First-line Oxaliplatin-based Chemotherapy Research Articles

First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Abstract 2522: Predictive value of tumor mutational burden (TMB) in patients with metastatic microsatellite-stable (MSS) colorectal cancer (CRC) given first-line oxaliplatin-based chemotherapy and immune checkpoint blockade (ICB)

Abstract Purpose: Most CRC patients harbor primarily non-immunogenic MSS tumor. The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab) repeatedly. Half of study patients assigned to this experimental treatment had significantly extended progression-free survival (PFS) while the other half had shortened PFS, compared to the control-group patients given standard FLOX chemotherapy with median PFS 9.3 months. Here we explored if somatic mutations (mut) unveiled by next-generation sequencing might provide insights into responsiveness to the METIMMOX regimen. Procedures: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the experimental group of alternating 2 cycles each of FLOX Q2W and nivolumab Q2W, with prespecified break periods. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Diagnostic tumor biopsies and baseline metastasis biopsies were sequenced with the TruSight Oncology 500 assay. TMB was calculated using only coding, non-synonymous single-nucleotide variants and insertions/deletions with variant allele frequency ≥5% and sequencing depth ≥50 ×, applying the effective panel size as the megabases (Mb) denominator. Results: Sequencing data were acquired from 20 experimental-group patients with median PFS 7.9 months (minimum 2.0, maximum 41.6). Median TMB was 5.1 mut/Mb (minimum 0.8, maximum 11.8), concordant in patient-paired primary tumor and metastasis specimens. The TMB was associated with treatment outcome; the higher TMB, the better PFS with hazard ratio 0.83 (95% confidence interval (CI) 0.70-0.98; p = 0.026, Cox regression) for a PFS event with increasing TMB. TMB cut-off as low as 5.0 mut/Mb distinguished between patient groups (p = 0.007, log-rank test) with median PFS 34.9 months (95% CI 10.6-59.2; TMB&amp;gt;5, n = 10) and median PFS 4.6 months (95% CI 2.7-6.5; TMB≤5, n = 10). In the TMB&amp;gt;5 group, 8/10 were KRAS- or BRAF-mutant cases. In the TMB≤5 group, 9/10 metastasis specimens were RAS/BRAF-wildtype cases. Conclusions: TMB &amp;gt;5 mut/Mb was associated with tumor KRAS or BRAF driver mutation and remarkably long PFS in first-line treatment of patients with abdominal metastases from MSS-CRC with alternating short-course oxaliplatin-based chemotherapy and ICB. Citation Format: Anne Hansen Ree, Paula A. Bousquet, Hilde L. Nilsen, Torben Lüders, Shixiong Wang, Tina Visnovska, Diana L. Bordin, Eirik Høye, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Kjersti Flatmark, Sebastian Meltzer. Predictive value of tumor mutational burden (TMB) in patients with metastatic microsatellite-stable (MSS) colorectal cancer (CRC) given first-line oxaliplatin-based chemotherapy and immune checkpoint blockade (ICB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2522.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study.

To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients with MCRC were randomly assigned, in a 2 × 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). A total of 1,401 patients were randomly assigned in this 2 × 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

Maintenance therapy with Fluoropyrimidine and cetuximab or bevacizumab after first line FOLFOX-chemotherapy in metastatic colorectal cancer according to RAS or BRAFV600E mutation status.

Fluoropyrimidine (FP) with oxaliplatin-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (mCRC); however, oxaliplatin-induced neuropathy critically affects the quality of life of patients. Maintenance strategies with FP plus bevacizumab have been well-established; nonetheless, the real-world outcomes of maintenance therapy with FP and cetuximab are unclear. We investigated the clinical outcomes of patients who underwent maintenance therapy with cetuximab. We retrospectively identified and analyzed patients with mCRC who were treated between 2012 and 2021 with first-line oxaliplatin-based induction chemotherapy (IC) plus biologic agents (either cetuximab or bevacizumab), and underwent maintenance therapy (IC regimen without oxaliplatin) after IC. In total, 19 patients who were treated with mFOLFOX6 (FP/leucovorin/oxaliplatin) with cetuximab, and 26 patients who were treated with mFOLFOX6 with bevacizumab were included. In the cetuximab group, all patients were KRAS-, NRAS-, and BRAF-wild type, whereas most patients in the bevacizumab group harbored KRAS or BRAFV600E or NRAS mutants. During the maintenance treatment, seven patients (four [21%] in the cetuximab group and three [11%] in the bevacizumab group) achieved partial response after achieving nadir during induction chemotherapy. The disease control rates of maintenance therapy were 79% and 74% in the cetuximab and bevacizumab groups, respectively. The median progression-free survival of maintenance therapy and overall survival was 5.98months and 32.4months in the cetuximab group, and 4.83months and 25.6months in the bevacizumab group, respectively. Maintenance therapy with FP plus biologic agents (either bevacizumab or cetuximab) is a feasible strategy for appropriate mCRC patients according to their RAS/BRAF status. Further large-scale randomized studies are needed to validate the efficacy of anti-epidermal growth factor receptor-based maintenance therapy.

