Efficacy and safety of fruquintinib plus sintilimab in third-line treatment of metastatic colorectal cancer: A single-center experience

Abstract

BACKGROUND

There are few drugs available for the third-line treatment of metastatic colorectal cancer (mCRC), and efficacy is generally poor. Fruquintinib, an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor, has been approved for mCRC; however, its efficacy as a single agent is not satisfactory. Most patients with mCRC are microsatellite stable (MSS), and not sensitive to immunotherapy. The combination of fruquintinib and immunotherapy may improve the survival of patients with mCRC.

AIM

To report the real-world experience using this combination therapy for MSS mCRC in routine clinical practice.

METHODS

The medical records of six patients with MSS mCRC who received third-line treatment with fruquintinib plus sintilimab between January 2022 and June 2024 were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier method.

RESULTS

One patient achieved a complete response, one had stable disease, and four experienced progressive disease. Median progression-free survival was 3.8 months, and median overall survival was 5.7 months. Common adverse reactions included bone marrow suppression, liver function impairment, and hypothyroidism, predominantly grades 1-2, with no grade 4 adverse reactions reported.

CONCLUSION

Our single-center experience in a small cohort implies fruquintinib combined with sintilimab may be efficacious and safe for select patients in the third-line treatment of mCRC. This combination therapy warrants further exploration.

Key Words: Metastatic colorectal cancer; Third-line treatment; Fruquintinib; Sintilimab; Immunotherapy; Prognosis

Core Tip: This study evaluated the safety and efficacy of fruquintinib plus sintilimab in third-line treatment of metastatic colorectal cancer (mCRC). One patient achieved complete response, one had stable disease, and four experienced progressive disease. Median progression-free survival was 3.8 months, and median overall survival was 5.7 months. Fruquintinib combined with sintilimab was well tolerated. Common adverse reactions included bone marrow suppression, liver function impairment, and hypothyroidism, predominantly grades 1-2. Fruquintinib combined with sintilimab as a third-line treatment for mCRC appeared effective in patients with microsatellite stable mCRC and a low tumor burden, who experienced a survival benefit. This treatment warrants further exploration.

INTRODUCTION

Colorectal cancer (CRC) is among the most prevalent malignant tumors of the digestive system. Globally, in 2020, there were an estimated 1.9 million new cases of CRC with 930000 deaths; in 2040, there will be an estimated 3.2 million new cases and 1.6 million deaths[1]. Among patients newly diagnosed with CRC, 20% present with metastatic disease, while an additional 25% of patients initially diagnosed with localized disease will later develop metastases[2]. Guideline recommended first-line and second-line treatments for metastatic CRC (mCRC) include chemotherapy and targeted therapy. Chemotherapy agents comprise oxaliplatin (OXA), irinotecan, 5-fluorouracil, and capecitabine, while targeted therapies comprise bevacizumab (Bev), cetuximab, and panitumumab[3]. Approximately 50% of patients with mCRC who receive first-line treatment will require third-line treatment[4]. However, third-line treatment options for mCRC are limited to a few agents, such as regorafenib, fruquintinib and trifluridine/tipiracil, with suboptimal efficacy, evidenced by median progression-free survival (mPFS) of only 1.9 months, 3.7 months, and 2.0 months, respectively[5-7]. Currently, there remains a critical unmet clinical need for advancements in the treatment of mCRC in the third-line setting.

In recent years, immunotherapy has been extensively utilized in the treatment of various tumors, including melanoma[8], lung cancer[9], and liver cancer[10], significantly extending patient survival. In mCRC, only the 5% of patients with microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) tumors benefit from immunotherapy, while the remaining 95% of patients, who have microsatellite stable (MSS) tumors, experience no significant improvement[11]. Compared to MSS tumors, MSI-H/dMMR tumors have a higher accumulation rate of mutations and neoantigens, which can be recognized by the immune system, diminished immunosuppressive cells, higher levels of immunoinhibitory molecules and tumor-infiltrating lymphocytes, increased expression of immune checkpoint proteins, and decreased myeloid-derived suppressor cells and regulatory T cells, explaining the favorable clinical response of MSI-H/dMMR CRCs to immunotherapy[12].

