Cytochrome P450 (CYP) 3A plays a significant role in fruquintinib metabolism in vitro. This 2-part, 2-period fixed-sequence study investigated the impact of CYP3A inhibition (itraconazole) and CYP3A induction (rifampin) on the pharmacokinetics (PK) of fruquintinib and M11, its main metabolite. Fourteen healthy subjects in each part received a single dose of fruquintinib 5 mg alone in Period 1 and with itraconazole (Part A) or rifampin (Part B) in Period 2 under fasted conditions. Itraconazole or rifampin was administered daily 4 or 7 days before coadministration, respectively; administration of both continued throughout the PK sampling period. PK samples were collected before dosing and over 168 hours after fruquintinib dosing. Coadministration with itraconazole resulted in an increase of fruquintinib systemic exposure, determined by area under the plasma concentration-time curves (AUCs) by approximately 10%. Decreases in M11 AUCs and maximum plasma concentration (Cmax) ranged from 44% to 55% but were not considered clinically meaningful. Rifampin reduced fruquintinib Cmax and AUCs by 12% and 65%, respectively. Rifampin had a marginal effect on M11 AUCs and increased M11 Cmax by 2.3-fold. Data support that concomitant use of fruquintinib with potent CYP3A inducers of rifampin-like potency should be avoided, but no dose adjustment is recommended when coadministered with CYP3A inhibitors.

Fruquintinib (FRUZAQLATM) is a highly selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3). Two Phase 1, open-label, single-dose studies investigated the impact of hepatic or renal impairment on the pharmacokinetics and tolerability of fruquintinib. Participants with moderate renal impairment (creatinine clearance [CrCl] 30-59 mL/min; eight participants) and matched healthy controls (eight participants for each study) received fruquintinib 5 mg. Participants with moderate hepatic impairment (Child-Pugh B; eight participants) and severe renal impairment (CrCl 15-29 mL/min; eight participants) received fruquintinib 2 mg. Pharmacokinetic samples were collected over 240 h. Fruquintinib pharmacokinetics were similar between participants with moderate hepatic impairment and healthy controls; geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax), area under the plasma concentration-time curve from 0 to time of last measurable concentration (AUC0-t), and AUC from 0 to infinity (AUC0-inf) were 1.04 (0.87-1.24), 0.89 (0.64-1.23), and 0.91 (0.66-1.26), respectively. Fruquintinib pharmacokinetics were similar between participants with severe or moderate renal impairment and healthy controls. Compared with healthy controls, the respective GMRs (90% CIs) for Cmax, AUC0-t, and AUC0-inf for participants with severe renal impairment were 0.89 (0.78-1.03), 0.97 (0.83-1.14), and 1.01 (0.85-1.19), and for participants with moderate renal impairment were 0.95 (0.78-1.15), 1.06 (0.89-1.26), and 1.07 (0.89-1.28). Fruquintinib was generally well tolerated. These results support fruquintinib use without dose adjustment (5 mg daily, 3 weeks on, and 1 week off) in patients with moderate hepatic impairment or moderate to severe renal impairment.

To conduct pooled estimates and comparative evaluations of safety and efficacy, alongside cost-effectiveness and value-based pricing analyses, for systemic treatments recommended by the National Comprehensive Cancer Network in refractory colorectal cancer.

A comprehensive search for related randomized controlled trials was conducted on PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov. Safety was evaluated by aggregating treatment-related adverse events (TRAEs) and performing Bayesian network meta-analysis (NMA) for indirect comparisons. Pooled survival estimates of overall survival (OS) and progression-free survival (PFS) were conducted to assess treatment efficacy. For NMA of OS and PFS, time-variant fractional polynomial models were employed as the primary analysis, with Cox proportional hazards models used for result validation. Economic evaluations were performed using partitioned survival models from the US public sector perspective. Clinical parameters were sourced from meta-analyses; cost parameters included drug treatment, follow-up and administration, end-of-life care, and adverse event management expenses, which were obtained from the Federal Supply Schedule, public databases or published literature. Utility values were sourced from the CORRECT trial. Price simulations were also conducted. Robustness of results was confirmed by sensitivity and scenario analyses RESULTS: We included nine studies comprising 3,978 patients and incorporating six treatments recommended by NCCN, including best supportive care (BSC), regorafenib, regorafenib dose optimization (REDo), trifluridine/tipiracil (TAS-102), TAS-102 with bevacizumab (TAS-BEV), and fruquintinib. Targeted treatments increased serious TRAEs and grade 3 + TRAEs compared to BSC. However, no significant safety differences were found among the targeted therapies. Regarding efficacy, REDo led in median OS, while fruquintinib led in median PFS. NMA indicated that TAS-BEV had the greatest PFS and OS survival benefit, followed by fruquintinib and REDo. Cost-effectiveness analysis favored BSC as the least expensive and the most cost-effective profile. TAS-BEV had the greatest effectiveness, with TAS-102 being the most cost-effective among targeted therapies. For cost-effectiveness against BSC, the price reductions of TAS-102, fruquintinib, REDoS, regorafenib, and TAS-BEV were 39%, 24%, 14%, 8%, and 7%, respectively.

