Real-world efficacy and safety of fruquintinib plus PD-1 inhibitors with or without radiotherapy in refractory metastatic colorectal cancer: a single-center retrospective cohort study

Introduction

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality worldwide (1,2). While standard first- and second-line regimens—comprising chemotherapy combined with anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) targeted therapies—have improved outcomes, the prognosis for heavily pretreated patients remains poor (3,4). In the third-line setting and beyond, current guidelines recommend regorafenib, trifluridine/tipiracil (TAS-102), and fruquintinib (4-6).

Fruquintinib is a highly selective small-molecule inhibitor of VEGFR1, VEGFR2, and VEGFR3. Phase III trials have shown clinically meaningful activity and manageable toxicity in refractory Fruquintinib is a highly selective small-molecule inhibitor of VEGFR1, VEGFR2, and VEGFR3. Phase III trials have shown clinically meaningful activity and manageable toxicity in refractory mCRC (6-8). However, the absolute survival benefit of antiangiogenic monotherapy remains modest. Immune checkpoint inhibitors have transformed treatment for microsatellite instability-high mCRC but show little activity in microsatellite-stable (MSS) disease (9,10). MSS tumors account for approximately 95% of mCRC and remain a major therapeutic challenge (3,10,11).

Combination strategies are being investigated to overcome immune resistance in MSS mCRC. Fruquintinib may normalize tumor vasculature and modify the immunosuppressive microenvironment, thereby facilitating T-cell infiltration (12,13). Early-phase studies of fruquintinib plus programmed death-1 (PD-1) blockade have reported encouraging activity, including an objective response rate (ORR) of 23.8% (14). However, prospective trials often exclude patients with complex or symptomatic metastases who are commonly encountered in practice. Real-world studies have therefore evaluated this combination in less selected populations (15,16). Even with dual therapy, many MSS tumors remain resistant, and evidence supporting further treatment escalation is limited. Radiotherapy can induce DNA damage, increase antigen release, and modulate programmed deathligand 1 (PD-L1) expression, providing a rationale for combining it with immunotherapy (17-20). Preliminary evidence suggests that targeted therapy, immunotherapy, and radiotherapy may improve disease control in heavily pretreated patients (21).

We therefore conducted a retrospective study of 145 patients with refractory mCRC. Using 1:1:1 propensity score-matched (PSM), we compared fruquintinib monotherapy (FM), fruquintinib plus a PD-1 inhibitor (FP), and the trimodal combination of fruquintinib, a PD-1 inhibitor, and concurrent radiotherapy (FPR) with respect to effectiveness and safety in routine clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0430/rc).

Methods

Study design and patient

This retrospective cohort study included patients with mCRC who received fruquintinib-based treatment at Jiangxi Cancer Hospital between June 2021 and June 2024. Patients were classified into three groups according to treatment received: FM, FP, or FPR. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Jiangxi Cancer Hospital (No. 2025ky004). The requirement for informed consent was waived because of the retrospective study design.

Patients were considered eligible for inclusion if they met the following criteria: (I) age ≥18 years; (II) pathologically or cytologically confirmed mCRC; (III) documented disease progression following at least two prior lines of systemic therapy, with fruquintinib administered in the third-line setting or beyond; (IV) an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; (V) at least one measurable lesion per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); and (VI) adequate baseline organ and bone marrow function. Patients were excluded if they had a history of severe active autoimmune diseases, uncontrolled severe medical comorbidities, major organ failure, or missing critical medical records.

