hmpl-013 and Colorectal-Neoplasms

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Continuity of Patient Care; Humans; Rectal Neoplasms; Vascular Endothelial Growth Factor A

Direct randomized comparisons of regorafenib, TAS-102, and fruquintinib for treating metastatic colorectal cancer (mCRC) are lacking. Here, we evaluated the efficacy and safety of three agents by a systematic review and a network meta-analysis.. We included phase III randomized controlled trials in the PubMed, Embase, and Scopus Cochrane databases and ClinicalTrials.gov registry from initiation until January 2019. Data from randomized controlled trials including overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. Direct meta-analysis and indirect meta-analysis using network meta-analysis were assessed.. Five trials comprising a total of 2586 patients were included. For efficacy analysis of OS, no statistically significant differences were observed between regorafenib and TAS-102 (HR 0.945, 95% CI [0.677, 1.320], P = 0.753), regorafenib and fruquintinib (HR 1.056, 95% CI [0.690, 1.621], P = 0.814), or TAS-102 and fruquintinib (HR 1.117, 95% CI [0.740, 1.685], P = 0.610). However, fruquintinib was superior in PFS compared with TAS-102 (HR 1.756, 95% CI [1.079, 2.857], P = 0.023). Regorafenib and TAS-102 appeared to have a similar effect on PFS (HR 0.907, 95% CI [0.611, 1.346], P = 0.641), as did regorafenib and fruquintinib (HR 1.592, 95% CI [0.968, 2.618], P = 0.067). None of the three agents were better in terms of all grade AEs or any grade of 3-5 AEs. However, subgroup analysis of AEs exhibited different toxicity profiles between the three drugs.. Indirect comparison suggested that the three agents had similar OS but that fruquintinib was superior in terms of PFS compared with that of TAS-102. These three agents had different toxicity profiles.

Topics: Antineoplastic Agents; Benzofurans; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Progression-Free Survival; Pyridines; Pyrrolidines; Quinazolines; Randomized Controlled Trials as Topic; Thymine; Time Factors; Trifluridine; Uracil

BACKGROUND This study aimed to conduct a systematic review of the literature to identify key randomized controlled clinical trials (RCTs), followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal carcinoma (mCRC). MATERIAL AND METHODS Systematic literature review was performed using the Medline, Embase, and Cochrane library online databases to identify published randomized controlled trials (RCTs). Hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and the odds ratios (ORs) for the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), serious adverse events (SAEs), and fatal adverse events (FAEs) were compared indirectly using network meta-analysis based on a random-effects model. RESULTS Five RCTs that included 2,604 patients fulfilled the eligibility criteria and were analyzed. Indirect comparisons showed that fruquintinib was associated with significant superiority for PFS (HR, 0.57; 95% CI, 0.34-0.95) and DCR (OR, 1.80; 95% CI, 1.08-3.01) when compared with TAS-102 in patients with mCRC. However, there was no significant difference between OS or ORR between regorafenib, fruquintinib, and TAS-102. Fruquintinib was associated with a significantly higher risk of SAEs when compared with TAS-102 or regorafenib. There was no significant difference in the risk of AEs or FAEs following indirect comparison between fruquintinib, regorafenib, and TAS-102. CONCLUSIONS The findings from network meta-analysis showed that fruquintinib was associated with significant superiority for PFS and DCR compared with TAS-102, but fruquintinib was associated with significantly increased risk for SAEs compared with regorafenib and TAS-102.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Pyrrolidines; Quinazolines; Rectal Neoplasms; Thymine; Trifluridine; Uracil

Topics: Angiogenesis Inhibitors; Animals; Benzofurans; Colorectal Neoplasms; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Quinazolines; Receptors, Vascular Endothelial Growth Factor

