Metastatic colorectal cancerOverview

In recent years, the incidence of colorectal cancer worldwide has presented a rising trend year by year. Nearly 20% of patients with colorectal cancer are diagnosed with metastasis at the first visit, and their 5-year survival is only 14%. Therefore, more effective treatments are urgently needed for a portion of patients with mCRC who have failed at least three lines of standard treatment (who failed standard 3 + line) [25,26,27]. Fruquintinib, a highly selective TKI, may offer a new therapeutic strategy for patients with mCRC driven by genetic mutations, potentially minimizing the adverse cytotoxicity and resistance to systemic chemotherapy [28].

Phase III clinical trials

In the FRESCO trial (a randomized, double-blind, placebo-controlled, and multi-center clinical trial conducted in China) [23], 416 patients (mean age: 54.6 years) were randomized to the fruquintinib group (278 patients) or the placebo group (138 patients). The primary study endpoint of the trial was overall survival (OS), and the secondary study endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The results of the FRESCO trial illustrated that the median OS in the fruquintinib group (9.3 months) was better than that in the placebo group (6.6 months), with a significant prolongation of the median PFS by 1.9 months. Moreover, the ORR and the DCR were apparently higher compared with those in the placebo group. This phase III clinical study preliminary confirmed that fruquintinib could remarkably improve the OS and the PFS in patients with colorectal cancer, demonstrating safe and effective therapeutic effects.

In 2018, fruquintinib received its first global approval in China for the treatment of patients with mCRC who had failed previous second-line and third-line therapies [9]. Subsequently, an international, randomized, double-blind, and placebo-controlled phase III study (FRESCO-2) was conducted in 124 hospitals and cancer centers in multiple countries worldwide, enrolling a total of 934 patients with mCRC [29]. The results of the FRESCO trial demonstrated that the median OS (7.4 months) in the fruquintinib group was evidently better than that in the placebo group (4.8 months) (p < 0.001). Additionally, the median duration of remission (10.7 months) and DCR (56%), respectively, were higher in the fruquintinib group than in the placebo group. These data indicated that fruquintinib was effective and well-tolerated in patients with mCRC who had failed at least three lines of standard therapy.

The results of these two phase III studies displayed that fruquintinib had significant efficacy in the treatment of mCRC. Fruquintinib, compared to regorafenib, presented no significant difference in OS. However, it showed better trends in PFS, the overall incidence of adverse reactions, and cost-effectiveness [30,31,32]. A direct comparative clinical trial of the efficacy and safety of these two drugs revealed [33] that fruquintinib was superior to regorafenib in terms of the median PFS, median OS, and ORR (Table 2).

Table 2 Comparison of the efficacy of fruquintinib and regorafenib in the treatment of metastatic colorectal cancerCombination therapy with programmed death-1 inhibitors

Treatment options for patients with mCRC are limited. Approximately 95% of patients with CRC have proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors that show little response to programmed death-1 (PD-1) antibody therapy [34]. In Japan, regorafenib in combination with nivolumab has shown promising anticancer activity in patients with refractory mCRC, providing a new therapeutic option [35].

Studies have shown that PD-1 promotes tumor angiogenesis by binding to the immunosuppressive molecule PD-ligand 1 (PD-L1). VEGF/VEGFR promotes tumor angiogenesis by inducing a variety of intracellular pathways to regulate cell division, survival, budding, and endothelial cell migration. Both PD-1/PD-L1 and VEGF/VEGFR are equally involved in cancer immune evasion [36, 37]. Anti-angiogenic therapy can activate the immune responses of antitumor CD8 T cells and enhance the infiltration of these cells. This mechanism may be achieved through the activation of endothelial cells and vascular normalization, coupled with the inhibition of regulatory T cell infiltration [16, 38]. Fruquintinib, when administered at lower doses, has the ability to shift the inherently immunosuppressive tumor microenvironment to an immune-supportive state. Furthermore, it can also enhance the response to immunotherapy in both colon cancer model mice and clinical patients with colorectal cancer, thereby improving the efficacy of anti-PD-1 therapy [4, 39]. In a preclinical study, the combination of fruquintinib with PD-1 inhibitors presented stronger tumor growth suppression in the models that represented MSS and microsatellite instability (MSI) CRC compared to either agent alone [4]. Gou et al. [40] demonstrated that, compared to fruquintinib monotherapy (11.1% vs. 4.9%), the ORR was obviously higher when fruquintinib was combined with PD-1 inhibitors for the treatment of patients with refractory non-microsatellite instability-high/pMMR mCRC. Wang et al. [16] disclosed in a murine syngeneic model of CT26 cells that the combination of fruquintinib and PD-1 inhibitors could optimize the antitumor microenvironment by reducing regulatory T cells and enhancing T lymphocyte function, thereby showing remarkable synergistic antitumor effects. Li et al. [4] discovered in an allograft transplantation tumor model established using colon cancer cells of mice CT26 and MC38 that the combination of fruquintinib and sintilimab greatly inhibited the growth of CRC by altering the immune microenvironment of tumors.