Treatment regimens

Treatment continued until disease progression, unacceptable toxicity, or death. In the FM group, oral fruquintinib was given at 3–5 mg once daily for 3 weeks, followed by 1 week off treatment. This schedule constituted a four-week cycle. In the FP group, fruquintinib was combined with intravenous or subcutaneous PD-1 inhibitors. The PD-1 inhibitor was generally administered on day 1 of the fruquintinib cycle. Regimens included camrelizumab (200 mg intravenously every 3 weeks), envafolimab (150 mg subcutaneously weekly), sintilimab (200 mg intravenously every 3 weeks), or tislelizumab (200 mg intravenously every 3 weeks). In the FPR group, the FP regimen was combined with individualized concurrent radiotherapy. A multidisciplinary team selected target volumes and dosimetric parameters according to metastatic burden and anatomical constraints. To compare different fractionation schedules, the biologically effective dose (BED) was calculated using an α/β ratio of 10 Gy for tumor tissue. The equation was BED = nd [1+d/(α/β)], where n is the number of fractions and d is the dose per fraction (22).

Efficacy and safety assessments

Two investigators (A.Y. and L.H.) independently extracted baseline characteristics, treatment histories, and clinical variables from electronic medical records. Discrepancies were resolved by consensus. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were ORR and disease control rate (DCR). Two independent senior radiologists assessed tumor response by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every 8–12 weeks. Assessments followed RECIST version 1.1 (23), and classified responses as complete response, partial response, stable disease, or progressive disease. ORR was the proportion of patients with a complete or partial response. DCR was the proportion with a complete response, partial response, or stable disease. PFS was measured from treatment initiation to progression or death from any cause. OS was measured from treatment initiation to death from any cause or last follow-up. Safety was monitored throughout treatment. Treatment-related adverse events (TRAEs) were recorded and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Survival status and long-term safety data were obtained from electronic medical records and telephone follow-up. The data cutoff was December 31, 2024.

Statistical analysis

Analyses were performed using R version 3.6.3. A 1:1:1 PSM analysis was used to reduce selection bias and baseline confounding (24). Matching covariates were clinicopathological factors that differed significantly among groups during univariable screening. All continuous variables were categorized before analysis. Categorical variables are reported as counts and percentages. Between-group differences were tested using Pearson’s chi-square test or Fisher’s exact test, as appropriate. Kaplan-Meier curves and log-rank tests were used to compare PFS and OS before and after PSM. Univariable and multivariable Cox proportional hazards models evaluated associations between clinical factors and PFS or OS. Exploratory subgroup analyses used Kaplan-Meier estimates and log-rank tests. All tests were two-sided, and P<0.05 was considered statistically significant.

Results

Patient characteristics

From June 2021 to June 2024, 145 eligible patients with refractory mCRC were included (Figure 1). The median age was 55 years (range, 27–76 years), and 94.5% had an ECOG performance status of 0 or 1. All patients had progressed after at least two systemic treatment lines. Prior treatments included fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF or anti-EGFR therapy. The FM, FP, and FPR groups included 41, 86, and 18 patients, respectively.

Figure 1 Flowchart of patient enrollment and study design. ECOG, Eastern Cooperative Oncology Group; PD-1, programmed death-1.

Before PSM, the FM, FP, and FPR groups differed significantly in the prevalence of brain, lymph node, and bone metastases (all P<0.05; Table S1). These three metastatic sites were therefore included as matching covariates. The FPR group was the smallest before matching (n=18), limiting the matched sample size. PSM yielded 48 patients, with 16 patients in each group. All measured baseline characteristics were balanced after matching (all P>0.05; Table 1).

Treatment

Across the study population, the majority of patients (81.4%) initiated fruquintinib at the standard 5 mg dosage. In the combination arms, sintilimab and tislelizumab were the most frequently utilized PD-1 inhibitors in both the FP group (46.5% and 39.5%, respectively) and the FPR group (38.9% and 33.3%, respectively). Detailed drug regimen distributions are provided in Table S2. For the 18 patients in the FPR group receiving concurrent individualized radiotherapy, the most common irradiated target volumes were bone (38.9%) and lymph node (33.3%) metastases. Radiotherapy was predominantly delivered via intensity-modulated radiation therapy (IMRT, 50.0%), with a median BED of 59.8 Gy (range, 26.4–67.5 Gy). Comprehensive dosimetric parameters are detailed in Table S3.

