Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma.

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

[Computational medical imaging (radiomics) and potential for immuno-oncology]. / Imagerie médicale computationnelle (radiomique) et potentiel en immuno-oncologie.

The arrival of immunotherapy has profoundly changed the management of multiple cancers, obtaining unexpected tumour responses. However, until now, the majority of patients do not respond to these new treatments. The identification of biomarkers to determine precociously responding patients is a major challenge. Computational medical imaging (also known as radiomics) is a promising and rapidly growing discipline. This new approach consists in the analysis of high-dimensional data extracted from medical imaging, to further describe tumour phenotypes. This approach has the advantages of being non-invasive, capable of evaluating the tumour and its microenvironment in their entirety, thus characterising spatial heterogeneity, and being easily repeatable over time. The end goal of radiomics is to determine imaging biomarkers as decision support tools for clinical practice and to facilitate better understanding of cancer biology, allowing the assessment of the changes throughout the evolution of the disease and the therapeutic sequence. This review will develop the process of computational imaging analysis and present its potential in immuno-oncology.

Promises and challenges for the implementation of computational medical imaging (radiomics) in oncology.

Medical image processing and analysis (also known as Radiomics) is a rapidly growing discipline that maps digital medical images into quantitative data, with the end goal of generating imaging biomarkers as decision support tools for clinical practice. The use of imaging data from routine clinical work-up has tremendous potential in improving cancer care by heightening understanding of tumor biology and aiding in the implementation of precision medicine. As a noninvasive method of assessing the tumor and its microenvironment in their entirety, radiomics allows the evaluation and monitoring of tumor characteristics such as temporal and spatial heterogeneity. One can observe a rapid increase in the number of computational medical imaging publications-milestones that have highlighted the utility of imaging biomarkers in oncology. Nevertheless, the use of radiomics as clinical biomarkers still necessitates amelioration and standardization in order to achieve routine clinical adoption. This Review addresses the critical issues to ensure the proper development of radiomics as a biomarker and facilitate its implementation in clinical practice.

Impact of centralization on aCGH-based genomic profiles for precision medicine in oncology.

BACKGROUND: Comparative genomic hybridization (CGH) arrays are increasingly used in personalized medicine programs to identify gene copy number aberrations (CNAs) that may be used to guide clinical decisions made during molecular tumor boards. However, analytical processes such as the centralization step may profoundly affect CGH array results and therefore may adversely affect outcomes in the precision medicine context. PATIENTS AND METHODS: The effect of three different centralization methods: median, maximum peak, alternative peak, were evaluated on three datasets: (i) the NCI60 cell lines panel, (ii) the Cancer Cell Line Encyclopedia (CCLE) panel, and (iii) the patients enrolled in prospective molecular screening trials (SAFIR-01 n = 283, MOSCATO-01 n = 309), and compared with karyotyping, drug sensitivity, and patient-drug matching, respectively. RESULTS: Using the NCI60 cell lines panel, the profiles generated by the alternative peak method were significantly closer to the cell karyotypes than those generated by the other centralization strategies (P < 0.05). Using the CCLE dataset, selected genes (ERBB2, EGFR) were better or equally correlated to the IC50 of their companion drug (lapatinib, erlotinib), when applying the alternative centralization. Finally, focusing on 24 actionable genes, we observed as many as 7.1% (SAFIR-01) and 6.8% (MOSCATO-01) of patients originally not oriented to a specific treatment, but who could have been proposed a treatment based on the alternative peak centralization method. CONCLUSION: The centralization method substantially affects the call detection of CGH profiles and may thus impact precision medicine approaches. Among the three methods described, the alternative peak method addresses limitations associated with existing approaches.

[Management of the cardiovascular complications of treatment in thoracic oncology]. / Prise en charge des complications cardiovasculaires des traitements en oncologie thoracique.

The management of patients suffering from bronchial and lung tumors depends on conventional chemotherapy and/or targeted molecular therapies. The prescription of these chemotherapies may be accompanied by cardiovascular complications, principally congestive heart failure, arterial hypertension and arterial or venous thrombo-embolism, the frequency of which varies with the molecule administered. The management of these complications is currently poorly standardized and should take account of the patient's oncological prognosis.

[Pharmacological targeting of Mdm2: rationale and perspectives for radiosensitization]. / Ciblage pharmacologique de Mdm2 : bases biologiques et perspectives de radiosensibilisation.

The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities.

FOLFIRI chemotherapy in patients with advanced non resectable esophageal or junctional adenocarcinoma: a pilot study.

In this prospective pilot study, we assessed the efficacy and safety of the FOLFIRI regimen (irinotecan 180 mg/m², leucovorin 200 mg/m² d1 followed by bolus 400 mg/m² 5-fluorouracil (5-FU) and by a 46-h 2400 mg/m² 5-FU infusion, every 2 weeks) in patients with advanced esophageal or junctional adenocarcinoma. Twenty-nine patients were included. A complete response was obtained in 2 patients, a partial response in 7 patients (objective response rate 31.0%). Stable disease was obtained in 13 patients (disease control rate 75.9%). The median progression-free and overall survivals were 5.9 and 8.6 months, respectively. One patient died from chemotherapy-related diarrhea after one cycle but this patient presented concomitant disease progression with cerebral metastases. We observed one additional grade 4 diarrhea, one grade 3 vomiting, and two grade 3 neutropenias. To conclude, FOLFIRI regimen appears quite active, with an acceptable safety profile in patients with advanced esophageal or junctional adenocarcinoma.

[Clinical equipoise and randomised clinical trials in oncology]. / Equipoise clinique et études cliniques randomisées en cancérologie.

We had defined, discussed and illustrated the principle of clinical equipoise that ethically and methodologically justifies the randomisation in clinical trials.

[Prognostic and predictive factors of soft tissue sarcoma: a daily use of translational research]. / Facteurs pronostiques et prédictifs des sarcomes des tissus mous : application concrète de la recherche translationnelle.

Soft-tissue sarcoma is a heterogeneous group of diseases. Prognostic factors for local recurrence, metastatic recurrence, and overall survival are different and optimal treatment strategies need to take them into account.