FOLFIRI-bevacizumab as a second-line treatment for advanced biliary tract cancer after gemcitabine-based chemotherapy

BackgroundAdvanced biliary tract cancer (BTC) has a poor prognosis. Gemcitabine with platinum chemotherapy was the standard first-line chemotherapeutic regimen until the recent addition of anti-PD-1/PD-L1 antibodies. After disease progression, the only second-line chemotherapy that has demonstrated a survival benefit versus supportive care is FOLFOX (folinic acid, fluorouracil, and oxaliplatin), with a modest benefit. This study aimed to assess the efficacy and safety of second-line FOLFIRI (folinic acid, fluorouracil, and irinotecan) combined with bevacizumab for advanced BTC.MethodsThis single-center retrospective study enrolled patients with metastatic BTC (intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma [ECC], or gallbladder carcinoma) that progressed after first-line gemcitabine-based chemotherapy. FOLFIRI-bevacizumab was administered intravenously every 2 weeks [folinic acid 200 mg/m², fluorouracil 400 mg/m² (bolus), fluorouracil 2400 mg/m² (46-h continuous intravenous infusion), irinotecan 180 mg/m², and bevacizumab 5 mg/kg] until unacceptable toxicity, patient refusal, or disease progression.ResultsOverall, 28 patients received the FOLFIRI-bevacizumab regimen after gemcitabine-based chemotherapy. The median overall survival (OS) was 9.0 months (95% CI 6.4–16.5). The OS rate was 39.3% (95% CI 24.8–62.3) and 10.7% (95% CI 3.7–32.1) at 12- and 24-months respectively. The median progression-free survival (PFS) was 5.2 months (95% CI 3.1–10.2) with FOLFIRI-bevacizumab. The PFS rates at 12 months and 24 months were 17.9% (95% CI 8.19–39.5] and 10.7% (95% CI 3.7–31.2), respectively. The overall response rate (ORR) to FOLFIRI-bevacizumab was 23.1%, with a disease control rate (DCR) of 69.3%. Grade 3-4 adverse events (sAE) were reported in 20 patients (71.4%) treated with FOLFIRI-bevacizumab.ConclusionFOLFIRI-bevacizumab as a second-line treatment for advanced BTC after gemcitabine-based chemotherapy showed efficacy and safety with a promising tumor response rate in this retrospective single-center study

Genomic Instability Is Defined by Specific Tumor Microenvironment in Ovarian Cancer: A Subgroup Analysis of AGO OVAR 12 Trial

Background: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed by carboplatin-paclitaxel chemotherapy +/− nintedanib. Methods: 103 HGSOC patients’ tumor samples from phase III AGO-OVAR-12 were analyzed. A comprehensive analysis of the TME was performed by immunohistochemistry on tissue microarray. Comparative genomic hybridization was carried out to evaluate genomic instability signatures through homologous recombination deficiency (HRD) score, genomic index, and somatic copy number alterations. The relationship between genomic instability and TME was explored. Results: Patients with high intratumoral CD3+ T lymphocytes had longer progression-free survival (32 vs. 19.6 months, p = 0.009) and overall survival (OS) (median not reached). High HLA-E expression on tumor cells was associated with a longer OS (median OS not reached vs. 52.9 months, p = 0.002). HRD profile was associated with high HLA-E expression on tumor cells and an improved OS. In the multivariate analysis, residual tumor, intratumoral CD3, and HLA-E on tumor cells were more predictive than other parameters. Conclusions: Our results suggest HLA-E/CD94-NKG2A/2C is a potential immune target particularly in the HRD positive ovarian carcinoma subgroup

Etude du microenvironnement tumoral des cancers de l’ovaire en fonction de l’instabilité génomique