Given the suboptimal efficacy of single-agent tyrosine kinase inhibitors (TKIs) such as regorafenib and fruquintinib, and the insensitivity of most MSS mCRCs to immunotherapy, several studies have explored the combination of TKIs with programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors for MSS mCRC. For example, the REGONIVO and REGOTORI phase 1b/2 clinical trials evaluated the effects of regorafenib in combination with nivolumab and toripalimab, respectively, in patients with MSS/MMR-proficient/MSI-low mCRC who had received ≥ 2 previous lines of therapy, yielding mPFS of 1.8 months and 2.1 months[13,14]. These results remain unsatisfactory, emphasizing the urgency of establishing an optimal third-line drug regimen for patients with MSS mCRC.

Fruquintinib is a potent and selective small-molecule inhibitor targeting vascular endothelial growth factor receptors 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3). In both Chinese and global populations, fruquintinib has demonstrated statistically significant clinical benefits compared to placebo in patients with mCRC who have experienced tumor progression after receiving at least two prior chemotherapy regimens[15]. Sintilimab, an anti-PD-1 monoclonal antibody, has been approved for the treatment of various tumors, including gastric cancer, esophageal cancer, and nasopharyngeal carcinoma in China[16-18]. In mouse models of MC38 or CT26 xenograft tumors, which represent MSS and MSI-H CRC, the combination of these two drugs significantly inhibited tumor growth and prolonged survival compared to either fruquintinib or sintilimab alone[19]. These data provide evidence for the efficacy of combining fruquintinib and sintilimab in the treatment of patients with mCRC. This study reports our real-world experience using this combination therapy for MSS mCRC in routine clinical practice.

MATERIALS AND METHODS

Study population

Medical records of patients diagnosed with mCRC through histopathology or cytology at The First Affiliated Hospital of Nanjing Medical University from January 2022 to June 2024 were retrospectively reviewed. Inclusion criteria were: (1) Aged 18 to 80 years; (2) Eastern Cooperative Oncology Group (ECOG) score of 0 or 1; (3) Confirmed diagnosis of CRC through histology and/or cytology; (4) Confirmed diagnosis of mCRC via at least one imaging method, such as computed tomography or magnetic resonance imaging; (5) Presence of at least one measurable lesion according to the RECIST version 1.1 criteria; and (6) Received third-line treatment with fruquintinib combined with sintilimab following the failure of second-line systemic therapy. Exclusion criteria were: (1) CRC other than adenocarcinoma; (2) History of severe bleeding or coagulation disorders; or (3) History of immunodeficiency diseases.

Patients were followed from diagnosis until September 2025, during which enhanced computed tomography scans of the chest and abdomen were performed. If necessary, non-contrast and enhanced magnetic resonance imaging scans of the upper abdomen were also conducted, along with serum carcinoembryonic antigen testing and monitoring of previously elevated tumor markers.

Data collection

Patient demographic and clinical data were recorded, including: (1) Gender, age, ECOG score, primary tumor site, metastatic site, surgical history, RAS/RAF gene status, MSI status, and the Combined Positive Score (CPS) of PD-L1 expression; (2) Previous systemic treatments, including first-and second-line treatment regimens and PFS; and (3) Third-line treatment regimen, including the number of treatment cycles, efficacy evaluations, follow-up results, PFS, overall survival (OS), and adverse reactions.

PFS was recorded as PFS1, defined as time from the initiation of first-line treatment to first disease progression, PFS2, defined as time from the initiation of second-line treatment to second disease progression, and PFS3, defined as time from the initiation of fruquintinib combined with sintilimab to third disease progression. OS was defined as time from the initiation of fruquintinib combined with sintilimab to either patient death or the last follow-up.

