Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study.
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PROVIDER: S-EPMC5244709 | BioStudies |
REPOSITORIES: biostudies
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Project description:Angiogenesis plays a critical role in the neoplastic growth, progression, and metastasis of colorectal cancer (CRC) in a process regulated by vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR). Several small-molecule anti-VEGFR tyrosine kinase inhibitors (TKIs), such as regorafenib, famitinib, axitinib and apatinib, have been shown to be effective in treating metastatic colorectal cancer (mCRC). Fruquintinib (ELUNATE®) is a novel oral anti-VEGFR TKI, originated and developed by Hutchison MediPharma. Fruquintinib is a potent and highly selective small-molecule inhibitor of VEGFR-1, -2 and -3. In the Phase 3 FRESCO trial, fruquintinib improved both overall survival (OS) and progression-free survival (PFS) in patients with mCRC, compared with placebo. Fruquintinib also showed an acceptable safety and tolerability profile. Based on the data from this trial, fruquintinib was approved by the China Food and Drug Administration (CFDA) in 2018, for the treatment of patients with mCRC who had undergone at least two prior standard anticancer therapies. The existing clinical trials and future prospects of fruquintinib in mCRC will be discussed in this article. In addition, to better understand the role of fruquintinib in this setting, recent advances in other anti-VEGFR TKIs for mCRC treatment are also reviewed herein.
| S-EPMC6701622 | BioStudies
Project description:<b>Purpose: </b>Fruquintinib is an anti-vascular endothelial growth factor receptor (VEGFR) agent. The FRESCO trial demonstrated that patients with metastatic colorectal cancer (mCRC) refractory to standard therapies could benefit from fruquintinib with tolerable adverse events (AEs). However, the efficacy and safety of fruquintinib in clinical practice has scarcely been reported, especially in patients with previous use of anti-VEGFR agents.<br><br><b>Methods: </b>This retrospective study investigated the efficacy and safety of fruquintinib in patients with mCRC between January 2019 and December 2019. Progression-free survival (PFS) and overall survival (OS) were assessed by a Kaplan-Meier analysis and log-rank test. A Cox regression model was performed to identify independent prognostic factors.<br><br><b>Results: </b>A total of 46 patients were included. The median PFS and OS were 3.1 months (95% confidence interval [CI], 1.9-4.3 months) and 9.0 months (95% CI, 7.2-10.8 months), respectively. Patients previously treated with anti-VEGFR agents had shorter median PFS compared with those without previous use of anti-VEGFR agents (1.9 <i>vs.</i> 3.7 months, P = 0.006), while the median OS was similar between the two groups (8.5 <i>vs.</i> 9.0 months, P = 0.992). Multivariate analysis revealed that the neutrophil-lymphocyte ratio (NLR) was an independent prognostic factor in PFS (hazard ratio [HR], 2.230; 95% CI, 1.191-4.517, P = 0.014) and OS (HR, 4.221; 95% CI, 1.683-10.586; P = 0.002). The most common non-hematological and hematological AEs were hand-foot syndrome (37.0%) and anemia (39.1%), respectively.<br><br><b>Conclusion: </b>Fruquintinib was an effective third-line therapy in mCRC with tolerable AEs. Efficacy of fruquintinib was decreased in patients with previous use of anti-VEGFR agents. NLR was an independent prognostic factor in PFS and OS in patients treated with fruquintinib.
| S-EPMC7691567 | BioStudies
Project description:Background:The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC. Methods:A literature search for randomized controlled trials (RCTs) was conducted in PubMed, Embase, and Cochrane Library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102, and nintedanib as third-line therapies in patients with mCRC. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes, while objective response rate (ORR) and safety were the secondary outcomes. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response, and safety data. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results:We identified eight RCTs comparing regorafenib (two studies), fruquintinib (two studies), TAS-102 (three studies), and nintedanib (one study) against placebo. The OS with regorafenib was significantly better when compared with nintedanib (HR?=?0.66; 95% CI: 0.45, 0.95, p?=?0.02) but was similar to that of fruquintinib (HR?=?1.01; 95% CI: 0.67, 1.52, p?=?0.94) and TAS-102 (HR?=?0.97; 95% CI: 0.68, 1.38, p?=?0.88). The PFS and ORR for regorafenib were slightly better than those of TAS-102 (PFS: HR?=?0.86, 95% CI: 0.54, 1.37, p?=?0.5; ORR: RR?=?1.13, 95% CI: 0.11, 11.05, p?=?0.92) and nintedanib (PFS: HR?=?0.68, 95% CI: 0.42, 1.10, p?=?0.12; ORR: not reported) but were lower than those for fruquintinib (PFS: HR?=?1.53, 95% CI: 0.93, 2.52, p?=?0.08; ORR: RR?=?0.68269, 95% CI: 0.045, 10.32, p?=?0.79). Safety analysis showed that the RR of adverse events (AEs) was lesser in patients treated with regorafenib in comparison with that in patients treated with fruquintinib, but was similar to that in patients treated with nintedanib and TAS-102. Conclusion:Regorafenib has efficacy similar to that of TAS-102 and better safety when compared with fruquintinib. Considering the mechanism of action of regorafenib, which targets multiple factors in the angiogenic pathway, it could be an ideal option for treatment in the beyond second-line setting.
| S-EPMC7364795 | BioStudies
Project description:We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.Patients with wild-type KRAS exon 2 mCRC were randomised 1?:?1 to panitumumab (6?mg?kg-1 Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57-0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53-0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49-2.00). No new safety signals were observed.Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.
| S-EPMC5104888 | BioStudies
Project description:Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.
| S-EPMC4371780 | BioStudies
Project description:<h4>Objective</h4>The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.<h4>Methods</h4>Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.<h4>Results</h4>A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.<h4>Conclusion</h4>Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.<h4>Clinicaltrialsgov identifier</h4>NCT02314819.
| S-EPMC8364970 | BioStudies
Project description:Background:The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo?+?FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods:Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results:Biomarker results were available from?>80% (n?=?894) of patients. Analysis of the ME subset determined a VEGF-D level of 115?pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME?+?MC populations found that the median OS in the ramucirumab?+?FOLFIRI arm compared with placebo?+?FOLFIRI showed an improvement of 2.4?months in the high VEGF-D subgroup [13.9?months (95% CI 12.5-15.6) versus 11.5?months (95% CI 10.1-12.4), respectively], and a decrease of 0.5?month in the low VEGF-D subgroup [12.6?months (95% CI 10.7-14.0) versus 13.1?months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions:The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration:NCT01183780.
| S-EPMC5888948 | BioStudies
Project description:Importance:Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective:To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants:FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions:Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n?=?278) or placebo (n?=?138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures:The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ?8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results:Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P?<?.001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P?<?.001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance:Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration:ClinicalTrials.gov Identifier: NCT02314819.
| S-EPMC6583690 | BioStudies
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235919 | GEO
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235917 | GEO