Survival Analysis and Prognostic Factors for Metastatic Colorectal Cancer Patients Treated with Chemotherapy

Background: Currently, there are limited data on prognostic factors in metastatic colorectal cancer (mCRC) patients treated with chemotherapy. Prognostic factors in colorectal cancer remain varied in each situation when considering their use in different contexts. Objective: To analyze the independent prognostic factors of mCRC in patients receiving chemotherapy. Materials and Methods: Data from 156 mCRC patients completely treated by first-line chemotherapy were collected between 2013 and 2018. A retrospective observational cohort study was conducted to evaluate the survival analysis and prognostic factors. A univariate and multivariate Cox’s proportional-hazards model were used to explore and identify the independent prognostic factors for overall survival. An analysis of the restricted mean survival time (RMST) method was used to estimate the event-free time from zero to 24 months. Results: Median overall survival was 18.3 months (96% CI 15.31 to 20.95). The multivariate Cox’s proportional-hazards model revealed two rognostic factors for decreased survival, poor Eastern Cooperative Oncology Group (ECOG) performance status greater than or equal to 2 (HR 2.05, 95% CI 1.08 to 3.86; p=0.027) and hypoalbuminemia lower than 3.5 g/dL (HR 3.47, 95% CI 2.10 to 5.75, p&lt;0.001). Analysis of the RMST method was used to estimate the event-free time from zero to 24 months in the group receiving first-line oxaliplatin-based chemotherapy, secondline oxaliplatin-based chemotherapy, and second-line irinotecan-based chemotherapy. It was found that only the group receiving second-line oxaliplatin-based chemotherapy had significantly longer survival time than the comparison groups, with an adjusted mean of survival time of 21.12 months (different mean 5.99, 95% CI 3.99 to 8.00, p&lt;0.001). Conclusion: Poor ECOG performance status greater than or equal to 2, and hypoalbuminemia lower than 3.5 g/dL can be used as prognostic factors in mCRC patients receiving chemotherapy. Keywords: Survival; Prognostic factors; Metastatic colorectal cancer; Chemotherapy

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases.

Simple SummaryOxaliplatin-based chemotherapy remains the mainstay of first-line therapy in patients with metastatic colorectal cancer (mCRC). Unfortunately, only approximately 60% of treated patients achieve response, and half of responders will experience an early onset of disease progression. Furthermore, some individuals will develop a mixed response due to the emergence of resistant tumor subclones. The ability to predicting which patients will acquire resistance could help them avoid the unnecessary toxicity of oxaliplatin therapies. Furthermore, sorting out lesions that do not respond, in the context of an overall good response, could trigger further investigation into their mutational landscape, providing mechanistic insight towards the planning of a more comprehensive treatment. In this study, we validated a delta-radiomics signature capable of predicting response to oxaliplatin-based first-line treatment of individual liver colorectal cancer metastases. Findings could pave the way to a more personalized treatment of patients with mCRC.The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies.

Predictive Value of Circulating Tumor Cells in Prognosis of Stage III/IV Colorectal Cancer After Oxaliplatin-based First-line Chemotherapy.

