Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). Patients and methods:We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression.Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)].Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.Key words: cetuximab, colorectal cancer, EGFR, KRAS, survival introduction A recent advance in oncology is the targeting of the epidermal growth factor receptor (EGFR) in the treatment of many tumor types. Cetuximab (CTX) (ErbituxÒ, Merck KGaA, Darmstadt, Germany) is a chimeric immunoglobulin G1 monoclonal antibody which binds the EGFR with high affinity and competitively inhibits ligand binding [1]. This prevents activation of downstream signalling pathways such as the PI3K/ Akt, RAS/Erk and STAT pathways, resulting in the inhibition of cellular proliferation and in the induction of apoptosis. However, for many tumor types including metastatic colorectal cancer (mCRC), it is not clear what proportion of tumors are dependent on EGFR signalling for their survival, nor how additional molecular alterations present in the tumor may influence primary or secondary resistance to EGFR inhibitors. CTX is approved for irinotecan-resistant mCRC expressing EGFR by immunohistochemistry (IHC). Response rates in this group however only amount to 23% in combination with chemotherapy and about 10% in monotherapy [2,3]. Increased response rates in the combination arm did not translate into increased survival. As yet no clinical or molecular markers are available to identify those patients with a longer overall survival (OS). Predictive markers of response and survival benefit after CTX are urgently required to allow the rational and effective use of these drugs.In a small series, Lièvre et al. [4] have shown objective response (OR) to CTX to be excluded in KRAS-mutated CRC and most importantly, showed an increase in OS for the KRAS wild-type (WT) patients. We retrospectively studied the ability of KRAS mutations and tumo...

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[FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. RESULTS: Forty-six patients were randomly assigned and 44 were eligible for analy... Document type : Article de périodique (Journal article)Référence bibliographique A B S T R A C T PurposeLiver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the ␤-emitting isotope yttrium-90 ( 90 Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues. Patients and MethodsWe conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m 2 days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m 2 days 1 through 14 then 300 mg/m 2 days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. ResultsForty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n ϭ 23; arm B, n ϭ 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] ϭ 0.38; 95% CI, 0.20 to 0.72; P ϭ .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR ϭ 0.51; 95% CI, 0.28 to 0.94; P ϭ .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P ϭ .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR ϭ 0.92; 95% CI, 0.47 to 1.78; P ϭ .80). Conclusion Radioembolization with90 Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.

BackgroundNext-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA.MethodsThis multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks.ResultsTwenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04–9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%).ConclusionDerazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).

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Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN z2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of a variety of agents, including small inhibitory molecules and monoclonal antibodies (mAb). Two such mAbs, panitumumab and cetuximab, are active in metastatic colorectal cancer, but only subgroups of patients respond to these agents (1 -3) and reliable markers predictive of treatment benefit still need to be defined.Variations of gene copy numbers (GCN), either in terms of gains or losses, reflect the many different routes taken by individual tumors to disrupt/escape mechanisms governing normal cellular behavior. These genomic aberrations have been successfully investigated by fluorescence in situ hybridization (FISH) in a number of malignancies. Importantly, three recently published series have reported on enhanced sensitivity to anti-EGFR mAbs in colorectal cancer patients harboring an increase of mean EGFR GCN by FISH (4 -6). In most solid tumors, including non -small-cell lung cancer and colorectal cancer, the best characterized mechanisms underlying increased EGFR GCN are gene amplification and chromosome 7 polysomy (4 -7). Generally, amplification is representative of high-level genomic gain and it is readily identifiable by FISH. Conversely, polysomy mirrors variable degrees of chromosomal ga...