The optimal treatment in the third-line and later-line setting for metastatic colorectal cancer (mCRC) has not been established. As reported, regorafenib and fruquintinib have shown to be superior to placebo in mCRC. However, no direct clinical comparison of regorafenib and fruquintinib has been conducted; we performed a systematic review and network meta-analysis to compare the efficacy and safety of regorafenib and fruquintinib.. PubMed, Embase, and the Cochrane Library were systematically searched and randomized-controlled trials (RCTs) assessing the effect and safety of regorafenib or fruquintinib versus placebo for patients with mCRC were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. After that, we performed pairwise direct meta-analyses (regorafenib vs. placebo and fruquintinib vs. placebo) and indirect comparison (regorafenib vs. fruquintinib) using network meta-analyses methods.. Three RCTs involving 1380 patients were included in the meta-analysis. In the direct meta-analysis, regorafenib and fruquintinib both showed survival benefits when compared with placebo. For the indirect comparison, fruquintinib shows no significant difference in OS compared to regorafenib (HR 0.97; 95% CI 0.64-1.46). Regarding PFS, there was a tendency that fruquintinib was superior to regorafenib (HR 0.65; 95% CI 0.39-1.08); however, there was no statistic difference. For the safety analysis, in indirect comparison, fruquintinib showed significant difference in all-grade toxicity compared to regorafenib (OR 0.73; 95% CI 0.65-0.82), especially in subgroup of proteinuria (OR 0.31; 95% CI 0.11-0.86). For the grade 3-5 toxicity, fruquintinib showed no significant difference when compared with regorafenib (OR 0.92; 95% CI 0.64-1.32).. Based on efficacy and safety, there was a tendency that fruquintinib was superior to regorafenib, as a whole, regorafenib and fruquintinib demonstrated similar clinical benefit for patients with refractory mCRC. It seems that fruquintinib has less toxic in all-grade toxicity when compared with regorafenib.

Topics: Benzofurans; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Quinazolines; Treatment Outcome

Fruquintinib (Elunate

Topics: Antineoplastic Agents; Benzofurans; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Quinazolines; Vascular Endothelial Growth Factor Receptor-1

There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer.. We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting.. Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group).. Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population.. HUTCHMED.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Double-Blind Method; Humans; Quality of Life; Rectal Neoplasms; Trifluridine; Vascular Endothelial Growth Factor A

Lay abstract In this analysis of the FRESCO trial, we evaluated the efficacy and safety of fruquintinib in two different groups of patients (subgroups) with metastatic colorectal cancer - patients who received prior targeted therapy (PTT) and patients who did not (non-PTT). Of the 278 patients treated with fruquintinib, 111 patients received PTT. Patients treated with fruquintinib had longer overall survival and it took longer for their disease to worsen in both PTT and non-PTT subgroups compared with placebo. Patients in both subgroups treated with fruquintinib showed measurable reduction in their tumor size and disease control with similar side effects in patients of both the subgroups. These results suggest that fruquintinib is safe and effective in patients with metastatic colorectal cancer in both subgroups.

Topics: Aged; Benzofurans; Colorectal Neoplasms; Double-Blind Method; ErbB Receptors; Female; Humans; Male; Middle Aged; Progression-Free Survival; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Survival Rate; Treatment Outcome; Vascular Endothelial Growth Factor A

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if. Lay abstract Fruquintinib is a drug that slows down, reduces or prevents the growth of vessels that supply blood to certain tumors. Fruquintinib is approved in China for the treatment of cancer of the colon and rectum that has spread to these parts of the body from the primary site of cancer: metastatic colorectal cancer. The FRESCO-2 study is being conducted globally to determine how safe and effective fruquintinib is at treating patients with metastatic colorectal cancer that has grown or spread following other forms of treatment, such as chemotherapy. About 687 patients will be enrolled globally to receive either fruquintinib or a matching placebo in a 2:1 ratio, respectively. The FRESCO-2 study is enrolling patients in the USA, Europe, Australia and Japan.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzofurans; Colorectal Neoplasms; Double-Blind Method; Humans; Protein Kinase Inhibitors; Quinazolines

In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial.. In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized.. A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib.. The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population.. Clinical Trials identifier NCT02314819.