Insufficient data exist to support the concept of the circulating tumor cell (CTC) level as a prognostic factor for platinum-based first-line chemotherapy. This study investigated the impact of CTCs on the prognosis of patients with advanced colorectal cancer (CRC) after receiving platinum-based chemotherapy. Analyses were carried out of clinicopathological features and molecular phenotypes to clarify independent risk factors for a high CTC count. Patients diagnosed with stage III/IV CRC (n=76) were included in the study. The blood samples of patients were evaluated for CTCs using the CellRich™ platform system. Immunohistochemistry (Ias used to analyze epithelial-mesenchymal transition-associated biomarkers E-cadherin and vimentin. Univariate and logistic regression analyses were then conducted to analyze the risk factors for CTC expression. Additionally, the influence of oxaliplatin on disease-free survival after first-line chemotherapy or during chemotherapy was analyzed through a 2-year follow-up. Patients in the CTC+ group experienced shorter DFS after receiving oxaliplatin first-line chemotherapy than patients in the CTC- group (p<0.01). In addition, univariate analysis revealed that the tumor M-stage, tumor location, RAS mutation, high expression of vimentin, and deletion of E-cadherin expression were correlated with a high CTC count. Multivariate analysis suggested that the presence of RAS gene mutations and high vimentin expression were independent risk factors for high CTC loads (p<0.01). CTC positivity can indicate the efficacy of first-line chemotherapy with oxaliplatin in stage III/IV colorectal cancer. This may be linked to tumor epithelial-mesenchymal transition in patients with CTCs. Moreover, RAS gene mutation and high expression of vimentin were identified as independent risk factors for a high CTC count.

A Nomogram Combining Neutrophil-to-Lymphocyte Ratio and D-Dimer Predicts Chemosensitivity of Oxaliplatin-Based First-Line Chemotherapy in Patients with Unresectable Advanced Gastric Cancer.

Introduction: No effective peripheral blood predictors have been establoshed for first-line chemotherapy in patients with advanced gastric cancer. In this study, a nomogram combining the neutrophil-to-lymphocyte ratio/D-dimer with gender, number of metastases, and histological grade was established to predict progression-free survival in patients with unresectable advanced gastric cancer. Methods: We retrospectively collected baseline clinical characteristics and blood parameters from 153 patients diagnosed with advanced gastric cancer that underwent oxaliplatin-based first-line chemotherapy. Kaplan–Meier analysis and Cox regression analysis were used to determine the factors associated with progression-free survival. The concordance index (C-index) and calibration curve were used to determine the prediction accuracy and discriminative ability of the nomogram as a visual complement to the prognostic score system. Results: Determined by the X-tile software, the optimal cut-off points for the neutrophil-to-lymphocyte ratio and D-dimer were 3.18 and 0.56 mg/L, respectively. Multivariate analysis identified four independent prognostic factors: two or more metastatic organs (HR: 1.562, 95% CI: 1.009-2.418, P = .046), poor differentiation (HR: 0.308, 95% CI: 0.194-0.487, P < .001), neutrophil-to-lymphocyte ratio >3.18 (HR: 1.427, 95% CI: 1.024-1.989, P = .036), and D-dimer >0.56 mg/L (HR: 1.811, 95% CI: 1.183-2.773, P = .006). Receiver operating characteristic curves showed that the combination of the neutrophil-to-lymphocyte ratio and D-dimer in the prediction model exhibited the highest predictive performance (area under the curve, 0.800). The prognostic nomogram yielded a C-index of 0.800. Decision curve analysis demonstrated that the prognostic nomogram was clinically useful. A nomogram-based risk classification system was also constructed to facilitate risk stratification of advanced gastric cancer for optimal clinical management. Conclusion: We identified the neutrophil-to-lymphocyte ratio and D-dimer level as independent prognostic factors for advanced gastric cancer. The prognostic nomogram combining the neutrophil-to-lymphocyte ratio and D-dimer level can be applied in the individualized prediction of treatment outcome in patients with advanced gastric cancer.

ASO Author Reflection: Radiomics-Based Prediction for the Responder to First-Line Oxaliplatin-Based Chemotherapy in Patients with Colorectal Liver Metastasis.

ASO Author Reflection: Radiomics-Based Prediction for the Responder to First-Line Oxaliplatin-Based Chemotherapy in Patients with Colorectal Liver Metastasis.

Clinical Validation of a Machine-learning-derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer.

FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC. A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints. A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma. Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.

Radiomics Texture Analysis for the Identification of Colorectal Liver Metastases Sensitive to First-Line Oxaliplatin-Based Chemotherapy.

The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy. Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n=94) and validation (n=32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort. The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p<0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p<0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than -0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p<0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p=0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p=0.0025) were independently associated with good response. Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.

Association of XPD Asp312Asn polymorphism and response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer.