A retrospective single-center analysis conducted by Yang et al. [41] evaluated the outcomes of patients with MSS mCRC who were treated with fruquintinib in combination with anti-PD-1 antibodies (sintilimab and toripalimab) after the failure of standard therapies. The analysis outcomes revealed that the combination of fruquintinib and anti-PD-1 antibodies improved the OS and PFS of patients with refractory MSS mCRC in China and exhibited a tolerable toxicity profile. Li et al. [42] denoted that fruquintinib in combination with sintilimab provided the higher DCR and the longer median PFS and was better tolerated compared with a trifluridine-tipiracil hydrochloride mixture. Ma et al. [43] conducted a single-arm, single-center, prospective, phase II clinical study on the third-line treatment of refractory advanced mCRC using sintilimab combined with toripalimab. This study demonstrated that the ORR of the combination was 21.05%, which was superior to that of patients treated with fruquintinib alone (ORR = 4.7%). This result supported the conclusion that fruquintinib in combination with an anti-PD-1 monoclonal antibody had better efficacy than fruquintinib alone for the third-line treatment of patients with advanced colorectal cancer with MSS in China. Another retrospective study verified that fruquintinib in combination with a PD-1 inhibitor significantly improved patients’ PFS time compared with regorafenib in combination with a PD-1 inhibitor in the treatment of advanced mCRC with MSS/pMMR [44].

However, all current studies on the combination of anti-angiogenic agents and PD-1 inhibitors are small-sample phase I/II prospective or retrospective studies with a single-arm design. The conclusions vary somewhat, and there is a lack of double-blind, randomized controlled phase III studies. The LEAP-017 study is the only ongoing phase III study (NCT04776148) [41]. More well-structured, prospective, and extensive studies are needed in the future to confirm and validate the efficacy of fruquintinib in combination with PD-1 inhibitors.

Combination with other comprehensive therapies

PD1/PD-L1 inhibitors have been shown to be effective in patients with mCRC with microsatellite instability-high or mismatch repair-deficient genes [45, 46]. However, immune checkpoint inhibitors (ICIs) have limited efficacy in patients with advanced colon cancer with microsatellite instability-low or pMMR genes [47]. Studies have shown that systemic antitumor immune responses induced by radiotherapy through an “abscopal effect” can reverse the immunosuppressive tumor microenvironment and promote antitumor immunity [48,49,50]. In addition, radiotherapy also affects the tumor vascular system, where a single high-dose irradiation induces endothelial cell apoptosis and senescence, causing vascular regression and collapse, leading to tissue hypoxia. Conversely, fractionated low-dose irradiation increases the expression of growth factors by inducing angiogenesis (e.g., VEGF) [48, 51]. This provides an opportunity for intervention with anti-angiogenic drugs, potentially enhancing immunotherapy sensitivity in patients with MSS.

According to recent studies, patients with mCRC who have a limited number of metastases may benefit from a combination of radical local treatment and systemic therapy. This combined approach has the potential to achieve long-term tumor control. Wang et al. [48] conducted the RIFLE study (a Phase II trial of stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in mCRC), which provided a new therapeutic strategy for patients and improved their prognosis. Moreover, the objective of this trial was to enhance the current understanding of the combination of radiotherapy, targeted therapy, and immunotherapy. In addition, the trial is also intended to optimize the clinical application of systemic treatment for mCRC. Combining ICI with an anti-VEGFR-TKI and local radiation interventions may be an effective strategy for heavily pretreated patients with mCRC exhibiting a MSS phenotype. In addition, Wang et al. [52] reported a case report of a patient with mCRC treated with fruquintinib who exhibited microsatellite instability as well as a KRAS exon 2 p. G12D mutation. This patient underwent local radiotherapy and then continued to receive fruquintinib, which resulted in sustained partial remission, and his PFS exceeded 30 months. Such outcomes suggested that fruquintinib may be an effective treatment for specific populations following local radiotherapy and that in-depth studies by expanding the sample size are needed.