Tumor response

Tumor response was first assessed in the unmatched cohort (n=145). No complete responses were observed, and all four partial responses occurred in the FP group. ORR and DCR did not differ among the groups (ORR, P=0.44; DCR, P=0.38; Table S4).

No objective responses occurred in the matched cohort, yielding an ORR of 0% in all three groups (P>0.99; Table 2). The FPR group had the highest DCR at 87.5%, with 14 cases of stable disease and two of progressive disease. The DCR was 62.5% in both the FM and FP groups, each with 10 cases of stable disease and six of progressive disease. The between-group difference was not statistically significant (P=0.20). Figure 2 shows changes in target-lesion size and treatment duration.

Figure 2 Clinical responses in the matched cohorts. (A) Waterfall plot illustrating the maximum percentage change in target lesion size; (B) swimmer plot detailing treatment duration and clinical status. BOR, best overall response; FM, fruquintinib monotherapy; FP, fruquintinib plus a programmed death-1 inhibitor; FPR, trimodal combination of fruquintinib, a PD-1 inhibitor, and concurrent radiotherapy; PD, progressive disease; SD, stable disease.

Survival outcomes

At the December 31, 2024 data cutoff, median follow-up was 16.0 months (95% CI, 13.9–19.6). Before matching, median PFS was 4.7 months with FM, 4.9 months with FP, and 7.2 months with FPR, with no significant between-group difference (P=0.72). Median OS was 15.9 months with FM, 14.6 months with FP, and 13.7 months with FPR, and did not differ significantly among the groups (P=0.29; Figure S1).

After PSM, PFS differed among the three groups (P=0.01; Figure 3). Median PFS was longer with FP than with FM (5.0 vs. 3.5 months; P=0.04). It was also longer with FPR than with FM (7.2 vs. 3.5 months; P=0.002). PFS did not differ between the FP and FPR groups (P=0.54). PFS events occurred in 14 FM patients (87.5%), 14 FP patients (87.5%), and 12 FPR patients (75.0%). Exploratory analyses assessed treatment heterogeneity within the matched groups. PFS did not differ by the starting fruquintinib dose (3–4 vs. 5 mg) or PD-1 inhibitor used (all P>0.05). Within the FPR group, PFS did not differ when BED was dichotomized at the median (all P>0.05; Figure 4). After PSM, median OS was 15.8 months with FM, 17.4 months with FP, and 12.5 months with FPR (P=0.62). Death occurred in 8 FM patients (50.0%), 8 FP patients (50.0%), and 12 FPR patients (75.0%). Exploratory analyses found no significant OS differences according to fruquintinib dose, PD-1 inhibitor, or radiation BED (all P>0.05).

Figure 3 Kaplan-Meier survival curves for the matched cohorts after propensity score matching. (A) Progression-free survival; (B) overall survival. FM, fruquintinib monotherapy; FP, fruquintinib plus a programmed death-1 inhibitor; FPR, trimodal combination of fruquintinib, a PD-1 inhibitor, and concurrent radiotherapy; PD-1, programmed death-1.

Figure 4 Kaplan-Meier curves for treatment variations within the matched groups. (A) Fruquintinib dose in the FM group. (B) Fruquintinib dose in the FP group. (C) PD-1 inhibitor in the FP group. (D) Fruquintinib dose in the FPR group. (E) PD-1 inhibitor in the FPR group. (F) Radiotherapy BED dichotomized at the median in the FPR group. BED, biologically effective dose; FM, fruquintinib monotherapy; FP, fruquintinib plus a programmed death-1 inhibitor; FPR, trimodal combination of fruquintinib, a PD-1 inhibitor, and concurrent radiotherapy; PD-1, programmed death-1; PSM, propensity score matching.