Statistical analysis

Analyses were performed using SPSS (version 22.0, IBM, Armonk, NY, United States). Patient clinical characteristics are reported using a narrative summary. The Kaplan-Meier method was used to construct survival curves. No formal statistical comparisons were performed and survival estimates are descriptive due to the small cohort and limited number of events.

RESULTS

Study population

Between January 2022 and June 2024, 42 patients with mCRC were admitted to our institution. Among these, 13 patients were receiving first-line treatment, 15 patients were receiving second-line treatment, and 14 patients were receiving third-line treatment due to disease progression. Of the 14 patients receiving third-line treatment, four patients received trifluridine/tipiracil combined with Bev, three patients received fruquintinib monotherapy, one patient received a combination of cadonilimab, fruquintinib, and trifluridine/tipiracil, and six patients received fruquintinib combined with sintilimab (Figure 1).

Figure 1 Flowchart of patient selection. SD: Stable disease; PD: Progression disease; CR: Complete response.

The six patients treated with fruquintinib combined with sintilimab were included in this study. Patients were followed from diagnosis until September 2025. Patients had a median age of 54 years, (range, 39 to 66 years), and there were three males and three females. Four patients had an ECOG score of 0 and two patients had an ECOG score of 1. Primary tumor sites included the ascending colon in one patient, the descending colon in two patients, the sigmoid colon in one patient, and the rectum in two patients. The liver was the only metastatic site in two patients, while four patients had multi-organ metastases. Primary tumors were resected in four patients and unresected in two patients. RAS/RAF status was wild-type in one tumor, with KRAS mutations in three tumors, NRAS mutation in one tumor, and BRAF mutation in one tumor. All six patients had MSS CRC. The CPS of PD-L1 expression was 0 for two tumors, 1 for one tumor, 5 for two tumors, and 6 for one tumor (Table 1, Figure 2).

Figure 2 Combined Positive Score. A: Patient 1, Combined Positive Score (CPS) = 1; B: Patient 2, CPS = 5; C: Patient 3, CPS = 5; D: Patient 4, CPS = 0; E: Patient 5, CPS = 0; F: Patient 6, CPS = 6. CPS: Combined Positive Score.

Table 1 Patient demographic and clinical characteristics.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Sex	Female	Male	Male	Male	Female	Female
Age (years)	47	63	39	66	57	51
ECOG	0	0	0	1	0	1
Primary location	Descending colon	Rectum	Descending colon	Sigmoid colon	Ascending colon	Rectum
Primary resection	No	Yes	Yes	Yes	Yes	No
Metastatic lesion	Liver, lung, peritoneum, bone	Liver	Liver, peritoneum	Liver, bone	Liver	Liver, bone
RAS/BRAF status	BRAF mutant	NRAS mutant	Wild	KRAS mutant	KRAS mutant	KRAS mutant
MSS status	MSS	MSS	MSS	MSS	MSS	MSS
CPS	1	5	5	0	0	6
First-line	mFOLFOX6 + Bev	OXA + RTX	mFOLFOX6 + Cet	XELOX + Bev	XELOX	XELOX + Bev
PFS1 (months)	7.8	17	13.2	3.5	4.2	2.2
Second-line	CPT-11 + RTX + Bev	CPT-11 + RTX + Bev	CPT-11 + RTX + Bev	CPT-11 + RTX + Bev	CPT-11 + RTX	CPT-11 + RTX + Bev
PFS2 (months)	6.1	12.5	3.3	1.8	1.9	1.9
Third-line	Fruquintinib + sintilimab	Fruquintinib + sintilimab	Fruquintinib + sintilimab	Fruquintinib + sintilimab	Fruquintinib + sintilimab	Fruquintinib + sintilimab
PFS3 (months)	3.8	11	2.8	5.1	10	1.7
Third-line cycles	3	12	3	6	12	2
Efficacy	PD	SD	PD	PD	CR	PD
OS	5.1	17.1	5.7	6.9	10	5

ECOG: Eastern Cooperative Oncology Group; MSS: Microsatellite stability; CPS: Combined Positive Score; PFS: Progression-free survival; OS: Overall survival; mFOLFOX6: Oxaliplatin + leucovorin + fluorouracil; Bev: Bevacizumab; OXA: Oxaliplatin; RTX: Raltitrexed; Cet: Cetuximab; XELOX: Oxaliplatin + capecitabine; CPT-11: Irinotecan; CR: Complete response; SD: Stable disease; PD: Progression disease.

Patient management

Among the six patients, one received first-line treatment with mFOLFOX6 (OXA + leucovorin + fluorouracil) + Bev, one with OXA + raltitrexed (RTX), one with mFOLFOX6 + cetuximab, one with XELOX (OXA + capecitabine), and two with XELOX + Bev. One patient received second-line treatment with irinotecan + RTX and five patients received second-line treatment with irinotecan + RTX + Bev. All six patients received third-line treatment with fruquintinib plus sintilimab. Details of the treatment regimens are provided in Table 2.

Table 2 Treatment regimens.

Treatment regimens
mFOLFOX6 + Bev	Oxaliplatin 100 mg/m2 on day 1, leucovorin 400 mg/m2 on days 1-2, and fluorouracil 2400 mg/m2 once over 46 hours on days 1-3, bevacizumab 5 mg/kg on day 1
OXA + RTX	Oxaliplatin 130 mg/m2 on day 1, raltitrexed 3 mg/m2 on day 1
mFOLFOX6 + Cet	Oxaliplatin 100 mg/m2 on day 1, leucovorin 400 mg/m2 on days 1-2, and fluorouracil 2400 mg/m2 once over 46 hours on days 1-3, cetuximab 500 mg/m2 on day 1
XELOX	Oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1-14
XELOX + Bev	Oxaliplatin 130 mg/m2 on day 1, capecitabine 1000 mg/m2 twice daily on days 1-14, bevacizumab 7.5 mg/kg on day 1
CPT-11 + RTX	Irinotecan 200 mg/m2 on day 1, raltitrexed 3 mg/m2 on day 1
CPT-11 + RTX + Bev	Irinotecan 200 mg/m2 on day 1, raltitrexed 3 mg/m2 on day 1, bevacizumab 7.5 mg/kg on day 1
Fruquintinib + sintilimab	Fruquintinib 3 mg once daily on days 1-21, sintilimab 200 mg on day 1

mFOLFOX6: Oxaliplatin + leucovorin + fluorouracil; Bev: Bevacizumab; OXA: Oxaliplatin; RTX: Raltitrexed; Cet: Cetuximab; XELOX: Oxaliplatin + capecitabine; CPT-11: Irinotecan.

Efficacy

A total of 37 cycles of third-line treatment were administered to the six patients, with a median of 4.5 cycles per patient (range: 2 to 12 cycles). One patient achieved stable disease, with a 4.7% reduction in tumor diameter, while another patient underwent resection of the primary tumor followed by resection of liver metastases, resulting in a postoperative assessment of complete response (CR). After third-line treatment, this patient maintained CR, as no new lesions were observed over a follow-up of nine months. Four patients experienced progressive disease, with tumor diameters increasing by 51.8%, 73.6%, 26.3%, and 49.6%, respectively. No patient experienced a partial response. Disease control rate was 33.3% (n = 2/6 patients) (Figure 3). By the end of follow-up, there were five deaths, with one patient remaining alive. The mPFS for the six patients was 3.8 months (95% confidence interval: 1.04-6.56), and the mOS was 5.7 months (95% confidence interval: 3.54-7.86) (Figure 4).

Figure 3 Imaging. A: Patient 1, baseline; B: Patient 1, after 3 cycles; C: Patient 2, baseline; D: Patient 2, after 4 cycles; E: Patient 3, baseline; F: Patient 3, after 3 cycles; G: Patient 4, baseline; H: Patient 4, after 6 cycles; I: Patient 5, baseline; J: Patient 5, after 12 cycles; K: Patient 6, baseline; L: Patient 6, after 2 cycles. Orange arrows indicate the main lesions. Baseline refers to imaging at initiation of fruquintinib combined with sintilimab.

Figure 4 Survival analysis. A: Median progression-free survival of third-line treatment; B: Median overall survival of third-line treatment. PFS: Progression-free survival; OS: Overall survival; CI: Confidence interval.

Adverse reactions

All patients reported grade 1-2 adverse reactions. Treatment-related hematological adverse reactions included leukopenia, neutropenia, anemia, thrombocytopenia, and liver function impairment. Treatment-related non-hematological adverse reactions included hypothyroidism, myocarditis, proteinuria, hypertension, and hand-foot skin reactions. Patient 1 independently adjusted the dose of fruquintinib from 3 mg once daily to 5 mg during the first treatment cycle, and reported grade 3 palmar-plantar erythrodysesthesia syndrome after 10 days. Due to intolerance, the dose of fruquintinib was readjusted to 3 mg, after which the palmar-plantar erythrodysesthesia syndrome gradually resolved. There were no instances of treatment interruption due to severe adverse reactions, and there were no treatment-related deaths (Table 3, Figure 5).

Figure 5 Palmar-plantar erythrodysesthesia syndrome in patient 1. A: Right hand; B: Left hand; C: Right foot; D: Left foot.

Table 3 Adverse reactions, n (%).

AEs	Grade 1	Grade 2	Grade 3
White blood cell decreased	0 (0)	1 (16.7)	0 (0)
Neutropenia	1 (16.7)	1 (16.7)	0 (0)
Anemia	4 (66.7)	0 (0)	0 (0)
Thrombocytopenia	2 (33.3)	0 (0)	0 (0)
Alanine aminotransferase increased	5 (83.3)	0 (0)	0 (0)
Aspartate aminotransferase increased	5 (83.3)	0 (0)	0 (0)
Urinary protein increased	0 (0)	1 (16.7)	0 (0)
Fatigue	0 (0)	0 (0)	0 (0)
Anorexia	0 (0)	0 (0)	0 (0)
Hypertension	0 (0)	1 (16.7)	0 (0)
Hemorrhage	0 (0)	0 (0)	0 (0)
Palmar-plantar erythrodysesthesia syndrome	0 (0)	0 (0)	1 (16.7)
Hypothyroidism	2 (33.3)	1 (16.7)	0 (0)
Myocarditis	1 (16.7)	0 (0)	0 (0)

AEs: Adverse events.

DISCUSSION

In recent years, immunotherapy has emerged as an important modality for anti-tumor treatment, complementing chemotherapy and targeted therapy[20]. However, only a limited number of patients with MSI-H CRC derive substantial benefits from immunotherapy. Most MSS CRCs are typically classified as immunologically “cold” tumors, characterized by a scarcity of effector T cells and an abundance of immunosuppressive cells within the tumor microenvironment. Consequently, the efficacy of immunotherapy as a standalone treatment for MSS CRCs is poor. Addressing this therapeutic bottleneck and converting MSS “cold” tumors into “hot” tumors akin to MSI-H tumors presents an urgent challenge[21]. The combination of targeted therapy with immunotherapy may represent one potentially effective strategy[22,23]. When administered alone, immunotherapy encounters obstacles such as aberrant tumor vasculature, which impedes the infiltration of immune cells into tumor tissue and restricts the delivery of therapeutic agents. However, integration of small molecule TKIs can facilitate vascular normalization through anti-angiogenic effects, enhance drug delivery, and promote the infiltration of primed CD8+ T cells into the tumor core, thereby transforming the tumor microenvironment from “cold” to “hot” and improving the efficacy of immunotherapy[24]. This study reports our real-world experience using fruquintinib (an anti-VEGFR TKI) combined with sintilimab (an anti-PD-1 monoclonal antibody) for third-line treatment of mCRC in routine clinical practice.