Topics: Benzofurans; China; Colorectal Neoplasms; Humans; Quinazolines

Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.. 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.. 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.. 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.. 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.. 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.. 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.. ClinicalTrials.gov Identifier: NCT02314819.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; China; Colorectal Neoplasms; Combined Modality Therapy; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Quinazolines; Survival Analysis; Vascular Endothelial Growth Factor A; Young Adult

To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients.. A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS).. In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86-5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95-1.58); (hazard ratio [HR] 0.30; 95% CI 0.15-0.59; P < 0.001). The median OS was 7.72 versus 5.52 months (HR 0.71; 95% CI 0.38-1.34). The most common grade 3-4 adverse events were hypertension and hand-foot skin reaction.. Fruquintinib showed a significant PFS benefit of 3.7 months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway.. NCT01975077 and NCT02196688.

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor

Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo.. The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses.. In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis, and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group.. The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Mice; Trifluridine; Vascular Endothelial Growth Factor A

Fruquintinib, also called HMPL-013, was first discovered by Hutchison Whampoa Pharmaceuticals Co. Ltd., Shanghai, China, and it is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor. In clinical trials, fruquintinib has demonstrated a survival benefit in metastatic colorectal cancer (mCRC) patients. The purpose of this study was to retrospectively evaluate the efficacy and toxicity of fruquintinib in real-world patients. We collected data from patients with mCRC treated with oral fruquintinib from 2018 to 2020 in six different institutions. Patients with mCRC initially received 5 mg of oral fruquintinib daily for 3 weeks. Progression-free survival (PFS) was evaluated using the KaplanMeier method. The efficacy and safety of fruquintinib were also assessed. Seventy-five patients were involved in our study, and 29.3% of patients achieved stable disease (SD). Median PFS was 5.4 months (95% CI: 4.8415.959). The treatment-emergent adverse events (TEAEs) with fruquintinib were acceptable with grade 3 TEAEs of 6%. The grade 3 TEAEs were handfoot skin reaction (HFSR), fatigue, and stomatitis. The ECOG performance status was associated with PFS. In this real-world study, the clinical activity of fruquintinib was consistent with what has been reported in previous clinical trials. The level of safety was acceptable, and the side effects were manageable.

Topics: Benzofurans; China; Colonic Neoplasms; Colorectal Neoplasms; Humans; Quinazolines; Retrospective Studies; Vascular Endothelial Growth Factor A

Regorafenib and fruquintinib are tyrosine kinase inhibitors that are recommended for refractory colorectal cancer (CRC) in China. However, to date, no head-to-head trials have been conducted to guide clinical practice.. An ambispective observational cohort study was conducted in Beijing Cancer Hospital. Patients with metastatic CRC who received regorafenib or fruquintinib were retrospectively collected between January 2018 and April 2020, and prospectively enrolled between May 2020 and February 2021. The primary outcome was time-to-treatment failure (TTF), and secondary outcomes were overall survival (OS) and adverse events. An additional goal of the study was to explore the appropriate sequence of regorafenib and fruquintinib treatment.. A total of 366 patients with metastatic CRC were enrolled to receive regorafenib (n = 260) or fruquintinib (n = 106) between January 2018 and February 2021. No difference was observed for median TTF (regorafenib 2.7 months vs. fruquintinib 3.1 months, P = .200) or median OS (regorafenib 13.8 months vs. fruquintinib 11.3 months, P = .527). The propensity score analysis showed similar results for median TTF and median OS between the 2 groups, as did the results of subgroup analysis for prospective set (n = 146). For sequence analysis, patients with regorafenib followed by fruquintinib (n = 84) showed longer OS than that with the reverse (n = 29) (28.1 months vs. 18.4 months, P = .024). Most patients tolerated regorafenib at a reduced dose (93.1%), and most patients tolerated fruquintinib at a standard dose (68.9%). The incidences of most adverse events were similar between the two groups, while any grade of hand-foot skin reaction and hyperbilirubinemia were more frequently observed in the regorafenib group and ≥grade 3 hypertension was more common in the fruquintinib group.. Regorafenib and fruquintinib had similar efficacy and toxicity profiles with various frequency. Regorafenib followed by fruquintinib showed longer OS than the reverse, but the sequence needs to be further confirmed.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Humans; Phenylurea Compounds; Prospective Studies; Pyridines; Quinazolines; Rectal Neoplasms; Retrospective Studies