Identification of biomarkers predicting a response to chemotherapeutic drugs would greatly ease the selection of personalized therapy. The protein xeroderma pigmentosum group D (XPD) functions in nucleotide excision repair (NER) to remove DNA cross-links and in the regulation of transcription. The potential role of the Asp312Asn polymorphism in predicting the response to chemotherapy has not been established. This prospective study was designed to determine the role of the XPD Asp312Asn polymorphism in predicting the response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer. A total of 106 patients treated with 2 cycles of either FOLFOX4 (n = 72) or XELOX (n = 34) regimen as the chemotherapy were enrolled. The genotype of XPD Asp312Asn polymorphism was analyzed using TaqMan probe-based real-time polymerase chain reaction (PCR). Logistic regression was applied to predict the response to treatment protocols. Cox regression models were applied to predict overall survival. The overall response to chemotherapy was 57.6% (61/106). FOLFOX4 and XELOX regimens demonstrated comparable efficacy. The XPD Asp312Asn polymorphism was not associated with the response to either FOLFOX4 or XELOX regimen in univariate and in multivariate logistic regression analyses. Levels of carcinoembryonic antigen (CEA) ≥5 ng/mL and female gender were associated with a lack of response to FOLFOX4, but not to XELOX regimen. In a multivariate survival analysis, XPD Asp312Asn AA genotype, lack of response to chemotherapy, CEA ≥ 5 ng/mL, and age ≥65 were significantly associated with worse overall survival. The XPD Asp312Asn polymorphism is associated with overall survival, but it is not a biomarker in predicting the response to oxaliplatin-based first-line chemotherapy in patients with metastatic colorectal cancer.

Rationale and design of the TRUSTY study: a randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy

BackgroundTrifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the TRiflUridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC.Patients and methodsEligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022.Clinical trial registrationJapicCTI-173618 (JapicCTI).

O-026 - Total circulating cell-free DNA (cfDNA) as a prognostic biomarker in metastatic colorectal cancer prior to first-line oxaliplatin-based chemotherapy

Introduction: Small fragments of circulating cell-free DNA (cfDNA) can be detected in blood from cancer patients. Previous studies have shown a prognostic value mainly prior to second and subsequent lines of metastatic colorectal cancer (mCRC). We aimed to analyze the prognostic value of total plasma cfDNA in a patient population prior to first-line oxaliplatin-based chemotherapy for non-resectable mCRC in the NORDIC-VII study. Methods: A total of 547 patients had blood samples available for pre-treatment quantification of total cfDNA. Plasma samples were used for DNA purification and quantification of total cfDNA by droplet digital polymerase chain reaction (measuring beta-2-microglobulin DNA concentration) with controls for contamination from normal lymphocytes. Clinical endpoint was overall survival (OS). Results: Total cfDNA levels were successfully quantified in plasma from 499 patients, 48 samples were excluded mainly due to lymphocyte contamination. The median level was 7,833 alleles per mL plasma (range 1,050 – 1,645,000). High total cfDNA levels were associated with poor performance status, intact primary tumor and presence of liver metastases. There was no significant difference in cfDNA levels according to treatment arms. When dividing patients into groups of cfDNA quartiles, worse survival was seen with increasing pre-treatment levels of total cfDNA ( p < 0.001). Patients with total cfDNA above median levels (n = 250) had an OS of 16.1 months (95% CI 14.4 – 17.8) compared to patients with below median levels (n = 249) with an OS of 25.1 months (95% CI 22.4 –27.8, p < 0.001). In a Cox regression multivariate analysis (n = 496), total cfDNA level remained an independent prognostic marker ( p = 0.001) after adjusting for performance status, carcinoembryonic antigen (CEA) and alkaline phosphatase (ALP) levels. Conclusion: The level of total cfDNA in plasma has prognostic value in patients with mCRC prior to first-line oxaliplatin-based chemotherapy.

Preliminary results from a study of sevacizumab in Chinese patients with metastatic colorectal cancer resistant to oxaliplatin-based first-line chemotherapy.

e15530Background: The purpose of this study was to evaluate the safety, the maximum tolerated dose, the antitumor activity, and pharmacokinetics of sevacizumab in patients with mCRC resistant to ox...