Prognostic factors

Univariable and multivariable Cox models were fitted in the matched cohort. In univariable analysis, treatment group, ECOG PS, lymph node metastasis, and prior irinotecan exposure were associated with PFS. Treatment group and ECOG PS remained independently associated with PFS after adjustment (Table 3). Compared with FM, FP or FPR was associated with a 79% lower hazard of progression [hazard ratio (HR), 0.21; 95% confidence interval (CI), 0.07–0.61; P=0.004]. ECOG PS 2 was associated with a higher progression hazard (HR, 23.43; 95% CI, 4.57–120.21; P<0.001). BRAF mutation, bone metastasis, and prior regorafenib exposure were associated with OS in univariable analysis. None remained independently associated with OS in the multivariable model (all P>0.05; Table S5).

Safety

TRAEs were evaluated in the entire unmatched cohort (n=145; Table 4). Most events were grade 1 or 2. The most common any-grade TRAEs were proteinuria (29.0%), hypertension (28.3%), and increased aspartate aminotransferase (27.6%). Hypothyroidism was more frequent with FP than with FM (26.7% vs. 7.3%; P=0.01). Thrombocytopenia occurred most often in the FPR group (27.8% vs. 12.8% with FP and 9.8% with FM), although the difference was not significant.

Twenty-one grade 3–4 TRAEs occurred: six with FM, 13 with FP, and two with FPR. Hyperbilirubinemia was the most common grade 3–4 event. The incidence of severe TRAEs did not differ significantly among the groups (all P>0.05). Figure S2 shows the distribution of adverse events.

Discussion

To our knowledge, this propensity score-matched study provides the first comparative real-world evidence for these fruquintinib-based regimens. Adding PD-1 inhibitors, with or without concurrent radiotherapy, was associated with significantly longer PFS in refractory mCRC than fruquintinib monotherapy. This improvement was not accompanied by an apparent increase in severe toxicity. These findings support further prospective evaluation of fruquintinib-based combination strategies in patients with MSS mCRC receiving later-line treatment. Fruquintinib is a highly selective oral VEGFR tyrosine kinase inhibitor with established efficacy in chemorefractory mCRC. In the pivotal phase III FRESCO trial, median PFS, median OS, and DCR were 3.7 months, 9.3 months, and 62.2%, respectively (8,25). In our unmatched FM cohort, median PFS was 4.7 months, median OS was 15.9 months, and DCR was 65.9%. These findings are broadly consistent with the disease-control benefit reported in FRESCO. The longer median OS observed in our FM cohort may partly reflect selection toward patients with favorable performance status. Overall, 94.5% of the unmatched population had an ECOG PS of 0 or 1. This favorable baseline profile may limit the generalizability of our findings to patients with poorer performance status. Differences in treatment era and subsequent therapies may also have contributed to the longer survival observed in our contemporary cohort.

The modest survival gains achieved with antiangiogenic monotherapy provide a rationale for combination treatment. VEGFR inhibition may modify the immunosuppressive tumor microenvironment by normalizing tumor vasculature, enhancing T-cell infiltration, and reducing regulatory T-cell activity (12,13,26). These effects may complement immune checkpoint inhibition, particularly in MSS/pMMR tumors that respond poorly to checkpoint inhibitor monotherapy (10). Early-phase studies of fruquintinib plus PD-1 inhibitors have reported ORRs of 20–33% and median PFS values of 5.98–7.33 months (14,27,28). Real-world studies have reported more modest outcomes, with ORRs of 5.2–11.4% and median PFS values of 5.1–5.5 months (29,30). Consistent with these real-world findings, our unmatched FP cohort achieved a median PFS of 4.9 months, median OS of 14.6 months, and ORR of 4.7%. The lower response rate relative to early-phase trials may reflect greater tumor heterogeneity and more extensive prior treatment exposure in routine clinical practice.