Targeted therapies have comparable safety; TAS-BEV is highly effective, TAS-102 is the top cost-effective targeted therapy. Treatment choice should balance individual patient needs with safety, efficacy, and cost.

Fruquintinib, a selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown considerable efficacy in colorectal cancer (CRC) treatment. Despite its promising therapeutic effects, the precise molecular mechanisms underlying its therapeutic effects remain incompletely understood. In this study, we explored the functional roles and molecular mechanisms of fruquintinib in CRC therapy.

Human CRC cells (HCT-116 and LOVO) were cultured and treated with fruquintinib. Cell counting kit-8 assay kit (CCK-8) and colony formation assays were performed to investigate the effects of fruquintinib on cell proliferation. Wound healing and transwell assays were conducted to explore the role of fruquintinib on migration and invasion. RNA sequencing and bioinformatics analysis was used to investigate the potential mechanism of fruquintinib in the development of CRC. Western blot was used to measure the protein level.

Fruquintinib significantly inhibited the proliferation, migration, and invasion of colorectal cancer cells. Bioinformatics analysis indicated that fruquintinib modulated the epithelial-mesenchymal transition (EMT) pathway, and experimental validation confirmed its regulatory effects on core EMT-associated protein biomarkers. Notably, fruquintinib treatment resulted in the upregulation of E-cadherin and the downregulation of N-cadherin, vimentin, and MMP9. Western blot analysis revealed that fruquintinib dose-dependently suppressed SMAD2/3 expression. Notably, treatment with the TGF-β receptor agonist KRFK TFA attenuated fruquintinib's effect, reversing the upregulation of E-cadherin as well as the downregulatin of N-cadherin and SMAD2/3. Additionally, KRFK TFA partially restored CRC cell migration and invasion in transwell assays, counteracting fruquintinib's inhibitory impact.

These findings indicate that Fruquintinib effectively hampers the migration and invasion of CRC cells by disrupting the EMT process via the TGF-β/Smad signaling pathway. This study sheds light on the mechanisms by which fruquintinib inhibits CRC progression and underscores its potential for further clinical investigation.

Maintaining or improving health-related quality of life (HRQoL) is as important as extending survival in metastatic colorectal cancer. We report an HRQoL analysis from FRESCO-2 (NCT04322539).

Patients were randomized to fruquintinib +best supportive care (BSC; n = 461) or placebo +BSC (n = 230). Instruments of EORTC QLQ-C30 and 5-level EQ-5D, and ECOG performance status (PS) were assessed. Changes from baseline scores for QLQ-C30 and EQ-5D were evaluated and minimally important difference thresholds were used to define stable, improved, or deteriorated QoL. Time to deterioration (TTD) was assessed.

With fruquintinib versus placebo, baseline QLQ-C30 global health status (GHS) and EQ-5D visual analog scale (VAS) scores were 65.2 versus 64.6 and 67.0 versus 66.6, respectively. Least-squares mean changes from baseline fluctuated throughout treatment. At end of treatment (EOT), mean scores with fruquintinib versus placebo were 53.8 versus 52.3 (QLQ-C30 GHS) and 58.9 versus 58.5 (EQ-5D VAS). For QLQ-C30 GHS, 38.3 % versus 36.5 % of patients receiving fruquintinib versus placebo had stable or improved scores at EOT; median TTD was 2.1 versus 1.8 months (HR, 0.9; 95 % CI, 0.7-1.0). For EQ-5D VAS, 47.9 % versus 42.7 % had stable or improved scores at EOT; median TTD was 2.6 versus 1.9 months (HR, 0.8; 95 % CI, 0.6-0.9). Median TTD to ECOG PS ≥ 2 or death within 30+ /7 days after EOT was 6.6 versus 2.9 months with fruquintinib versus placebo (HR, 0.6; 95 % CI, 0.4-0.7).