Ovarian cancers have a poor prognosis and their management is based on surgery and medical treatment with chemotherapy and targeted therapy. PARP inhibitors have significantly improved the prognosis of these cancers over the last decade. On the other hand, immunotherapy, which is revolutionizing the management of many cancers, has not been shown to be effective in ovarian cancer. We have shown that genomic instability signatures have an interesting prognostic impact. The combined use of several signatures improved the prognostic value. Secondly, we demonstrated that the immune infiltrate within the tumor is different according to the genetic profile of the tumor. Thus, HRD positive tumors frequently present an over expression of HLA-E. This provides a potential rationale for the use of anti NKG2A therapy in these tumors. Finally, we have shown with the IMMUNOPARP trial that the use of PARP inhibitors in patients treated for ovarian cancer, acting on the genetics of the tumor, could modify the immune populations in the blood and in particular the T lymphocyte functionality. All these data reinforce the rationale for combining PARP inhibitors with immunotherapy. The phase II GUIDE2REPAIR trial, evaluating the combination of olaparib durvalumab tremelimumab in patients with a homologous recombination gene mutation who have responded to treatment with olaparib alone, will allow us to validate the data and to continue investigations on this treatment strategy.Les cancers de l’ovaire sont des cancers de mauvais pronostics dont la prise en charge est basée sur une chirurgie et un traitement médical par chimiothérapies et thérapie ciblées. Les inhibiteurs de PARP ont permis d’améliorer très significativement le pronostic de ces cancers lors de la dernière décennie. A contrario, l’immunothérapie qui révolutionne la prise en charge de nombreux cancers n’a pas montré d’efficacité dans les cancers de l’ovaire. Nous avons montré que les signatures d’instabilité génomique avaient un impact pronostique intéressant. L’utilisation combinée de plusieurs signatures améliorait la valeur pronostique. Ensuite, nous avons mis en évidence que l’infiltrat immunitaire au sein de la tumeur est différent selon le profil génétique de la tumeur. Ainsi les tumeurs HRD positives présentent fréquemment une sur expression d’HLA-E. Ceci apporte un rationnel potentiel à l’utilisation de traitement anti NKG2A dans ces tumeurs. Enfin, nous avons montré avec l’étude IMMUNOPARP que l’utilisation d’inhibiteurs de PARP chez des patientes traitées pour un cancer de l’ovaire, agissant sur la génétique de la tumeur, pouvait modifier les populations immunitaires dans le sang et en particulier la fonctionnalité lymphocytaire T. L’ensemble de ces données renforce le rationnel d’association des inhibiteurs de PARP avec l’immunothérapie. La mise en place de l’étude GUIDE2REPAIR, évaluant l’association olaparib durvalumab tremelimumab chez des patients avec une mutation d’un gène de la recombinaison homologue et ayant répondu à un traitement par olaparib seul, permettra de valider les données et de poursuivre les investigations sur cette stratégie de traitement

Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts

International audienceTreatment with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) can generate durable responses in various cancer types, but only in a subset of patients. The use of predictive biomarkers for response to PD-1/PD-L1 inhibitors is critical for patient selection. Expression of PD-L1 has demonstrated utility in patient selection. Tumour mutational burden (TMB) is an emerging biomarker for response to PD-1/PD-L1 inhibitors. The evaluation of this biomarker is based on the hypothesis that a high number of mutations in somatic exonic regions will lead to an increase in neoantigen production, which could then be recognised by CD8+ T cells, resulting in improved immune responses. In this review, we will discuss rationale and implementation of TMB usage in patients, development of different methods to assess it, current limitations and technical issues to use this biomarker as a diagnostic test and propose future perspectives beyond TMB

Bevacizumab-based Chemotherapy for Poorly-differentiated Neuroendocrine Tumors

IF 1.865 (2018)International audienceAIM:To assess and report the efficacy of and tolerance to bevacizumab-based chemotherapy in treatment outcome of metastatic poorly differentiated neuroendocrine tumors.PATIENTS AND METHODS:From 2007 to 2018, 11 consecutive patients with metastatic poorly differentiated neuroendocrine treated in first- or second-line with bevacizumab-based chemotherapies were included in this monocentric retrospective cohort. Tumor response was evaluated by computed tomographic scans.RESULTS:Administered treatment included 5-fluorouracil and irinotecan (FOLFIRI) bevacizumab, 5-fluorouracil and oxaliplatin (FOLFOX) bevacizumab and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) bevacizumab for four, two and five patients, respectively. Three were treated in first-line and eight in second-line after cisplatin-etoposide regimen. Using Response Evaluation Criteria in Solid Tumors, partial response was observed for seven patients, and stable disease for one patient, giving a response rate of 63.6% (95% confidence interval=35.2-92.1%) and disease control rate of 72.7% (95% confidence interval=46.6-99.0%). All patients had died by the time of analysis, median progression-free survival was 14 months, and median overall survival was 15.3 months. Observed toxicity with such protocols was classical with 10 grade 3-4 toxic events, including three of hematological toxicity, three of infection, and three of digestive toxicity.CONCLUSION:Bevacizumab-based chemotherapy gave surprising efficacy and safety in first-or second-line treatment for metastatic poorly differentiated neuroendocrine tumor in this retrospective cohort. Prospective randomized trials of such therapy are warranted.Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved

Successfully treatment by eribulin in visceral crisis: a case of lymphangitic carcinomatosis from metastatic breast cancer

Abstract Background Metastatic breast cancer (MBC) rest an incurably disease associated with bad prognosis and a median overall survival of 23–31 months. There are several treatment options including chemotherapy and sometimes endocrine therapy. Currently, there is no standard treatment for patients with MBC who have already benefited from anthracyclines and taxanes therapy. Many drugs like capecitabine, eribulin, gemcitabine, vinorelbin and liposomal doxorubicin are conventionally used as monotherapy. One important complication from MBC is life threating visceral crisis that needs a fast-effective treatment. Case presentation We report here a case of an evolution of metastatic breast cancer with lymphangitic carcinomatosis after taxane based chemotherapy and endocrine therapy. This 37-year-old woman was referred to our hospital with complaints of dyspnea and dry cough. There was clinical concern for visceral crisis and a chemotherapy with eribulin was initiated. Pulmonary lymphangitic carcinomatosis disappeared and the patient achieved a good partial response. Conclusion We reported a case of rapid, positive treatment response using eribulin on metastatic breast cancer with visceral crisis and we could quoted others. Therefore, eribulin may be an appropriate chemotherapeutic option in instances requiring rapid symptom control

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

International audience5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy