Phase II Clinical Study Evaluating the Efficacy and Safety of Cetuximab Rechallenge in Patients with Wild-Type RAS, Unresectable, Progressive/Recurrent Colorectal Cancer Refractory to Fluoropyrimidines, Oxaliplatin, Irinotecan, Cetuximab and Bevacizumab: The E-Rechallenge Trial
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2631760 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2-3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9-20.6); whereas 44/77 (57.1%) patients with grade 0-1 ST exhibited mOS of 8.2 months (CI 95%, 5.5-10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29-0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4-5.7) in patients with grade 2-3 ST, compared to patients with grade 0-1 ST with mPFS of 3.4 months (CI 95%, 2.7-4.1; HR, 0.49; CI 95%, 0.3-0.8; p = 0.004). Grade 2-3 ST (HR, 0.51; CI 95%, 0.29-0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27-0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27-0.9; p = 0.023), whereas there was a trend towards ST grade 2-3 (HR, 0.54; CI 95%, 0.29-1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.
| S-EPMC8616320 | biostudies-literature
Project description:Introduction Immunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the rationale of overcoming immune resistance and developing effective immune response against colorectal tumor cells. Preclinical studies have demonstrated that cetuximab may modulate immune response to cancer cells. In this scenario, the inhibition of PD-L1 with IgG1 MAb avelumab in combination with anti-EGFR IgG1 monoclonal antibody cetuximab could be a strategy for potentiating antitumor activity. The CAVE phase II single-arm clinical trial provided the first evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS wild-type (WT) mCRC. This combination had a good toxicity profile, with a low rate of common grade 3 adverse events. Patients and Methods Based on results obtained with the CAVE clinical trial, here we describe the design and rationale for the phase II, randomized CAVE 2 clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre-treated RAS, BRAF WT mCRC patients treated in first line with chemotherapy in combination with cetuximab and who have had a clinical benefit (complete or partial response) from treatment. A total of 173 patients will be randomized (2:1) to cetuximab + avelumab (115) or cetuximab as a single agent (58). The primary endpoint is overall survival. Key secondary endpoints include overall response rate, progression-free survival, and safety. For each patient, before treatment, a blood sample will be obtained and analyzed for circulating free tumor DNA according to NGS (Foundation/Roche), to identify RAS/BRAF WT patients to be enrolled. The same procedure will be performed at the progression of the disease. Additional blood/plasma, tumor, and fecal samples will be collected and centrally stored for additional translational studies. Discussion This study will provide the rationale to test immunotherapy-based combinations in the clinical setting, offering new opportunities for RAS WT mCRC patients. Clinical Trial Registration [https://clinicaltrials.gov/ct2/show/NCT05291156], identifier [NCT05291156].
| S-EPMC9272566 | biostudies-literature
Project description:ImportanceBased on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA).ObjectiveTo prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy.Design, setting, and participantsMulticenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment.InterventionsBiweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2.Main outcomes and measuresOverall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA.ResultsTwenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03).Conclusions and relevanceThis is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients.Trial registrationClinicalTrials.gov Identifier: NCT02296203.
| S-EPMC6439839 | biostudies-literature
Project description:Interventions: This is a multicentric phase II trial that examines patients who had a clinical benefit [confirmed stable disease (SD) for at least 6 months or clinical response] after a line of cetuximab- plus FOLFOX/FOLFIRI therapy and then a progression of disease, during cetuximab-based therapy, for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same or another Cetuximab based chemotherapy.
Primary outcome(s): Response rate(RR)
Study Design: Single arm Non-randomized
| 2625092 | ecrin-mdr-crc
Project description:PURPOSE:One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS:PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ? 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS:Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION:Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.
| S-EPMC7076055 | biostudies-literature
Project description:Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.
| S-EPMC5348362 | biostudies-literature
Project description:Missing Electronic Supplementary Materials.
| S-EPMC7645532 | biostudies-literature
Project description:BackgroundRegorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC).MethodsThis Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses.ResultsAmong 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4-60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group.ConclusionsIrinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial.Clinical trial registrationUMIN000010638.
| S-EPMC7652864 | biostudies-literature
Project description:Interventions: Oxaliplatin:85mg/m2/week iv, day1.15 q 4weeks Cetuximab:day1 400, day8 250, day15 500mg/m2, day15- q 2weeks S-1:80mg/m2, day1-14 q 4weeks
Primary outcome(s): Response ratte : RR
Study Design: Single arm Non-randomized
| 2621320 | ecrin-mdr-crc
Project description:BACKGROUND:Central nervous system tumors remain the leading cause of cancer-related mortality amongst children with solid tumors, with medulloblastoma (MB) representing the most common pediatric brain malignancy. Despite best current therapies, patients with recurrent MB experience have an alarmingly high mortality rate and often have limited therapeutic options beyond inadequate chemotherapy or experimental clinical trials. Therefore, a systematic review of the literature regarding treatment strategies employed in recurrent pediatric MB will evaluate previous salvage therapies in order to guide future clinical trials. The aim of this systematic review will be to investigate the efficacy and safety of salvage therapies for the management of children with progressive, treatment-refractory, or recurrent MB. METHODS:We will conduct literature searches (from 1995 onwards) in MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Central Register of Controlled Trials. Studies examining the survival and toxicity of therapies administered to treatment-refractory pediatric MB patients will be included. Two reviewers will independently assess the search results based on predefined selection criteria, complete data abstraction, and quality assessment. The primary outcomes of this review will be overall and progression-free survival. Secondary outcomes will include safety and toxicity of each therapy administered. The study methodological quality (or bias) will be appraised using an appropriate tool. Due to the nature of the research question and published literature, we expect large inter-study heterogeneity and therefore will use random effects regression analysis to extract the combined effect. In additional analyses, we will investigate the role of re-irradiation and mono- vs. poly-therapy in recurrent disease, and whether molecular subgrouping of MB influences salvage therapy. DISCUSSION:This systematic review will provide an overview of the current literature regarding salvage therapies for relapsed MB patients. Investigation of clinically tested therapies for children with recurrent MB has significant implications for clinical practice. By reviewing the efficacy and toxicity of MB salvage therapies, this study will identify effective therapeutic strategies administered to recurrent MB patients and can inform future clinical trials aimed to improve patient survivorship and quality of life. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42020167421.
| S-EPMC7055028 | biostudies-literature