The study included a total of six patients. Short-term efficacy results indicated that one patient exhibited tumor shrinkage and was evaluated as stable disease, one patient maintained CR following an R0 resection of a liver metastasis, with no new lesions observed, while the remaining four patients experienced progressive disease. The disease control rate for the six patients was 33.3%. Based on these observations, we speculate that the short-term efficacy of fruquintinib combined with sintilimab is limited, as significant inhibition of tumor growth was not achieved, and tumor regression was minimal. Long-term efficacy results revealed that the mPFS and median OS (mOS) for the six patients were 3.8 months and 5.7 months, respectively. Notably, patient 2 demonstrated superior treatment outcomes, with a PFS and OS of 11 months and 17.1 months, respectively, and patient 5 remained tumor-free following an R0 resection of a liver metastasis, with PFS and OS at 10 months each. The PFS of the remaining patients ranged from 1.7 months to 5.1 months.

Compared to previous clinical study data[5-7], the mPFS and mOS of our patients appeared to show some improvement. This may be attributable to several factors: (1) Patients in which the liver was the only metastatic site demonstrated better efficacy, whereas those with multiple organ metastases exhibited poorer outcomes. The liver was the only metastatic site in patients 2 and 5, while the other four patients had metastases in organs such as the lungs, abdominal cavity, and bones, as well as the liver. Multiple organ metastases typically indicate a more aggressive primary tumor, increased invasiveness, decreased drug sensitivity, and a more adverse prognosis. A retrospective study conducted in Japan analyzed 396 patients with CRC liver metastases, all of whom underwent resection of both the primary tumor and the liver metastases. Findings showed 65.7% of the patients experienced recurrence and metastasis postoperatively, with common metastatic sites including the liver, lungs, peritoneum, and adrenal glands. The proportions of patients with metastases in one, two, and three organs were 85.4%, 12.3%, and 1.5%, respectively. The involvement of multiple organs in metastasis correlated with a poorer prognosis[25]; and (2) Patients 2 and 5 had fewer liver metastases and a better prognosis compared to those with multiple liver metastases. Patient 2 had two liver metastases, while patient 5 had one liver metastasis, and the remaining patients presented with multiple liver metastases. A second retrospective study conducted in Japan investigated the relationship between the number of liver metastases and prognosis in 412 patients with liver metastases from gastric cancer[26]. Findings showed the mOS was 10.2 months for patients with fewer than four liver metastases and a longest diameter of less than 5 cm, compared to 3.1 months for those with five or more liver metastases and a longest diameter of 5 cm or greater. Notably, in the present study, patient 5 exhibited extreme insensitivity to chemotherapy during both first-line and second-line treatments, with PFS of only 4.2 months and 1.9 months, respectively. However, following an R0 resection of the liver metastasis, patient 5 remained tumor-free during third-line treatment with fruquintinib combined with sintilimab, achieving a PFS of 10 months. This finding implies that the combination of fruquintinib and sintilimab may confer enhanced survival benefits for patients with fewer liver metastases and a smaller tumor burden.

Interestingly, this study did not observe a correlation between the CPS of PD-L1 expression and immunotherapy outcomes in patients with MSS CRC. Patients 2 and 5 exhibited the most favorable therapeutic outcomes, with a CPS of 5 and 0, respectively. Patients 1 and 4 had a CPS of 1 and 0, respectively, but poor therapeutic outcomes. Patients 3 and 6 had a CPS of 5 and 6, respectively, but the shortest PFS at 2.8 months and 1.7 months Currently, CPS are widely utilized to assess the efficacy of immunotherapy. Multiple studies in gastric, breast, and head and neck cancer indicate that tumors with a higher CPS exhibit greater sensitivity to immunotherapy and improved prognoses compared to those with a lower CPS[27-29]. However, a meta-analysis[30] encompassing 24 studies, investigating the relationship between PD-L1 expression and CPS with prognosis in CRC revealed significant heterogeneity in PD-L1 expression among CRC tumors, and the CPS derived from this expression was not associated with efficacy or prognosis. Although adding to this evidence base, findings from the present study are exploratory, as they were derived from six heterogeneous cases, which varied significantly in terms of tumor burden, metastasis patterns, and previous treatments. At this time, CPS assessment in CRC remains inconclusive, and further research is warranted.