Analysis of Mutational Spectra in Metastatic Colorectal Carcinoma: KRAS as an Indicator of Oxaliplatin-Based Chemotherapy

Objective: Mutation spectra in colorectal cancer with metastasis and its response to chemotherapy. Summary of Background Data: No molecular markers are available for selecting the optimal chemotherapeutic regimen (irinotecan or oxaliplatin) for metastatic colorectal cancer (mCRC). Methods: We enrolled 161 mCRC patients who underwent surgery for their primary tumors at Taipei Veterans General Hospital from 2004 to 2010. The prevalence of gene mutations was measured and correlated with responses to different cytotoxic agents. Results: We detected 1,836 mutations in 12 genes. KRAS mutants affected 44.3% of the tumors. The rate of good response was insignificantly higher for patients with KRAS mutant tumors who received oxaliplatin-based chemotherapy compared with patients with KRAS wild-type tumors (65.6% versus 47.0%; P = 0.15). For patients who received irinotecan-based chemotherapy, the rate of good response was similar in patients with wild-type (55.0%; n = 11) and those with KRAS mutant tumors (54.5%; n = 12; P = 1). In patients with KRAS mutant tumors treated with an oxaliplatin-based regimen, the overall survival was 38.5 months (95% CI: 26.6–50.5 months), which was insignificantly better than that for patients treated with an irinotecan-based regimen (30.4 months; 95% CI: 15.8–45.1 months; P = 0.206). Conclusions: Our data could not come to the conclusion that patient with KRAS mutation mCRC may have better response with oxaliplatin-based first-line chemotherapy. Further study is needed to confirm the relationship between gene mutation and chemotherapy response.

TRUSTY: A randomized multicenter phase II/III study of trifluridine/tipiracil and bevacizumab versus irinotecan, fluoropyrimidine, and bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy.

TPS881 Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and tipiracil is a thymidine phosphorylase inhibitor that improves the bioavailability of trifluridine. Phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab (Bev) for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). Methods: We are conducting a randomized multicenter phase II/III non-inferiority study (JapicCTI-173618) to compare trifluridine/tipiracil plus Bev versus FOLFIRI plus Bev (in the control arm, S-1 can replace 5-FU) in second-line mCRC patients who have failed first-line oxaliplatin-based chemotherapy. Key eligibility criteria are a histologically confirmed colorectal adenocarcinoma, refractory to first-line chemotherapy including a fluoropyrimidine, oxaliplatin, and either Bev or an anti-EGFR antibody (if RAS wild-type), an age of 20 years or older, ECOG performance status of 0-1, and adequate oral intake. Patients are randomized in a 1:1 ratio to receive trifluridine/tipiracil plus Bev or FOLFIRI plus Bev using the minimization method stratified by RAS status, prior therapy (Bev/anti-EGFR antibody), and primary tumor sidedness. The primary endpoint is overall survival. The non-inferiority hypothesis will be achieved if the upper limit of the two-sided 95% CI of the HR is below 1.33 (as HR scale, power 0.80). If achieved, the non-inferiority hypothesis with the margin of 1.25 (as HR) and the superiority will be consequently tested. Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, subsequent treatment, time to post-study treatment failure, the quality of life, and adverse events. The target sample size is 524 patients. Patients will be enrolled from October 2017. Clinical trial information: 173618.

ISY2-3 - Anti-VEGF and EGFR antibodies in WJOG4407G and 6210G studies

Over the last decade, the unprecedented improvement in overall survival has been seen in metastatic colorectal cancer (mCRC). Clinical development of new active agents has contributed to this great progress in the prognosis of mCRC. Thus, we can access a lot of agent, however these circumstances complicate the treatment strategy for mCRC patients. The development of biomarkers has contributed to the precision medicine for cancer treatment. However, RAS mutational status for anti-EGFR antibody therapy is the only clinically useful biomarker for mCRC treatment. To date, West Japan Oncology Group (WJOG) has conducted two randomized clinical trials for mCRC patients. First, WJOG4407G study compared FOLFIRI plus bevacizumab with mFOLFOX6 plus bevacizumab for previously untreated mCRC patients (Yamazaki K et al. Ann Oncol 2016). This randomized phase III study demonstrated a non-inferiority of FOLFIRI plus bevacizumab to mFOLFOX6 plus bevacizumab in terms of progression-free survival (PFS), and similar overall survival (OS) and overall response rate (ORR) in both treatment groups. Second, WJOG6210G study compared FOLFIRI plus panitumumab with FOLFIRI plus bevacizumab for wild-type KRAS exon2 mCRC patients who are refractory to bevacizumab plus oxaliplatin-based first-line chemotherapy (Shitara K et al. Cancer Sci 2016.). This randomized phase II study showed similar OS and PFS in both treatment groups, and better ORR in FOLFIRI plus panitumumab compared to FOLFIRI plus bevacizumab. In this session, the results of these WJOG studies including biomarker research will be presented.

Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.