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Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

ABSTRACT: Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.

SUBMITTER: Recondo G

PROVIDER: S-EPMC7478969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimThe Gustave Roussy Immune Score (GRIm-Score) was originally designed to select cancer patients for immunotherapy, and later was reported to be a novel prognostic scoring system in lung cancer and esophageal cancer. This study was aimed to determine the prognostic role and predictive performance of GRIm-Score in colorectal cancer (CRC) CRC patients.MethodsWe conducted a single-institution study of 1,579 adult CRC patients receiving surgical removal, and those patients were divided into low GRIm-Score group (scores 0, 1) and high GRIm-Score group (scores 2, 3). Propensity score matching (PSM) was executed to balance the potential confounding factors between the two groups. Survival and time-dependent receiver operating characteristic (Td-ROC) analyses were applied to depict the prognostic role and predictive significance of GRIm-Score in CRC patients.ResultsThere were 200 cases CRC patients in high GRIm-Score group and 1,379 cases in low GRIm-Score group. CRC patients with high GRIm-Score correspond with higher level of CEA, CA125, and inflammatory indexes, such as NLR, PLR, SII, PNI, and ALRI. Correlation analysis exhibited that GRIm-Score correlated well with the established inflammatory indexes. Survival analysis revealed that CRC patients in high GRIm-Score group showed worse overall survival (OS, P <0.0001) and disease-free survival (DFS, P <0.0001) compared with those in low GRIm-Score group. Results from multivariate Cox regression implicated that high GRIm-Score was not only a potent prognostic index for unfavorable OS (HR = 1.622, 95%CI: 1.118-2.355, P = 0.0109), but also a potent risk factor for worse DFS (HR = 1.743, 95%CI: 1.188-2.558, P = 0.0045). Td-ROC analysis demonstrated that GRIm-Score exhibited the superior discriminatory power in the prediction of OS and DFS when compared to SII, PNI, and ALRI. Such strong associations between high levels of preoperative GRIm-Score and unfavorable survival outcomes remained robust after PSM analysis.ConclusionGRIm-Score, a novel inflammatory and nutritional risk scoring system, is a potent prognostic index in CRC patients receiving surgical removal. GRIm-Score can be used as an effective and simplified risk stratification tool for postoperative survival prediction of CRC patients.

Project description:The Gustave Roussy Immune (GRIm)-Score takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic value has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the prognostic and predictive value of baseline GRIm-Score (GRImT0) in advanced non-small cell lung cancer (aNSCLC) patients, we separately investigated two cohorts of patients treated with first-line pembrolizumab or chemotherapy. We also investigated whether GRIm-Score at 45 days since treatment initiation (GRImT1) and GRIm-Score difference between the two timepoints may better predict clinical outcomes (GRImΔ = GRImT0 - GRImT1). We retrospectively evaluated 222 aNSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy as the first-line regimen. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-Score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dL. Patients with a GRIm-Score < 2 were considered as having a low Score. In both cohorts, no difference in terms of overall survival (OS) between patients with low and high GRImT0 was found. Otherwise, median OS and progression free survival (PFS) of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, p = 0.004; median PFS 10.8 vs. 2.3 months, p = 0.002). Patients receiving pembrolizumab with stable/positive GRImΔ had better OS (median OS not reached vs. 12.0 months, p < 0.001), PFS (median PFS 20.6 vs. 2.6 months, p < 0.001) and objective response rate (58.2% vs. 7.6%, p = 0.003) compared to patients with negative GRImΔ. Our data shown that GRImT1 and GRImΔ are more reliable peripheral blood biomarkers of outcome compared to GRImT0 in aNSCLC patients treated with pembrolizumab and might represent useful biomarkers to drive clinical decisions in this setting.

Project description:Background: There is not yet an effective marker in predicting the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC) patients. The Gustave Roussy Immune Score (GRIm-Score) based on three objective variables, namely, neutrophil-to-lymphocyte ratio (NLR), serum albumin level (ALB), and lactate dehydrogenase (LDH), was developed as feasible prognostic indication in lung cancer patients receiving ICIs therapies. Our study aimed to adapt the GRIm-Score (HCC-GRIm-Score) in HCC patients who received ICIs therapies and thus improving the predictive ability. Methods: From January 2018 to September 2020, 261 patients who received ICIs therapy were retrospectively included and divided into training and validation groups. After determining the factors for HCC-GRIm-Score by multivariable analysis from training group, the optimized HCC-GRIm-Score was validated and compared to the original GRIm-Score and the Barcelona clinic liver cancer (BCLC) staging system. Results: One hundred sixty-one and 80 patients were assigned into the training and validation groups, respectively. Two more factors, aspartate transaminase-to-alanine transaminase ratio [hazard ratio (HR), 1.51; 95% confidence interval (CI), 0.94-2.42] and total bilirubin (HR, 1.76; 95% CI, 1.07-2.88), were identified as independent prognostic factors for overall survival (OS) and integrated in the HCC-GRIm-Score system according to the multivariable analysis. A risk score based on the HCC-GRIm-Score indicated that patients presenting high score (>2) suffered from significantly shorter median OS of 10.3 months compared to those with a low score (not reached; HR, 2.99; 95% CI, 1.89-4.75; p < 0.001). In the validation group of 80 patients, the patients presenting a high score showed an inferior OS (HR 5.62, 95% CI, 1.25-25.24; p = 0.024). HCC-GRIm-Score had the highest area under curve of 0.719 (95% CI, 0.661-0.773) compared to original GRIm-Score and BCLC staging system. Conclusion: The present study confirmed that the modified HCC-GRIm-Score system provided superior predictive ability in identifying the HCC patients potentially benefit from ICIs therapies, compared to the original GRIm-Score and the BCLC staging system.

Project description:To compare the characteristics, quality and treatment effects of randomised clinical trials (RCTs) by individual patient data (IPD) availability, in trials eligible for 18 IPD meta-analyses (MA).Trial characteristics, risk of bias (RoB) and hazard ratio (HR) for overall survival were extracted from IPD-MA publications and/or RCTs publications. Data for the RoB assessment were extracted for a subset of 73 RCTs. Two investigators blinded to whether IPD was available or not evaluated the RoB for these trials. Treatment effects were compared using ratios of global HRs (RHRs) of IPD-unavailable trials and IPD-available trials. RHR were pooled using a fixed-effect model.We examined the IPD availability for each trial eligible for each IPD-MA; when the IPD was not available for a trial, we used information from published sources.We selected all published IPD-MAs conducted at Gustave Roussy and the RCTs eligible for each.349 RCTs (73?018 patients) from 18 MAs were eligible: 60 RCTs (5890 patients) had unavailable IPD and 289 RCTs (67?128 patients) had available IPD. The main reason for IPD unavailability was data loss by investigators. IPD-unavailable trials were smaller (p<0.001), more often monocentric (p<0.001) and non-international (p=0.0004) than IPD-available trials. Geographical areas differed (p=0.054) between IPD-unavailable IPD-available trials. RoB was higher in IPD-unavailable RCTs for random sequence generation (p=0.007) and allocation concealment (p=0.006). The HR and 95% confidence interval (CI) for overall survival were extractable from publications in 23/60 IPD-unavailable trials included in 10 different MAs. Treatment effects were significantly greater for IPD-unavailable trials compared with IPD-available trials (RHR=0.86 (95% CI 0.75 to 0.98)).IPD-unavailable RCTs were significantly different from IPD-available RCTs in terms of trial characteristics and were at greater RoB. IPD-unavailable RCTs had a significantly greater treatment effect.

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Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

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