Lay abstract The objective of the study was to assess the benefit of fruqintinib, a chemotherapy drug for patients with metastatic colorectal cancer (mCRC) who do not respond well to previous chemotherapy. The study considered both the time of survival and the quality of life after patients received fruqintinib. In measuring patients’ quality of life, the study assessed the time that was free from cancer symptoms and any severe side effects from treatment. The study used data obtained from a Phase III clinical trial, FRESCO, which included 416 mCRC patients receiving fruqintinib or placebo. The results showed that fruqintinib significantly extended patients’ symptom-free and side effects-free survival time by approximately 2 months and 5 days. Fruqintinib was 16.7–39.9% more effective than placebo in extending mCRC patients’ high-quality life, regardless of prior targeted therapy.

Topics: Aged; Benzofurans; Cancer Survivors; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Placebos; Quality-Adjusted Life Years; Quinazolines; Randomized Controlled Trials as Topic; Survival Analysis

This study was to investigate the efficacy and safety of regorafenib or fruquintinib combined with camrelizumab in patients with microsatellite stable (MSS) and/or proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC). Medical records of MSS/pMMR mCRC patients who received regorafenib (80 mg) or fruquintinib (3 mg) once a day (21 days on/7 days off) plus camrelizumab (200 mg) every three weeks in Yuhuangding Hospital between January 2020 and June 2020 were retrospectively collected. Follow-up data up to November 1st, 2020 was gathered. The primary endpoint was the objective response rate (ORR) and disease control rate (DCR). The safety profile was the secondary endpoint. A total of 16 patients were enrolled. The ORR was 25.0% (4/16) and the DCR was 62.5% (10/16). The main adverse events (AEs) included reactive cutaneous capillary endothelial proliferation (RCCEP) (81.3%), fatigue (43.8%), hypertension (37.5%), hand-foot skin reaction (25.0%), and thyroid dysfunction (25.0%). Most AEs were grade 1 or 2, with only 1 patient of grade 3 liver dysfunction. All the AEs were ameliorated by effective symptomatic treatment. Regorafenib or fruquintinib plus camrelizumab exhibited promising efficacy in patients with MSS/pMMR mCRC. The toxicity was moderate and manageable.

Topics: Antibodies, Monoclonal, Humanized; Benzofurans; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Repeats; Phenylurea Compounds; Pilot Projects; Pyridines; Quinazolines; Retrospective Studies

To evaluate the cost-effectiveness of addition of fruquintinib to best supportive care (BSC) in third-line treatment for patients with metastatic colorectal cancer (CRC).. To conduct the cost-effectiveness analysis, a Markov model was established to simulate the course of metastatic CRC. Three health states-progression-free survival (PFS), progressive disease (PD), and death-were included. Clinical data were derived from the FRESCO trial and health utility values were extracted from previous literature. The primary outcome of the study was incremental cost-effectiveness ratio (ICER) in US dollars per quality-adjusted life-years (QALYs) from a Chinese societal perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to test the robustness of the study.. Addition of fruquintinib to BSC gained 0.54 QALY at a cost of $15,404.57 while the BSC group gained 0.38 QALY at a cost of $9603.94. ICER of fruquintinib versus BSC was $36,253.94/QALY. In the 1-way sensitivity analyses, utility for PD in both groups, utility for PFS in both groups, and cost of fruquintinib significantly influenced the results of the analysis. At the willingness-to-pay threshold of $28,988.40/QALY, probabilities of addition of fruquintinib to BSC or BSC alone as the cost-effective option were 0% and 100%, indicating addition of fruquintinib is not a dominant option compared with BSC.. Addition of fruquintinib to BSC is not a cost-effective regimen in the third-line setting for patients with metastatic CRC from the Chinese societal perspective.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Humans; Male; Markov Chains; Neoplasm Metastasis; Progression-Free Survival; Quality-Adjusted Life Years; Quinazolines