Fruquintinib delayed TTD of ECOG PS and did not negatively impact HRQoL versus placebo.

Fruquintinib is a highly selective, oral inhibitor of all 3 VEGF receptors. The global, randomized, double-blind phase 3 FRESCO-2 trial (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival in patients with refractory metastatic colorectal cancer (mCRC) who received fruquintinib plus best supportive care (BSC) versus placebo plus BSC. Here we report detailed safety data from FRESCO-2 including an analysis of treatment-related adverse events of special interest (AESIs).

Patients with mCRC eligible for FRESCO-2 had received all standard chemotherapies and prior anti-VEGF and anti-EGFR therapies if indicated, and displayed progression on, or intolerance to, TAS-102 and/or regorafenib. Prespecified AESIs based on VEGFR tyrosine kinase inhibitor drug classes were evaluated.

Incidences of treatment-related AESIs were 64.9% with fruquintinib + BSC versus 23.0% with placebo + BSC. The most frequent all-grade treatment-related AESIs for fruquintinib were hypertension (28.9%; grade ≥3 10.7%), palmar-plantar erythrodysesthesia syndrome/hand-foot skin reaction (PPE 18.6%; grade ≥3 6.1%), and hypothyroidism (15.6%; grade ≥3 0.4%). Dose reductions due to treatment-related AESIs were reported in 10.3% of patients who received fruquintinib + BSC versus 0.4% with placebo + BSC. The most common treatment-related AESIs resulting in dose reduction for fruquintinib were PPE syndrome (5.0%), hypertension (2.9%), and proteinuria (1.3%). Overall, 5.9% versus 0.9% had treatment-related AESIs resulting in study drug discontinuation.

Fruquintinib + BSC demonstrated a predictable and manageable safety profile in pretreated patients with mCRC and is a novel oral treatment option that prolongs survival and enriches the continuum of care in this population.

Treatment toxicity and disease-related symptoms of metastatic colorectal cancer (mCRC) can adversely affect quality of life (QoL). Maintaining QoL is an important treatment goal alongside improving survival outcomes. Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) measures the quality of patients' survival by assessing the proportion of survival time that is free of symptoms/toxicity. The phase III FRESCO-2 study met its primary endpoint, demonstrating improved overall survival with fruquintinib plus best supportive care (BSC) versus placebo plus BSC [hazard ratio 0.66, 95% confidence interval (CI) 0.55-0.80, P < 0.001]. This post hoc Q-TWiST analysis compared the benefit-risk of fruquintinib versus placebo in all patients randomized in FRESCO-2.

Patients with refractory mCRC in the USA, Europe, Japan, and Australia were randomized to receive fruquintinib (n = 461) or placebo (n = 230) plus BSC until disease progression or unacceptable toxicity. Patients' survival time was partitioned as follows: time from randomization with grade 3/4 treatment-emergent adverse events (TEAEs) before progression (TOX); time from randomization to progression without grade 3/4 TEAEs (TWiST); and time from progression to death/censoring (REL). Q-TWiST was calculated as the combined utility-weighted mean durations of each health state, assuming utility coefficients of 1 for TWiST and 0.5 for TOX and REL.

Q-TWiST was improved when fruquintinib (versus placebo) was added to BSC, with a between-treatment difference of 2.0 months (95% CI 1.5-2.6 months, P < 0.05) and a relative improvement of 31.4%. This effect was primarily driven by the difference in the TWiST component [mean difference 2.1 months (95% CI 1.8-2.5 months), P < 0.05]. Q-TWiST improvements were consistent in all subgroups, including by age, sex, liver metastases, and primary tumor site. The subgroup and sensitivity analysis results confirmed the robustness of the primary analysis findings.

Fruquintinib provides a clinically meaningful quality-adjusted survival benefit versus placebo in refractory mCRC.