Although TKIs and ICIs have achieved certain successes in the treatment of MSS and CRC, the efficacy of their combination is still limited. Studies have suggested that modulating the composition of the gut microbiota can enhance the efficacy of anti-PD-1 immunotherapy. Zhao et al. [53] conducted the first prospective study evaluating the antitumor activity and safety of fecal microbiota transplantation in combination with tislelizumab and fruquintinib as a third-line or above treatment for patients with MSS mCRC. They observed a significant improvement in the survival benefit (9.6 months of median PFS and 13.7 months of median OS), and ORR and DCR were 20% and 95%, respectively. This suggested that the combination of the three treatments has good antitumor activity with controllable toxicity.

The above results suggest that local radiotherapy, acting as an immunomodulator, can further enhance disease control on the basis of ICI. Furthermore, fecal microbiota transplantation, based on the gut microbiome, can also serve as a promising adjuvant approach to enhance antitumor immunity and promote response to ICI. More treatment options and survival benefits for cancer patients can be provided through the study of different treatment regimen combinations and the conduct of more prospective and extensive trials.

Adverse reactions and safety

Li et al. [29] indicated that there were a range of adverse reactions associated with treatment with fruquintinib. To be specific, nearly 63% of the fruquintinib group had grade 3 or higher adverse reactions. Common adverse reactions included hypertension, fatigue, anorexia, diarrhea, hypothyroidism, and lethargy. Additionally, the most frequently observed serious adverse reactions included hypertension, hand-foot skin reactions, and proteinuria. Given the high incidence of hypertension induced by fruquintinib, close attention should be paid to patients during the first two weeks of treatment. Clinical pharmacists should provide pharmacotherapy recommendations to clinicians through pharmaceutical care. Also, supportive treatments and dosage adjustments should be implemented to prevent severe adverse reactions.

In a previous research, a patient with advanced colon cancer experienced elevated blood pressure during targeted therapy with fruquintinib. The blood pressure decreased after suspending fruquintinib and administering antihypertensive therapy. Subsequently, treatment with fruquintinib was continued in combination with levamlodipine and irbesartan-hydrochlorothiazide to maintain stable blood pressure [54]. In addition, some rare adverse effects were observed in the above study, including symptoms such as hyperuricaemia, chest pain, hemorrhoids, changes in the ST segment in the electrocardiogram, and insomnia [55]. Recently, Wang et al. [56] reported a case of posterior reversible encephalopathy syndrome associated with fruquintinib for the first time. This suggests that the administration of fruquintinib may increase the risk of posterior reversible encephalopathy syndrome.

Although treatment with fruquintinib leads to some adverse reactions, such as hypertension, hand-foot skin reactions, and proteinuria, most of these effects are target-related. They can be predicted, controlled, and reversed in clinical settings through pharmacological monitoring. Therefore, fruquintinib generally demonstrates a high safety profile [57].

Gastric cancerOverview

As one of the most common cancers worldwide, gastric cancer ranks fifth in incidence among malignant tumors, with an estimated annual occurrence of over one million new cases. Moreover, gastric cancer holds the fifth position in cancer-related mortality rates [1, 58]. Currently, the first-line treatment for advanced unresectable or metastatic gastric cancer primarily consists of platinum and fluorouracil two-agent chemotherapy, often combined with targeted agents [59]. Nevertheless, second-line treatment options for advanced gastric cancer after the failure of first-line treatment are still very limited. Despite the recommendation of paclitaxel combined with ramucirumab as the preferred regimen, the search for more effective and personalized treatment regimens for gastric cancer remains a priority for future research [60].

Clinical studies

Fruquintinib has been reported to enhance antitumor activity and exhibit good tolerability when combined with chemotherapeutic agents in a patient-derived xenograft model [5]. Zhang et al. [61] initially conducted a phase II study (NCT02415023) of fruquintinib in combination with paclitaxel for second-line treatment of advanced gastric cancer. They enrolled 34 patients and determined the recommended phase II dose. In addition, they observed that 7 patients in the 4 mg dose group achieved partial remission of the tumor response, with an ORR of 25.9%; 40.7% of patients achieved stable disease status, with a DCR of 66.7%; and 22 patients (81.5%) achieved tumor shrinkage. Such results further confirmed the antitumor activity of fruquintinib in combination with chemotherapy. A further phase III clinical trial (NCT03223376) was also conducted for the combination of fruquintinib and paclitaxel in the treatment of gastric cancer [9].

To fill the gap in the neoadjuvant treatment of gastric cancer with fruquintinib, Wu et al. [62] conducted a phase II, multicenter, single-arm, open-label clinical trial (NCT5122091). Through such a trial, they expected to evaluate the efficacy and safety of fruquintinib in combination with SOX (S-1 and oxaliplatin) in patients with locally advanced gastric cancer.