The clinical efficiency and adverse reactions of anlotinib in metastatic colorectal cancer (mCRC) as a third-line treatment compared with chemotherapy and regorafenib or fruquintinib was explored in this study. Clinical data from 105 mCRC patients who failed at least two lines of chemotherapy were collected. The patients were divided into three groups based on their third-line therapeutic regimen: third-line chemotherapy only (group A); anlotinib (group B); and fruquintinib or regorafenib (group C). The result showed that the ORR and DCR of group B (14.29%, 85.71%) were higher than those of group A (0%, 40.00%). The ORRs of group B and group C were 14.29% and 20.00%, respectively. Group B and group C had the same DCR, 85.71%. The mean PFS values of group B (3.46 months) and group C (3.33 months) were longer than that of group A (2.25 months) (χ2=84.255, p<0.001) and the mean PFS values of group B and group C were similar (χ2=0.884, p=0.347). The mean OS of group B was 9.22 months, which was longer than that of group A (6.95 months) (χ2=38.837, p<0.001). The mean OS values of group B (9.22 months) and group C (9.38 months) were not significantly different (χ2=0.456, p=0.499). The incidences of proteinuria, hand-foot skin reaction, myelosuppression, and gastrointestinal reaction were similar between group B and group C (p=0.173, 0.188, 1.00, 0.154, respectively). Myelosuppression and gastrointestinal reaction were more common in group A than in group B and group C (p<0.001). For mCRC, anlotinib as a third-line treatment is better than chemotherapy and similar to regorafenib or fruquintinib. The associated adverse reactions are tolerable.

Topics: Benzofurans; Colorectal Neoplasms; Humans; Indoles; Phenylurea Compounds; Pyridines; Quinazolines; Quinolines

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; CD8 Antigens; Cell Line, Tumor; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Male; Mice; Mice, Knockout; Microsatellite Instability; Programmed Cell Death 1 Receptor; Quinazolines; Receptors, Vascular Endothelial Growth Factor; T-Lymphocytes, Regulatory; Treatment Outcome; Tumor Microenvironment; Young Adult

In this study, we analyze the cost-effectiveness of fruquintinib as third-line treatment for patients with metastatic colorectal cancer in China, especially after a recent price drop suggested by the National Healthcare Security Administration.. A Markov model was developed to investigate the cost-effectiveness of fruquintinib compared to placebo among patients with metastatic colorectal cancer. Effectiveness was measured in quality-adjusted life years (QALY). The Chinese healthcare payer's perspective was considered with a lifetime horizon, including direct medical cost (2019 US dollars [USD]). A willing-to-pay threshold was set at USD 27,130/QALY, which is three times the gross domestic product (GDP) per capita. We examined the robustness of the model in one-way and probabilistic sensitivity analysis.. Fruquintinib was associated with better health outcomes than placebo (0.640 vs 0.478 QALYs) with a higher cost (USD 20750.9 vs USD 12042.2), resulting in an incremental cost-effectiveness ratio (ICER) of USD 53508.7 per QALY. This ICER is 25% lower than the one calculated before the price drop (USD 70952.6 per QALY).. After the price negotiation, the drug becomes cheaper and the ICER is lower, but the drug is still not cost effective under the standard of 3 times GDP willing-to-pay threshold. For patients with metastatic colorectal cancer in China, fruquintinib is not a cost-effective option under the current circumstances in China.

Topics: Benzofurans; China; Colorectal Neoplasms; Cost-Benefit Analysis; Humans; Neoplasm Metastasis; Quinazolines

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.

Topics: Angiogenesis Inhibitors; Benzofurans; Cell Proliferation; China; Clinical Trials as Topic; Colorectal Neoplasms; Europe; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphorylation; Quinazolines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Topics: Antineoplastic Agents; Benzofurans; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Humans; Male; Quinazolines; Salvage Therapy