This two-sequence, three-period study (NCT04645940) was designed to evaluate the effect of food and concomitant rabeprazole, a proton pump inhibitor, on the pharmacokinetics (PK) and safety of fruquintinib and its metabolite M11 after a single oral dose of fruquintinib 5 mg in healthy subjects. In the food effect treatment periods, 14 subjects were randomized in a 1:1 ratio utilizing a two-sequence (fed/fasted vs. fasted/fed), two-period, cross-over design. Fruquintinib was administered on Day 1 (Period 1) and Day 15 (Period 2). In the drug-interaction period (Period 3), all subjects received rabeprazole 40 mg 1 h prior to fruquintinib under fasted conditions, following a 6-day lead-in of rabeprazole 40 mg once daily. PK samples to measure fruquintinib and M11 were collected pre-dose and over 168 h after fruquintinib dosing. Administration of fruquintinib with a high-fat meal resulted in similar systemic exposure compared with fasted conditions. In addition, coadministration of fruquintinib with rabeprazole resulted in similar exposure compared with fruquintinib alone. For both evaluations, 90% confidence intervals for the ratio of geometric least square mean of the area under the curve and peak concentration for fruquintinib and M11 were entirely within 80%-125% bounds. The study results showed no effects of food or rabeprazole on fruquintinib PK, and support that fruquintinib can be taken without regard to food or concurrent gastric acid-reducing agents.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, with high morbidity and mortality rates. Conventional treatments, including surgery, radiotherapy, and chemotherapy, have limited effects on advanced and metastatic CRC (mCRC). Fruquintinib, a novel and highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown significant efficacy and tolerance in treating mCRC. The FRESCO and FRESCO-2 trials demonstrated that fruquintinib significantly prolongs progression-free survival and the overall survival of refractory mCRC patients, establishing it as the standard third-line treatment strategy for mCRC. In addition, the combination of fruquintinib with other anticancer drugs and immune checkpoint inhibitors demonstrated potential for enhanced efficacy, which warrants further exploration. In this review, we aimed to systematically summarize the current knowledge about the pharmacological mechanisms, pharmacokinetic characteristics, adverse events, and corresponding treatment options of fruquintinib and provide an update on the clinical trials related to fruquintinib in CRC by conducting a comprehensive literature search of PubMed and consulting the relevant clinical trials via ClinicalTrials.gov and the ChiCTR website, aiming to offer new insights into the role of fruquintinib in the comprehensive treatment of CRC.

Fruquintinib is a selective, oral tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors 1, 2, and 3, which is approved for patients with previously treated metastatic colorectal cancer regardless of biomarker status. This population pharmacokinetic (PK) analysis characterized sources of interpatient variability on the PK of fruquintinib and its major metabolite M11 using data from 557 subjects who received fruquintinib in five phase I/Ib studies and the FRESCO-2 phase III study. The integrated model was a one-compartment model with first-order absorption, lag time in absorption, and linear elimination for fruquintinib and a one-compartment model with linear elimination for M11. The half-life of fruquintinib and M11 were estimated to be 43.2 and 54 h, respectively. Fruquintinib PK demonstrated dose proportionality. Fruquintinib oral clearance and apparent volume of distribution (V/F) increased with increasing body weight. Fruquintinib absorption rate constant was 60.7% lower with concurrent use of proton-pump inhibitors (PPIs), and fruquintinib V/F was 9.08% lower in healthy subjects versus patients with cancer. Magnitudes of the covariate effects of body weight, concurrent use of PPIs, and health status on fruquintinib exposures were estimated to be <20%, which is not considered clinically meaningful. Age (18.0-82.0 years), sex, race (Asian, Black, and White), ethnicity (Hispanic vs non-Hispanic), Eastern Cooperative Oncology Group performance status score, tumor type, mild or moderate renal impairment, and mild hepatic impairment had no clinically meaningful impact on fruquintinib or M11 PK. This analysis supports the same fruquintinib starting dosage, without need for adjustments, for these patient-specific factors.

Programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors have shown limited effectiveness in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Combining anti-angiogenesis inhibitors with PD-1 inhibitors has the potential to reverse the immunosuppressive tumour microenvironment, synergistically enhancing the anti-tumour immune response in MSS mCRC. The goal is to present real-world data that prove the clinical efficacy and safety of fruquintinib combined with PD-1 inhibitors in MSS mCRC.

We conducted a real-world retrospective study in patients with MSS mCRC who received treatment with fruquintinib combined with PD-1 inhibitors between May 2019 and March 2023 in our centre.