Adverse reactions

During the treatment of advanced gastric cancer with fruquintinib + paclitaxel, patients experienced a range of adverse reactions, primarily grade 3 and above. These included leukopenia, neutropenia, hypertension, hand-foot syndrome, and hemorrhage. Among the 28 evaluable patients, the common all-grade adverse reactions were mainly leukopenia, neutropenia, alopecia, and anemia [63]. However, the sample size of the clinical studies at present is small, and most of the enrolled patients have good organ function. The real situation of the adverse reactions of fruquintinib treatment for advanced gastric cancer needs to be further explored, and the sample size needs to be enlarged for more in-depth studies.

Advanced non-small cell lung cancerOverview

Lung cancer is the leading cause of death from malignant tumors in the world, with more than 1.6 million deaths annually. Approximately 85% of these cases are non-small cell lung cancer (NSCLC), principally comprising lung adenocarcinoma and lung squamous cell carcinoma [63]. Recently, the development of new drugs and therapies has seen the application of fruquintinib in patients with NSCLC, with the aim of improving their prognosis.

Clinical studies

In a randomized, double-blind, placebo-controlled, multicenter phase II clinical study involving patients with advanced squamous NSCLC, patients in the fruquintinib group showed a longer-term survival benefit. The study included 91 evaluable patients and demonstrated that the median PFS in the fruquintinib group was 3.8 months (risk ratio for blinded independent central review was 0.34; 95% confidence interval: 0.20–0.57). The 3-month and 6-month survival rates of patients in the fruquintinib group (90.2% and 67.2%, respectively) were significantly higher than those in the placebo group (73.3% and 58.8%, respectively). Additionally, the ORR and the DCR (13.1% and 60.7%, respectively) were also significantly higher than those in the placebo group (0% and 13.3%, respectively) [64]. Lu et al. [6] conducted a phase III trial on advanced lung squamous NSCLC, enrolling 527 patients with advanced/metastatic lung squamous NSCLC. The enrolled patients were divided into two groups: the fruquintinib group (n = 354) and the placebo group (n = 173). They received either 5 mg of oral fruquintinib or placebo once daily. The median OS was 8.9 and 10.4 months, while the median PFS was 3.7 and 1.0 months for the fruquintinib and placebo groups, respectively. The ORR (13.8% vs. 0.6%) and DCR (66.7% vs. 24.9%) were significantly higher in the fruquintinib group than in the placebo group. All of these studies suggest that fruquintinib shows longer-term survival benefits in the treatment of advanced NSCLC.

Another experimental study exhibited that the combination therapy of fruquintinib and gefitinib also achieved favorable efficacy and safety in advanced NSCLC with epidermal growth factor receptor mutations [65]. The study has progressed to a phase II trial, and the results demonstrated that the ORR and DCR of fruquintinib in combination with gefitinib were 73.5% and 98.0%, respectively. Additionally, the median PFS of the combined drugs was significantly improved by approximately 30% compared with gefitinib monotherapy (14.72 months vs. 10.4 months). The study preliminarily verified that the efficacy of fruquintinib combined with gefitinib in the treatment of advanced NSCLC was superior to that of gefitinib monotherapy.

Adverse reactions

In terms of safety analysis, the most common grade ≥ 3 adverse reaction of fruquintinib for lung squamous NSCLC was hand-foot syndromes, followed by hypertension, proteinuria, and hemoptysis [66]. In the combination of fruquintinib and gefitinib, all patients (including the 4 mg fruquintinib group and the 5 mg fruquintinib group) experienced at least one adverse reaction of special concern, the most common of which were hepatotoxicity, thyroid dysfunction, and proteinuria [65]. A few patients experienced adverse reactions such as headache, alopecia, nasal bleeding, hyperthyroidism, anal fissure, dizziness, and femoral vein thrombosis [55]. Overall, most of the adverse reactions caused by fruquintinib treatment were within manageable limits, and the overall safety profile was favorable.

Other tumors

Two cases of patients with metastatic pancreatic cancer after failure of chemotherapy with fruquintinib treatment were recently reported, which showed that the PFS of these two patients was prolonged to 10 months [67]. In the treatment of Hodgkin lymphoma, a patient treated with fruquintinib + raltitrexed + S-1 also achieved a good survival benefit, suggesting the possibility of a combination regimen [68]. Clinical trials of fruquintinib for the treatment of a variety of other advanced malignancies are also progressing steadily, providing new ideas for the treatment of various malignancies. For instance, significant progress has been achieved in retrospective studies on advanced bone and soft tissue sarcomas. Additionally, a phase Ib/II trial (NCT04577963) focusing on breast cancer is currently in the enrollment phase [20]. Future clinical studies of fruquintinib in the treatment of other advanced malignancies still require continued attention.