Radiotherapy may further enhance antitumor immunity in MSS mCRC. It can induce immunogenic cell death, promote neoantigen release, and activate the cyclic GMP-AMP synthase–stimulator of interferon genes pathway (17,18,31,32). However, clinical evidence supporting this trimodal strategy remains limited. A recent prospective study (NCT05635149) reported a median PFS of 6.2 months, ORR of 28.0%, and DCR of 80.0% in its radiotherapy cohort (33). The phase II RIFLE trial (NCT04948034) is ongoing (21). In our matched FPR cohort, median PFS was 7.2 months and DCR was 87.5%. However, the ORR was 0%, compared with 28% in the study by Cheng et al. (33). This difference may reflect variation in the timing, targets, and clinical intent of radiotherapy. In our practice, radiotherapy was often added later as a concurrent, individualized salvage intervention for symptomatic bone or lymph-node lesions. It was not systematically initiated upfront to maximize tumor shrinkage. Consequently, local control of irradiated lesions may not have translated into an objective response under RECIST version 1.1 because of persistent unirradiated disease.

The strongest comparative signal emerged after PSM. Both FP and FPR were associated with longer PFS than FM (FP vs. FM: 5.0 vs. 3.5 months, P=0.04; FPR vs. FM: 7.2 vs. 3.5 months, P=0.002). Median PFS was numerically longer with FPR than with FP, but the difference was not statistically significant (7.2 vs. 5.0 months, P=0.54). Larger studies are required to determine the incremental contribution of radiotherapy. No objective responses occurred in the matched cohorts, whereas DCR ranged from 62.5% to 87.5%. Thus, the observed benefit appeared to arise mainly from disease stabilization and delayed progression rather than objective tumor shrinkage (6,8).

The absence of a significant OS difference across the matched groups may reflect the small matched sample and heterogeneous post-progression treatments. Median OS was 15.8 months with FM, 17.4 months with FP, and 12.5 months with FPR (P=0.62). In multivariable analysis, the combination regimens were associated with a 79% lower progression hazard than FM (HR, 0.21; P=0.004). ECOG PS 2 was associated with a substantially higher progression hazard (HR, 23.43; P<0.001). Exploratory subgroup analyses detected no significant survival differences according to fruquintinib dose, checkpoint inhibitor, or radiation BED. However, these null findings should not be interpreted as evidence of equivalence because the subgroup sample sizes were small.

The safety profiles were generally predictable and manageable. Proteinuria, hypertension, and hepatotoxicity were observed across the treatment groups. In an exploratory pairwise comparison, hypothyroidism was more frequent with FP than with FM (26.7% vs. 7.3%, P=0.01), supporting routine thyroid monitoring. Thrombocytopenia was numerically more frequent in the FPR group (27.8%). Grade 3–4 toxicity did not differ significantly among the groups. Nevertheless, the limited sample size restricts the precision of between-group safety comparisons.

This study has several limitations. First, the retrospective, single-center design may have introduced selection bias and unmeasured confounding, despite the use of PSM. Second, the matched sample was limited to 16 patients per group, reducing statistical precision and limiting assessment of OS and treatment heterogeneity. Third, incomplete molecular profiling, including mismatch repair status and PD-L1 expression, prevented biomarker-based subgroup analyses. Fourth, heterogeneity in drug doses, checkpoint inhibitors, radiotherapy parameters, and treatment timing may have introduced classification bias. Large multicenter prospective studies incorporating molecular biomarkers are therefore needed to validate these findings and refine patient selection.

Conclusions

Fruquintinib combined with PD-1 inhibitors, with or without concurrent radiotherapy, was associated with significantly longer PFS than fruquintinib monotherapy in refractory mCRC and had a manageable safety profile. This multimodal strategy warrants prospective evaluation in heavily pretreated patients with mCRC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0430/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0430/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0430/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82260607), the Science and Technology Project of Jiangxi Province (No. 20242BAB26138), and Shanghai General Hospital Research Startup Fund.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0430/coif). C.J. reports grants from the National Natural Science Foundation of China and the Science and Technology Project of Jiangxi Province, during the conduct of the study. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Jiangxi Cancer Hospital (No. 2025ky004). The requirement for informed consent was waived because of the retrospective study design.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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