Seventy seven patients with MSS mCRC received fruquintinib combined with PD-1 inhibitors. In total, 5.2% of patients (4/77) achieved a partial response (PR), while 50.6% (39/77) had a stable disease (SD). Notably, three lesions achieving PR were all lung metastases and the overall disease control rate (DCR) reached 55.8% (43/77). Median progression-free survival (PFS) and overall survival (OS) reached 5.1 months (95% CI: 3.6-6.7) and 14.6 months (95% CI: 9.6-15.6), respectively. Multivariate Cox analysis showed that prior treatment without vascular endothelial growth factor (VEGF) inhibitors was significantly associated with PFS and OS (p < 0.05). Further analysis indicated that total- or polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) significantly decreased after treatment (P = 0.039), especially in the PR/SD group (P = 0.003). Most adverse events included abdominal pain, rash, oedema, diarrhoea, and immunotherapy-associated hypothyroidism, yet symptoms were controllable.

Our results provided additional evidence that patients with MSS mCRC could benefit from the combination of fruquintinib and PD-1 inhibitors, especially those with lung metastases or without prior treatment with VEGF inhibitors. The detection of MDSCs may be an immune indicator for predicting of the combined therapy.

The emergence of targeted anti-tumor drugs has significantly prolonged the lifespan and improved the prognosis of cancer patients. Among these drugs, vascular endothelial growth factor (VEGF) inhibitors, particularly novel small molecule tyrosine kinase inhibitors (TKIs), are extensively employed as VEGF inhibitors; however, they are also associated with a higher incidence of complications, with hypertension being the most prevalent cardiovascular toxic side effect. Currently, it is widely accepted that TKIs-induced hypertension involves multiple mechanisms including dysregulation of the endothelin (ET) axis, reduced bioavailability of nitric oxide (NO), imbalance in NO-ROS equilibrium system, vascular rarefaction, and activation of epithelial sodium calcium channels; nevertheless, excessive activation of ET system appears to be predominantly responsible for this condition. Moreover, studies have demonstrated that ET plays a pivotal role in driving TKIs-induced hypertension. Therefore, this review aims to explore the significance of ET in the pathogenesis of hypertension induced by targeted anti-tumor drugs and investigate the potential therapeutic value of endothelin antagonists in managing hypertension caused by targeted anti-tumor drugs.

The FRESCO-2 trial established the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. However, its cost-effectiveness in the US context is not well documented.

This study evaluates the cost-effectiveness of fruquintinib versus placebo for this patient population from the perspective of US payers.

We developed a partitioned survival model on the basis of patient-level data reconstructed from the survival curves of the FRESCO-2 trial. Parametric estimation was conducted to estimate long-term clinical outcomes and medical costs over a lifetime horizon. Cost inputs and utilities were sourced from public data and previous literature. We used a discount rate of 3.0% per year for both clinical outcomes and costs. We adopted an incremental cost-effectiveness ratio (ICER) threshold of US$100,000 per quality-adjusted life-year (QALY) gained. We performed sensitivity and scenario analyses to examine the robustness of cost-effectiveness results.

Fruquintinib treatment resulted in incremental gains of 0.108 life years (LYs) and 0.073 QALYs compared with the placebo, at an additional cost of US$112,294, primarily driven by medication expenses. The ICER for fruquintinib versus placebo was calculated at US$1,037,855 per LY and US$1,546,619 per QALY gained, exceeding the predefined cost-effectiveness threshold. The cost-effectiveness results were robust across all sensitivity and scenario analyses.

Despite the survival benefit, fruquintinib was not cost-effective compared with the placebo in patients with refractory metastatic colorectal cancer in the US setting, on the basis of the conventional willingness-to-pay threshold. Our findings may provide a basis for informing the pricing and reimbursement decisions regarding fruquintinib.

Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.

To comprehend the effects of diverse therapeutic interventions on thromboelastography (TEG) and conventional coagulation parameters among individuals diagnosed with colorectal cancer, this study aims to explore the clinical relevance of both thromboelastography and conventional coagulation metrics in evaluating coagulation function and predicting the incidence of thrombotic and hemorrhagic events in patients with colorectal cancer.