The primary adverse reactions observed in this study included bone marrow suppression, liver function impairment, and hypothyroidism, predominantly classified as grades 1-2, with no reports of grade 4 adverse reactions. Bone marrow suppression was characterized by leukopenia, neutropenia, hemoglobin reduction, and thrombocytopenia. Specifically, four patients experienced grade 1 anemia, while two patients experienced grade 1 thrombocytopenia, both of which were promptly alleviated following symptomatic treatment. Two patients developed grade 1 hypothyroidism, and one patient developed grade 2 hypothyroidism, likely attributable to sintilimab. One patient experienced grade 1 myocarditis, which was also likely associated with sintilimab and resolved spontaneously. One patient experienced grade 2 proteinuria, likely related to fruquintinib. One patient independently adjusted their fruquintinib dosage from 3 mg once daily to 5 mg once daily during the initial treatment cycle, resulting in grade 3 palmar-plantar erythrodysesthesia syndrome. Due to intolerance, the dosage was reverted to 3 mg once daily, after which the palmar-plantar erythrodysesthesia syndrome resolved. The remaining five patients maintained the fruquintinib dosage at 3 mg once daily without experiencing any palmar-plantar erythrodysesthesia syndrome. Overall, patient tolerance of fruquintinib combined with sintilimab was good, with all patients completing more than two cycles of treatment, and no cases of treatment interruption due to severe adverse reactions were reported. These findings suggest that fruquintinib combined with sintilimab presents a favorable safety profile in the third-line treatment of mCRC.

In previous reports, common adverse reactions associated with 5 mg/day fruquintinib monotherapy were hypertension, palmar-plantar erythrodysesthesia syndrome, and proteinuria, with incidences of 55.4%, 49.3%, and 42.1%, respectively. The incidences of grade 3-4 adverse reactions were 21.2%, 10.8%, and 3.2%, respectively[6]. For sintilimab monotherapy, common adverse reactions were hypothyroidism, hyperthyroidism, and elevated amylase, with incidences of 13.7%, 6.1%, and 5.2%, respectively[16]. Based on our clinical experience, fruquintinib combined with sintilimab was associated with a similar incidence of hypothyroidism as reported for fruquintinib and sintilimab monotherapy, while fruquintinib was associated with palmar-plantar erythrodysesthesia syndrome, which has been recognized as a frequent and dose-limiting side effect associated with its use for mCRC.

The administration of targeted immunotherapy combination therapy in mCRC is increasing. In addition to fruquintinib, other TKIs combined with immunotherapy have shown good efficacy. A recent report showed targeted therapy combined with anti-programmed cell death 1 immunotherapy and trifluridine/tipiracil (TAS-102) combined with Bev demonstrated similar PFS in both crude and propensity score-adjusted analyses[31]. However, patients who derived benefits from targeted therapy combined with anti-programmed cell death 1 immunotherapy therapy exceeding 90 days showed more sustained clinical advantages compared to trifluridine/tipiracil (TAS-102) combined with Bev. Combinations with next-generation TKIs are also under investigation. Zanzalintinib plus atezolizumab demonstrated superior survival benefits in mCRC compared to regorafenib alone[32].

The findings from the present study should be interpreted in the context of several limitations. First, this was a single-center, retrospective real-world experience evaluating fruquintinib combined with sintilimab in a small patient population. The results should be considered hypothesis-generating observations that require verification in more patients and clinical settings. Second, the study lacked a control group such as fruquintinib monotherapy or other third-line regimens, precluding assessment of additive or synergistic benefit from sintilimab. Third, no formal statistical comparisons were performed and survival estimates were descriptive due to the small cohort and limited number of events. Last, inclusion of patients in the study was impacted by selection bias, physician decision-making bias, and survivor bias, especially as only some third-line patients at our institution received this regimen.

CONCLUSION

This single center study in a small cohort of patients provides preliminary findings showing that the combination of fruquintinib and sintilimab has efficacy and safety in select patients with mCRC.