Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial.

OBJECTIVE: The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system. DESIGN: A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values. OUTCOME MEASURES: The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted. RESULTS: The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively. CONCLUSIONS: This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.

Long Term Efficacy and Assessment of Tumor Response of Transarterial Chemoembolization in Neuroendocrine Liver Metastases: A 15-Year Monocentric Experience.

BACKGROUND: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival. METHODS: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003-2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTLP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan-Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS. RESULTS: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90-139 months). Median TTLP and TTUP were 19.3 months (95%CI 16.3-22.3) and 26.2 months (95%CI 22.3-33.1), respectively. Median OS was 5.3 years (95%CI 4.2-6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6-89.8) than in non-responders (39.6 months; 95%CI = 32.8-60.2; p < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS. CONCLUSION: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.

[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]. / Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects.

BACKGROUND: The identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment. METHODS: One hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds. RESULTS: At baseline, median CTC count was 1 (range, 0-415). While CTCs ≥1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs ≥2 were the optimal threshold, on D0 or D28. CTCs ≥2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003). CONCLUSION: Quantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold ≥2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient.

Prognostic value of health-related quality of life in patients with metastatic pancreatic adenocarcinoma: a random forest methodology.

PURPOSE: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is currently an important parameter in the choice of treatment strategy for metastatic pancreatic adenocarcinoma (mPA) patients. However, previous research has shown that patients' self-reported health-related quality of life (HRQOL) scales provided additional prognostic information in homogeneous groups of patients with respect to ECOG-PS. The aim of this study was to identify HRQOL scales with independent prognostic value in mPA and to propose prognostic groups for these patients. METHODS: We analysed data from 98 chemotherapy-naive patients with histologically proven mPA recruited from 2007 to 2011 in the FIRGEM phase II study which aimed to compare the effectiveness of two chemotherapy regimen. HRQOL data were assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. A random survival forest methodology was used to impute missing data and to identify major prognostic factors for overall survival. RESULTS: Baseline HRQOL assessment was completed by 60 % of patients (59/98). Twelve prognostic variables were identified. The three most important prognostic variables were fatigue, appetite loss, and role functioning, followed by three laboratory variables. The model's discriminative power assessed by Harrell's C statistic was 0.65. Fatigue score explained almost all the survival variability. CONCLUSION: HRQOL scores have prognostic value for mPA patients with good ECOG-PS. Moreover, the patient's fatigue, appetite loss, and self-perception of daily activities were more reliable prognostic indicators than clinical and laboratory variables. These HRQOL scores, especially the fatigue symptom, should be urgently included for prognostic assessment of mPA patients (with good ECOG-PS).

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.

PURPOSE: The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. RESULTS: The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). CONCLUSION: A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.