A cohort of 122 patients with colorectal cancer retrospectively recruited and divided into 2 groups: those undergoing surgical intervention (operation group) and those not subjected to surgery (non-operation group). According to the different types of treatment they received, the operation group was divided into chemotherapy-only group and a group receiving a combination of targeted therapy and chemotherapy. Blood samples were collected on admission and subjected to coagulation parameter assessment, including conventional coagulation tests and thromboelastography (TEG) assessment. Receiver operating characteristic (ROC) analysis was performed to predict the occurrence of complications in patients with colorectal cancer.

Compared with the operation group, the non-operation group showed significant reductions in reaction time(R-time) and kinetics time (K-time), and significant elevation in angle, maximum amplitude (MA), fibrinogen and platelets. Patients receiving targeted therapy and chemotherapy had lower angle and maximum amplitude and higher R-time and K-time, activated partial thromboplastin time and fibrinogen. The area under the curve for TEG in patients without treatment was 0.802. The area under the curve for TEG and conventional coagulation parameters were 0.654 and 0.660 respectively.

Diverse treatments distinctly impact on the coagulation indicators of individuals diagnosed with colorectal cancer. The coagulation parameters observed in patients prior to operation suggest a hypercoagulable state. Nevertheless, following postoperative chemotherapy and targeted therapy, this hypercoagulable state demonstrates a notable improvement, occasionally leading to a propensity for hypocoagulation. The findings of this investigation underscore the unique clinical importance of thromboelastography (TEG) alongside traditional coagulation parameters, demonstrating that these diagnostic tools possess complementary value and cannot be substituted interchangeably.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

Fruquintinib has received approval for the management of patients with chemotherapy-resistant metastatic colorectal cancer (mCRC). However, combination of fruquintinib with immune checkpoint inhibitors (ICIs) is yet to be extensively studied. This study aims to assess the clinical efficacy, safety, and prognostic indicators of treatment regimen combining fruquintinib with ICIs in mCRC patients.

We analyzed data from mCRC patients who were administered fruquintinib either as a monotherapy or in conjunction with ICIs following conventional chemotherapy. Parameters such as the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and incidence of adverse events were meticulously evaluated. Furthermore, the relationship between blood markers and patient prognosis was examined.

A total of 72 mCRC patients were included in this study, with a median observation period of 48 months, 19 were treated with fruquintinib alone, while 53 received a combination therapy involving fruquintinib and ICIs. The combined therapy group exhibited superior ORR and DCR compared to the fruquintinib monotherapy group. Additionally, significant improvements in OS and PFS were observed in the combined treatment group. The occurrence of adverse events was generally manageable and well-tolerated across both groups, with no significant difference in incidence rates. Notably, albumin levels were identified as a prognostic marker for PFS and OS in the univariate Cox regression analysis.

The combination of fruquintinib with ICIs demonstrated enhanced clinical efficacy and improved survival outcomes compared to fruquintinib monotherapy in mCRC patients. The safety of the combination regimen was deemed manageable and acceptable.

Colorectal cancer (CRC) is a prevalent and deadly cancer, with metastatic CRC (mCRC) often leading to poor outcomes despite advancements in screening and chemotherapy. Anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathways have become essential in mCRC treatment. Bevacizumab, a VEGF inhibitor, was the first agent used in this context. However, drug resistance prompted the development of more selective inhibitors, such as fruquintinib, a tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3. Fruquintinib has shown promise in clinical trials, particularly for third-line mCRC treatment. The Phase III FRESCO trial in China demonstrated its efficacy, significantly improving overall survival (OS) and progression-free survival (PFS) compared to placebo, with manageable safety concerns like hypertension and hand-foot skin reactions. The FRESCO-2 trial extended these findings to European and North American populations, leading to a recent FDA approval for previously treated mCRC patients. The pharmacodynamic profile of fruquintinib includes potent inhibition of VEGFR, angiogenesis, and lymphangiogenesis. It has shown synergistic effects when combined with other treatments like chemotherapy and immune checkpoint inhibitors (ICIs). Current research focuses on exploring fruquintinib's combination with ICIs, such as PD-1 inhibitors, to enhance treatment efficacy, especially in microsatellite stable (MSS) CRC. Ongoing trials are investigating Fruquintinib's potential in combination with other therapies and its use in earlier lines of treatment. While promising, further studies are required to optimize its place in therapy and identify predictive biomarkers for better patient selection.

Fruquintinib has been approved by the Food and Drug Administration for refractory metastatic colorectal cancer (mCRC). In clinical practice, fruquintinib is sometimes used in combination with other drugs, but its efficacy and safety are still unknown. In this study, we present a comprehensive analysis of the real-world treatment modalities involving fruquintinib in late-line settings for mCRC across six centers in China.

Patients with refractory mCRC who received fruquintinib treatment in six centers in China between 1 January 2021 and 31 June 2022 were included in this study. Patients were categorized into two cohorts: the monotherapy group (treated solely with fruquintinib) and the combined group (received fruquintinib combined with chemotherapy and/or anti-programmed cell death protein 1 antibodies). Demographic, clinical, survival, and safety data were retrospectively analyzed. The study was registered at clinicaltrials.gov as NCT06202417.

A total of 520 patients were included in this study. The median follow-up time was 9.7 months. The disease control rate was 64.8%. The median progression-free survival was 5.0 months and the median overall survival was 11.4 months. Of them, 387 (74.4%) were treated with fruquintinib alone, while 133 (25.6%) were administered fruquintinib plus chemotherapy and/or anti-programmed cell death protein 1 antibodies, respectively. Adverse events were reported by 91.3% (457/520) of patients. The rate of grade 3 or 4 toxicity was 42.4% (237/520). No treatment-related death occurred.

Fruquintinib, either as a standalone treatment or in combination with other medications, demonstrates substantial efficacy and favorable tolerability in refractory mCRC patients.

This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated.

Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p = 0.008) and after PSM (5.0 months vs. 4.4 months, p = 0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated.

In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Colorectal adenocarcinoma is the most prevalent form of colorectal cancer, representing the majority of cases in the United States. The disease is driven by a series of genetic mutations, including alterations in the adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS), human epidermal growth factor receptor 2 immunohistochemistry 3+ (HER-2 IHC3+), checkpoint kinase 2 (CHEK-2) and tumor protein P53 (TP53) genes, which lead to malignant transformation. While the standard treatment for metastatic colorectal cancer (mCRC) typically involves chemotherapy and targeted therapies, many patients experience disease progression, necessitating the exploration of novel treatments. Fruquintinib, a highly selective vascular endothelial growth factor (VEGFR) inhibitor, has emerged as a promising option for mCRC patients who have exhausted conventional therapies. However, its use is associated with significant bleeding risks, including rare but severe complications such as cerebellar hemorrhage. This case report presents a patient with mCRC who developed a cerebellar hemorrhage shortly after initiating fruquintinib therapy, highlighting the need for careful patient monitoring and individualized risk assessment to mitigate such serious adverse events.

This Perspective is a continuation of our analysis of U.S. FDA-approved small-molecule drugs (1938-2012) containing nitrogen heterocycles. In this study we report drug structure and property analyses of 321 unique new small-molecule drugs approved from January 2013 to December 2023 as well as information about frequency of important heteroatoms such as sulfur and fluorine and key small nitrogen substituents (CN and NO2). The most notable change is an incredible increase in drugs containing at least one nitrogen heterocycle─82%, compared to 59% from preceding decades─as well as a significant increase in the number of nitrogen heterocycles per drug. Pyridine has claimed the #1 high-frequency nitrogen heterocycle occurrence spot from piperidine (#2), with pyrimidine (#5), pyrazole (#6), and morpholine (#9) being the big top 10 climbers. Also notable is high number of fused nitrogen heterocycles, apparently driven largely by newly approved cancer drugs.

The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma.

Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs).

Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group.

Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.

Colorectal cancer (CRC) has remained the second and the third leading cause of cancer-related death worldwide and in the United States, respectively. Although significant improvement in overall survival has been achieved, death in adult populations under the age of 55 appears to have increased in the past decades. Although new classes of therapeutic strategies such as immunotherapy have emerged, their application is very limited in CRC so far. Microtubule (MT) inhibitors such as taxanes, are not generally successful in CRC. There may be some way to make MT inhibitors work effectively in CRC. One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices. A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs. In this Editorial review, we would like to discuss the potential of optogenetic approaches in CRC management.

Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy.

This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib.

Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

Immune checkpoint inhibitors (ICIs) have limited efficacy in mismatch repair proficient (pMMR) or metastatic microsatellite stable (MSS) advanced or metastatic colorectal cancer (mCRC). ICIs, in conjunction with tyrosine kinase inhibitors (TKIs) possessing anti-angiogenic properties, serve as a potential strategy for circumventing the resistance exhibited by MSS or pMMR mCRC to immunotherapeutic interventions. The present study aimed to evaluate efficacy and safety of ICIs + TKIs and provide a reference for the treatment of CRC. The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane, Web of Science and ClinicalTrials.gov databases were screened from January 1, 2003 to July 28, 2023. A total of 14 studies were included in qualitative and quantitative analyses, with a total of 819 patients enrolled. The Newcastle-Ottawa scale scores of the 14 cohort studies included were ≥7, indicating they were of a high quality. The objective response rate (ORR) of ICIs + TKIs was 14% [95% confidence interval (CI), 0.08-0.24; P=0.132] in patients with advanced or metastatic MSS/pMMR CRC. The disease control rate (DCR) was 65% (95% CI, 0.58-0.74; P<0.0001). The overall incidence of adverse events of varying severity linked to combination of ICIs and TKIs in patients with advanced or metastatic MSS/pMMR CRC was 64% (95% CI, 0.52-0.78; P<0.0001). The incidence of grade ≥3 adverse reactions was 24% (95% CI, 0.14-0.4; P<0.0001). The sensitivity analysis indicated that the exclusion of individual studies did not yield statistically significant variations in combined analysis results. Based on the examination of publication bias, ORR and DCR, Begg's and Egger's tests had P-values of 0.114 and 0.395, respectively. Overall publication bias overall was absent in the Begg's funnel plot, as there was no apparent asymmetry. Nonetheless, the P-values of the Egger's and Begg's tests for adverse reactions and adverse reactions grade ≥3 were P=0.008 and P=0.048, respectively. The asymmetry of the Begg's funnel plots was evident, suggesting the presence of potential publication bias regarding adverse event results. In conclusion, the combination of ICIs and TKIs demonstrates a favorable effectiveness and notable safety profile in the management of patients with advanced or metastatic MSS/pMMR CRC.

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC).

Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies.

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors are virtually unresponsive to programmed cell death protein 1 (PD-1) antibody treatment. This report shows that a patient with pMMR/MSS mCRC achieved significant response and the longest progression-free survival (PFS) of 28 months currently reported from tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) family (VEGFR-1,2,3) (fruquintinib) plus anti-PD-1 immunotherapy in the third line, providing a new and promising treatment option for some MSS mCRC patients.

This case details a 65-year-old male with CRC who was diagnosed with pT4aN2bM0, IIIC, and pMMR/MSS after curative surgery in August 2018. Subsequently, he received adjuvant chemotherapy [FOLFOX (folinic acid, fluorouracil, and oxaliplatin) for 5 cycles], first-line treatment (pelvic radiation plus capecitabine), and second-line treatment [TOMIRI (raltitrexed and irinotecan) plus cetuximab for 2 cycles]. Lung, liver, and pelvic cavity metastases worsened in October 2019. He began receiving the fruquintinib plus PD-1 inhibitor (FP) regimen as third-line treatment and after 3 cycles, the size of the lung lesions was significantly reduced and evaluated as partial response (PR), whereas the liver and pelvic cavity lesions remained stable. As of December 2021, he had received a total of 33 courses of FP regimen. In February 2022, liver metastases progressed. In brief, he achieved a long PFS of 28 months and an overall survival (OS) of 40 months from the third-line treatment. Additionally, the patient only experienced mild proteinuria after the combined treatment and tolerated well.

Fruquintinib combined with immunotherapy could exert good therapeutic effects with safety in MSS mCRC patients. And patients with lung metastasis may be the principal beneficiaries.

Gastrointestinal (GI) cancers encompass a group of malignancies affecting the digestive system, including the stomach, esophagus, liver, colon, rectum and pancreas. These cancers represent a significant global health burden, necessitating effective treatment strategies. Small-molecule drugs have emerged as crucial therapeutic options in the fight against GI cancers due to their oral bioavailability, targeted mechanisms of action, and well-established safety profiles. The review then elucidates the clinical applications and synthetic methods of clinically approved small-molecule drugs for the treatment of GI cancer, shedding light on their mechanisms of action and their potential in mitigating GI cancer progression. The review also discusses future prospects and the evolving landscape of small-molecule drug development in GI oncology, highlighting the potential for personalized medicine. In summary, this review provides valuable insights into cutting-edge strategies for harnessing clinically approved small-molecule drugs to combat GI cancer effectively.