reliable predictive biomarkers of response

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confi rmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratifi ed by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fl uorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defi ned retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identifi cation of patients and treatment. This trial is registered with ClinicalTrials. gov, number NCT00460265. Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11.1 months (95% CI 9.8-12.2) in the panitumumab group and 9.0 months (8.1-11.2) in the control group (hazard ratio [HR] 0.873, 95% CI 0.729-1.046; p = 0.1403). Median progression-free survival was 5.8 months (95% CI 5.6-6.6) in the panitumumab group and 4.6 months (4.1-5.4) in the control group (HR 0.780, 95% CI 0.659-0.922; p = 0.0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7-13.7] vs 8.6 months [6.9-11.1]; HR 0.73 [95% CI 0.58-0.93]; p = 0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3-12.9] vs 12.6 months [7.7-17.4]; 1.00 [0.62-1.61]; p = 0.998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0.70 [95% CI 0.47-1.04]). Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings

Update on novel antiangiogenic compounds

Les antiangiogéniques de 2e génération sont, pour la majorité, des inhibiteurs de récepteurs tyrosine-kinase membranaires dont nous retenons, dans cet article, les composés ayant atteint les phases II ou III randomisées. Leur rôle consiste, soit à améliorer la puissance d’inhibition sur des cibles déjà validées (VEGFR, PDGFR, KIT), soit à étendre leur spectre d’inhibition envers des cibles supplémentaires telles que FGFR, RET ou EGFR. En dehors de leurs propriétés sur le plan biologique, les chances de succès de ces nouveaux composés reposent également sur le choix judicieux des pathologies auxquelles ils s’adresseront.The second generation of antiangiogenics mainly includes membrane tyrosine kinase receptor inhibitors. This chapter summarizes clinical results of compounds that reached phase II and/or randomized phase III clinical trials. The aims of these agents are to improve the inhibition on validated targets (VEGFR, PDGFR, KIT) or to enlarge the spectrum of inhibition toward additional targets including FGFR, RET or EGFR. Beside intrinsic biological properties, the selection of appropriate disease appears critical to ensure future success in the development of those novel compounds

Mushrooms Red Book of Ukraine in Culture. 1. Patterns of Growth Hericium coralloides

На території НПП «Гуцульщина» виявлено лише три локалітети Hericium coralloides – гриба, занесеного до Червоної книги України. У результаті проведених досліджень виділено в чисту культуру аборигенний штам К01. Як для виділення, так і для підтримки та забезпечення життєздатності гриба в культурі картопельно-глюкозний агар виявився оптимальним серед апробованих середовищ. Індивідуальні особливості росту H. coralloides К01 вказують на вузькі трофічні можливості цього штаму при поверхневому культивуванні, оскільки з п’яти апробованих середовищ придатними для росту виявилися лише два. Цей штам гриба вважаємо перспективним для використання як інокулянта відповідних субстратів у природному середовищі, оскільки для нього характерні високі показники радіального росту, короткий період log-фази та утворення в чистій культурі стадії телеоморфи. The national park «Hutsulshchyna» found only three localities of Hericium coralloides − mushroom Red Book of Ukraine. The result of the research was to obtain in a pure culture of the native strain K01. As for the release, and to support and ensure the viability of the fungus in culture potato - glucose agar was the best among the tested environments. Individual features of the growth of H. coralloides K01 indicate the narrow trophic features of this strain at cultivation because from five tested media suitable for growth were only two. This strain K01 H. coralloides may be considered promising for use as an inoculant respective substrates in the environment , because it is characterized by high rates of radial growth , a short period of log- phase and ability to form stage teleomorfy in pure culture.Роботу виконано у НПП «Гуцульщина», ННЦ «Інститут біології» КНУ ім. Т. Шевченк