A. Hollebecque

Systemic treatment of advanced hepatocellular carcinoma: From disillusions to new horizons

Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomised trials.

A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma

SummaryBackground The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. Methods This first-in-man, single-center, open-label, phase I dose-escalation study (3u2009+u20093 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma. EMD 534085 (starting dose 2xa0mg/m2/day) was administered intravenously every 3xa0weeks. Doses were escalated in 100xa0% steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50xa0% until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25xa0%. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients. Results Forty-four patients received EMD 534085. Median treatment duration was 43xa0days (range, 21–337). Thirty-eight patients (86xa0%) received ≥2xa0cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135xa0mg/m2/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135xa0mg/m2/day). The maximum tolerated dose (MTD) was 108xa0mg/m2/day. The most common treatment-related adverse events were asthenia (50xa0%) and neutropenia (32xa0%). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52xa0%). Conclusions EMD 534085 appeared to be well tolerated; MTD was 108xa0mg/m2/day. Preliminary antitumor results suggested limited activity in monotherapy.

Prospective validation of a prognostic score for patients in immunotherapy phase I trials: The Gustave Roussy Immune Score (GRIm-Score).

INTRODUCTIONnLife expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT.nnnPATIENTS AND METHODSnWe conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score.nnnRESULTSnA total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.05-2.86) and LDHxa0>xa0upper limit normal (ULN) (HR 1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR)xa0>xa06 (HR 1.75, 95% CI 1.04-2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51-1.35). A risk score based on the results of the MVA (NLRxa0>xa06xa0=xa01; LDHxa0>xa0ULNxa0=xa01; albuminxa0<xa035xa0g/lxa0=xa01) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50-83.7) (HR 2.9, 95% CI 1.87-4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7-14.8).nnnCONCLUSIONnIn ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patients prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials.