Abstract
Background
Second-line treatment for metastatic colorectal cancer (mCRC) typically involves oxaliplatin- or irinotecan-based doublet chemotherapy with or without anti-angiogenic antibodies. Triplet regimens such as FOLFOXIRI have demonstrated synergy and improved efficacy as first-line therapy. Surufatinib, an oral multi-kinase inhibitor targeting VEGFR1–3, FGFR1, and CSF-1R, may enhance chemotherapy efficacy. We evaluated surufatinib combined with doublet (FOLFOX/FOLFIRI) versus triplet (FOLFOXIRI) chemotherapy as second-line treatment for mCRC.
Patients and Methods
This multicentre, open-label, randomized phase-II trial used Simon’s minimax two-stage design. Eligible patients had mCRC progressing on or within 6 months after first-line doublet chemotherapy. Patients were randomized 1:1 to surufatinib 250 mg once daily plus either mFOLFOX6/FOLFIRI (doublet cohort, selected based on prior regimen) or FOLFOXIRI (triplet cohort). The primary endpoint was objective response rate (ORR).
Results
From September 2021 to November 2023, 57 patients were randomized (28 per cohort after one withdrawal). In the doublet cohort, ORR was 35.7% (95% CI: 18.6–55.9), median progression-free survival (PFS) was 5.4 months (95% CI: 3.8–7.0), and median overall survival (OS) was 19.0 months (95% CI: 9.2–28.8). In the triplet cohort, ORR was 39.3% (95% CI: 21.5–59.4), median PFS was 5.8 months (95% CI: 3.3–8.2), and median OS was 10.9 months (95% CI: 6.0–15.8). Grade ≥3 treatment-emergent adverse events occurred more frequently in the triplet (71.4%) versus doublet (57.1%) cohort, with higher rates of treatment delays (89.3% versus 72.0%) and discontinuations (25.0% versus 14.3%).
Conclusions
Surufatinib plus doublet chemotherapy showed encouraging antitumor activity and acceptable tolerability in second-line mCRC, warranting further evaluation in a larger randomized trial. In contrast, surufatinib plus triplet chemotherapy was associated with increased toxicity, more frequent treatment delays or discontinuations, and shorter overall survival; this combination is not recommended for further investigation in this setting.
ClinicalTrials.gov: NCT04734249
Date of registration: January 31, 2021
Keywords: Metastatic colorectal cancer, surufatinib, doublet chemotherapy, triplet chemotherapy, second-line treatment, angiogenesis inhibitors
RECOMMENDED KEY MESSAGES
Surufatinib plus doublet chemotherapy achieved promising efficacy and tolerability in second-line metastatic colorectal cancer, with ORR 35.7%, median PFS 5.4 months, and median OS 19.0 months.
Surufatinib plus triplet chemotherapy (FOLFOXIRI) offered no clear advantage over the doublet regimen and was limited by greater toxicity and inferior overall survival.
Introduction
Fluoropyrimidine-based doublet chemotherapy (e.g. FOLFOX or FOLFIRI) forms the backbone of first-line regimens for advanced microsatellite-stable (MSS) or proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC). In eligible patients, the addition of a biologic agent, either an anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody (e.g. bevacizumab) or an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (e.g. cetuximab or panitumumab), is recommended [1–3].
In the second-line setting for patients without human epidermal growth factor receptor 2 (HER2) amplification, Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, or B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation, an irinotecan-based regimen (e.g. FOLFIRI) or irinotecan monotherapy is preferred following prior oxaliplatin-based therapy, while those progressing on first-line irinotecan-based therapy may switch to an oxaliplatin-based regimen (e.g. FOLFOX). Continuation or addition of an anti-angiogenic agent (e.g. bevacizumab, aflibercept, or ramucirumab) is recommended regardless of prior bevacizumab exposure, RAS status, or primary tumour location worldwide [1–3]. However, outcomes with chemotherapy plus anti-angiogenic agents remain modest, with objective response rates (ORR) of 5%–22.7%, median progression-free survival (PFS) of 5.7–7.3 months, and median overall survival (OS) of 11.2–13.5 months [4–7].
Preclinical and clinical evidence support the synergistic effects of irinotecan, oxaliplatin, and 5-fluorouracil [8–11]. FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab is an established first-line option for fit patients with mCRC, showing superior response rates and survival compared with doublet regimens plus bevacizumab [9,10]. In addition, our prior retrospective study of modified FOLFOXIRI as second-line therapy reported promising activity with an ORR of 25.0%, median PFS of 5.7 months, and median OS of 14.4 months [12]. These findings suggest that synergy among oxaliplatin, irinotecan, and fluorouracil/leucovorin may persist despite acquired resistance to individual components in the first-line setting.
Surufatinib is a novel oral multi-kinase inhibitor targeting vascular endothelial growth factor receptors 1–3 (VEGFR1–3), fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor 1 receptor (CSF-1R). Through simultaneous inhibition of tumor angiogenesis and immune evasion pathways, surufatinib may enhance antitumor activity [13–18]. Surufatinib is approved in China for advanced pancreatic and extrapancreatic neuroendocrine tumours [19,20]. In comparison, fruquintinib (a highly selective VEGFR1–3 inhibitor lacking FGFR or CSF-1R activity) has demonstrated efficacy in refractory mCRC after prior chemotherapy, anti-VEGF, and anti-EGFR therapies [21,22].
The SYLT-020 trial was designed to evaluate the efficacy and safety of surufatinib combined with doublet chemotherapy (mFOLFOX6 or FOLFIRI) versus triplet chemotherapy (FOLFOXIRI) as second-line treatment for patients with mCRC.
Patients and methods
Study design
The SYLT-020 trial was a multicentre, open-label, randomized, phase-II study conducted using Simon’s minimax two-stage design. Patients with mCRC were enrolled for second-line treatment from three oncology centres in China. All participants provided written informed consent before any study procedures. The study was approved by the Ethics Committee of Fujian Cancer Hospital (approval no. K2021-034-07) and prospectively registered at ClinicalTrials.gov on January 31, 2021 (identifier: NCT04734249). It was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Eligibility
Eligible patients were aged 18–75 years with histologically confirmed metastatic colorectal adenocarcinoma. Key inclusion criteria included: disease progression on or within 6 months after the last administration of first-line doublet chemotherapy (fluoropyrimidine plus oxaliplatin or irinotecan), with/without concomitant anti-VEGF or anti-EGFR agents (administered for metastatic disease or as adjuvant/neoadjuvant therapy); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; life expectancy of at least 12 weeks; at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [23]; and adequate bone marrow (absolute neutrophil count ≥1.5 × 109/L, platelets ≥100 × 109/L, haemoglobin ≥90 g/L), liver (alanine aminotransferase or aspartate aminotransferase ≤2.5 × upper limit of normal [ULN] without liver metastases or ≤5 × ULN with metastases; total bilirubin ≤1.5 × ULN without metastases or ≤3 × ULN with metastases), and renal function (creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min).
Key exclusion criteria included: prior treatment with surufatinib or other multi-kinase inhibitors; ascites requiring therapeutic paracentesis for symptom relief; major surgery within 4 weeks prior to study entry; unresolved toxicities > grade 1 from prior anticancer therapy (except alopecia) per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0; symptomatic brain or leptomeningeal metastasis (asymptomatic, stable lesions not requiring treatment for ≥2 weeks before enrollment were permitted); concurrent malignancy or prior malignancy within the last 5 years (except resected basal or squamous cell skin carcinoma or carcinoma in situ of the cervix or breast); clinically significant cardiovascular disease including myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months prior to enrollment, New York Heart Association class III or IV congestive heart failure, or uncontrolled arrhythmia; severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, active bleeding diatheses, or active infection) that, in the investigator’s opinion, made participation undesirable or jeopardized protocol compliance; refractory nausea, vomiting, or chronic gastrointestinal disease; inability to swallow oral medications; or prior significant bowel resection likely to impair surufatinib absorption.
Treatments
Eligible patients were randomly assigned in a 1:1 ratio into the doublet or the triplet cohort. In the doublet cohort, patients received induction chemotherapy with mFOLFOX6 (for prior irinotecan-based therapy) or FOLFIRI (for prior oxaliplatin-based therapy) consisting of oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2, respectively, plus levoleucovorin 200 mg/m2 and 5-fluorouracil 2.4 g/m2 as a 46-hour continuous infusion. In the triplet cohort, patients received induction therapy with FOLFOXIRI consisting of irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, levoleucovorin 200 mg/m2, and 5-fluorouracil 2.4 g/m2 as a 46-hour continuous infusion. In both cohorts, surufatinib was administered orally at 250 mg once daily. Induction treatment cycles were repeated every 14 days for up to 12 cycles, after induction, investigators could initiate maintenance therapy with surufatinib 250 mg daily monotherapy. Treatment (induction or maintenance) continued until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or investigator decision. Primary prophylaxis with granulocyte colony-stimulating factor was not recommended. Supportive care followed an enhanced recovery after chemotherapy (ERAC) strategy (Supplementary Table S1).
Treatment delays were preceded by dose modification for adverse event (AE) management. A delay of up to 28 days was permitted to allow resolution of toxicity; if toxicity did not resolve within this period, treatment was discontinued unless the investigators determined that benefits outweighed risks. For surufatinib-related grade 3–4 AEs, treatment was withheld until resolution to ≤ grade 1, then resumed at the same dose (first occurrence) or reduced (recurrence) per dose levels: 250 mg → 200 mg → 150 mg → 100 mg once daily (Supplementary Table S2). Chemotherapy agents were adjusted according to AEs (Supplementary Table S3). Dose re-escalation was not permitted.
Assessment
Patients underwent weekly assessments, including medical history, physical examination, haematology and biochemistry laboratory tests, urinalysis, and vital signs. Baseline assessments were performed within 7 days prior to the first dose; subsequent evaluations were conducted within 2 days prior to each treatment cycle starting from cycle 2. Tumour assessment by computed tomography or magnetic resonance imaging was performed every 6 weeks (±7 days) until documented disease progression, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [23]. All imaging studies were centrally reviewed by independent radiologists in a blinded manner. After disease progression, patients were contacted every 12 weeks via telephone or visit to assess survival and collect information on subsequent anticancer therapies. Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), were recorded from the time of written informed consent until 30 days after the last dose of study treatment (or until resolution to baseline or determination of irreversibility, loss to follow-up, or study withdrawal, whichever occurred first).
Endpoints
The primary endpoint was ORR, defined as the proportion of patients achieving a confirmed complete response (CR) or a partial response (PR) according to RECIST version 1.1 [23].
Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving CR, PR or stable disease (SD) as best overall response; duration of response (DoR), measured from the date of first documented CR or PR until disease progression or death due to any cause, whichever occurred first; PFS, measured from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurred first; OS, measured from the date of randomization to death due to any cause; and safety, assessed by the incidence, severity, and relationship of TEAEs per NCI-CTCAE version 5.0.
Statistical analysis
Sample size for each cohort was calculated using Simon’s minimax two-stage phase II design. For both the doublet and triplet cohorts, the target ORR was 35%, with a null hypothesis (unacceptable) ORR of 15% based on historical data [4–7]. With a one-sided α of 0.05 and power of 80%, 15 patients with measurable disease were required in Stage 1 per cohort. Advancement to Stage 2 required at least 3 responses in Stage 1. Stage 2 enrolled an additional 13 measurable patients per cohort (total 28 per cohort). A regimen was considered promising if ≥8 responses were observed among the 28 patients. Randomization was performed centrally using a variable block randomization with a block size of 4–6.
Efficacy analyses were conducted on the full analysis set (FAS), defined as all randomized patients who received at least one dose of study treatment. Safety analyses were performed on the safety analysis set (SAS), comprising all patients who received at least one dose of study treatment. Patients with missing response data were considered nonresponders.
Qualitative data were summarized using frequencies and percentages. Quantitative data were described using medians with interquartile range (IQR) and 95% confidence interval (CI) where appropriate. ORR and DCR were reported with 95% CI calculated by the Clopper–Pearson method. DoR, PFS, and OS were estimated using the Kaplan–Meier method. Hazard ratio (HR) and 95% CI were calculated using stratified Cox proportional hazards regression models. Comparisons between groups were performed using the stratified log-rank test. Safety data were summarized descriptively. All statistical analyses were conducted using R software version 4.2.1 (R Foundation for Statistical Computing). This study is reported in accordance with the CONSORT 2025 Statement. The trial flow diagram is presented in Figure 1, and the completed CONSORT 2025 checklist is provided as Supplementary Material.
Figure 1.
Trial profile.
Abbreviations: mFOLFOX6, modified fluorouracil, levoleucovorin and oxaliplatin; FOLFIRI, fluorouracil, levoleucovorin and irinotecan; FOLFOXIRI, fluorouracil, levoleucovorin, oxaliplatin and irinotecan.
Results
Patient demographics and baseline characteristics
Between September 3, 2021, and November 7, 2023, a total of 61 patients were screened at three oncology centres in China, of whom 57 patients were enrolled and randomized. One patient in the triplet cohort withdrew consent before receiving any study treatment due to toxicity concerns. Consequently, 28 patients in each cohort received at least one dose of study drug and were included in both the FAS and the SAS.
At the data cutoff date of July 31, 2025, the median follow-up was 27.3 months (95% CI: 21.0–33.6). Treatment discontinuation was primarily due to disease progression in both cohorts. Adverse events led to discontinuation in 4 patients (14.3%) in the doublet cohort and 7 patients (25.0%) in the triplet cohort. Patient refusal led to discontinuation in 4 patients (14.3%) in the doublet cohort and 6 patients (21.4%) in the triplet cohort. In addition, two patients died during the induction phase in the triplet cohort (Figure 1). Baseline demographics and disease characteristics were well balanced between the two cohorts (Table 1). All 56 treated patients had pMMR or MSS tumors. The median age was 58.0 years (IQR, 53.0–65.0). Prior anti-VEGF therapy had been received by 23 patients (41.1%), and prior anti-EGFR therapy by 14 patients (25.0%). In the doublet cohort, 20 patients (71.4%) received FOLFIRI and 8 (28.6%) received mFOLFOX6.
Table 1.
Demographics and baseline characteristics.
| Characteristic | Surufatinib + mFOLFOX6 or FOLFIRI (n = 28) |
Surufatinib + FOLFOXIRI (n = 28) |
P-value |
|---|---|---|---|
| Age, years; median (IQR) | 58.5 (46.8–64.0) | 58.0 (53.0–65.0) | 0.504 |
| Sex, n (%) | 1.000 | ||
| Male | 20 (71.4) | 20 (71.4) | |
| Female | 8 (28.6) | 8 (28.6) | |
| ECOG performance status, n (%) | 1.000 | ||
| 0 | 21 (75.0) | 21 (75.0) | |
| 1 | 7 (25.0) | 7 (25.0) | |
| Time to metastases, n (%) | 0.587 | ||
| Synchronous | 15 (53.6) | 18 (64.3) | |
| Metachronous | 13 (46.4) | 10 (35.7) | |
| First-line chemotherapy, n (%) | 0.295 | ||
| Fluoropyrimide + oxaliplatin | 21 (75.0) | 25 (89.3) | |
| Fluoropyrimide + irinotecan | 7 (25.0) | 3 (10.7) | |
| First-line target therapy, n (%) | 0.694 | ||
| Anti-VEGF | 10 (35.7) | 13 (46.4) | |
| Anti-EGFR | 8 (28.6) | 6 (21.4) | |
| Neither | 10 (35.7) | 9 (32.1) | |
| Primary tumor Site, n (%) | 0.503 | ||
| Right-sided | 4 (14.3) | 7 (25.0) | |
| Left-sided and rectum | 24 (85.7) | 21 (75.0) | |
| Number of metastatic sites, n (%) | 0.061 | ||
| 1 | 11 (39.3) | 18 (64.3) | |
| ≥2 | 17 (60.7) | 10 (35.7) | |
| Liver Metastasis, n (%) | 12 (42.9) | 17 (60.7) | 0.181 |
| Peritoneum Metastasis, n (%) | 9 (32.1) | 8 (28.6) | 0.771 |
| Surgery on primary tumor, n (%) | 23 (82.1) | 21 (75.0) | 0.515 |
| RAS and BRAF status, n (%) | 0.879 | ||
| RAS and BRAF wild type | 10 (35.7) | 12 (42.9) | |
| RAS mutated | 11 (39.3) | 12 (42.9) | |
| BRAF mutated | 2 (7.1) | 0 | |
| Unknown | 5 (17.9) | 4 (14.3) | |
| Primary tumor site and RAS and BRAF status; n (%) | 0.565 | ||
| Right-sided and RAS and BRAF wild type | 1 (3.6) | 1 (3.6) | |
| Right-sided and RAS/BRAF mutated | 1 (3.6) | 5 (17.9) | |
| Left-sided and RAS/BRAF wild type | 9 (32.1) | 11 (39.3) | |
| Left-sided and RAS/BRAF mutated | 12 (42.9) | 7 (25.0) | |
| Unknown | 5 (17.9) | 4 (14.3) | |
| Months between 1st- and 2nd-line therapy, median (IQR) | 2.89 (0.82–3.48) | 1.68 (0.86–3.29) | 0.696 |
| Number of chemotherapy cycles, median (IQR) | 7 (4–11.7) | 5 (3–8) | 0.231 |
| Total number of chemotherapy cyclesa | 203 | 169 | – |
| Total number of delayed cyclesb | 45 | 73 | 0.095 |
| Patients with ≥1 delayed chemotherapy, n (%) | 18 (72.0) | 25 (89.3) | 0.027 |
| Patients who received surufatinib maintenance, n (%) | 8 (28.6) | 5 (17.9) | |
| Patients who received systemic therapy, n (%) | 22 (78.6) | 12 (42.9) | 0.174 |
Abbreviations: ECOG, Eastern Cooperative Oncology Group; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; IQR, interquartile range; mFOLFOX6, modified fluorouracil, levoleucovorin and oxaliplatin; FOLFIRI, fluorouracil, levoleucovorin and irinotecan; FOLFOXIRI, fluorouracil, levoleucovorin, oxaliplatin and irinotecan.
a: Total cycles across the cohort.
b: Total delayed cycles across the cohort.
Treatment profile
The median interval from the end of first-line therapy to initiation of second-line treatment was 2.89 months (IQR, 0.82–3.48) in the doublet cohort and 1.68 months (IQR, 0.86–3.29) in the triplet cohort. Compared with the triplet cohort, patients in the doublet cohort received more chemotherapy cycles overall (203 versus 169 cycles), with a higher median number of cycles administered per patient (7 [IQR, 4–11] versus 5 [IQR, 3–8]). Maintenance surufatinib monotherapy was administered to 8 patients (28.6%) in the doublet cohort and 5 patients (17.9%) in the triplet cohort. Chemotherapy delays occurred less frequently in the doublet cohort (72.0% of patients and 22.2% of cycles) compared to the triplet cohort (89.3% of patients and 43.2% of cycles). Dose reductions were required in 2 patients (7.1%) in the doublet cohort and 5 (17.9%) in the triplet cohort. Relative dose intensity (RDI) of surufatinib was significantly higher in the doublet cohort (median 59.0%, IQR: 37.6–76.5%) than in the triplet cohort (median 42.3%, IQR: 18.6–58.1%; p = 0.009). In the doublet cohort, the relative dose intensities (RDIs) of 5-fluorouracil and oxaliplatin (or irinotecan) were 68% and 62% (or 60%), respectively. In the triplet cohort, the RDIs of 5-fluorouracil, oxaliplatin, and irinotecan were 58%, 55%, and 52%, respectively.
Subsequent systemic therapy was more common in the doublet cohort, both in the third-line setting (22 versus 12 patients; 78.6% versus 42.9%) and in fourth-line or later settings (15 versus 7 patients; 53.6% versus 25.0%), resulting in 41 versus 29 cycles of late-line regimens, respectively. Local interventions were performed in 7 patients (25.0%) in the doublet cohort (including radiotherapy for brain [n = 3] or bone [n = 1] metastases, surgical resection of ovarian [n = 1] or pulmonary [n = 1] metastases, and trans-arterial chemoembolization with radioactive seed implantation plus external beam radiotherapy [n = 1]) compared with none in the triplet cohort.
Efficacy
In the FAS population, the confirmed ORR was 35.7% (10/28; 95% CI: 18.6–55.9) in the doublet cohort and 39.3% (11/28; 95% CI: 21.5–59.4) in the triplet cohort (p = 0.787). The DCR was 85.7% (24/28; 95% CI: 67.3–96.0) and 92.9% (26/28; 95% CI: 76.5–99.1), respectively (p = 0.397). Detailed response data are presented in Table 2, and the maximum percentage change in target lesion size from baseline is depicted in Figure 2.
Table 2.
Response analysis for full analysis set (FAS) population.
|
Response Category |
Doublet cohort (n = 28) |
Triplet cohort (n = 28) |
P-value |
|---|---|---|---|
| Objective response rate (95% CI) | 35.7 (18.6–55.9) | 39.3 (21.5–59.4) | 0.787 |
| Complete response | 1 (3.6) | 0 | |
| Partial response | 9 (32.1) | 11 (39.3) | |
| Stable disease | 14 (50.0) | 15 (53.6) | |
| Progressive disease | 4 (14.3) | 2 (7.1) | |
| Disease control rate (95% CI) | 85.7 (67.3–96.0) | 92.9 (76.5–99.1) | 0.397 |
| Duration of response, months; median (95% CI) | 13.2 (9.0–20.4) | 9.0 (5.2–15.3) | 0.205 |
Percentages for objective response rate and disease control rate are calculated as the proportion of patients.
achieving the response with exact 95% confidence intervals (Clopper–Pearson method).
Note: Objective response rate includes confirmed CR + PR; disease control rate includes CR + PR + SD.
Figure 2.
Waterfall plot showing maximum percentage change from baseline in the sum of target lesion diameters (per RECIST version 1.1) in the full analysis set (FAS) population.
Note: Waterfall plot of the maximum percentage change from baseline in target lesion size (RECIST 1.1) for patients in the doublet cohort (top) and triplet cohort (bottom). Bars are color-coded by best overall response: orange (CR), light blue (PR), green (SD), and dark blue (PD). Dashed lines indicate RECIST thresholds for PR (–30%) and PD (+20%).
Median PFS was 5.4 months (95% CI: 3.8–7.0) in the doublet cohort and 5.8 months (95% CI: 3.3–8.2) in the triplet cohort (HR 1.00; 95% CI: 0.59–1.70; p = 0.995; Figure 3(A)). Median OS was significantly longer in the doublet cohort at 19.0 months (95% CI: 9.2–28.8) versus 10.9 months (95% CI: 6.0–15.8) in the triplet cohort (HR =2.35; 95% CI: 1.28–4.35; p = 0.006; favouring the doublet cohort; Figure 3(B)). Median DoR was 13.2 months (95% CI: 9.0–20.4) in the doublet cohort and 9.0 months (95% CI: 5.2–15.3) in the triplet cohort (p = 0.205). Exploratory post-hoc analyses according to prior bevacizumab exposure are provided in Supplementary Table S4.
Figure 3.
Kaplan–Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS) in the full analysis set (FAS) population.
Note: Kaplan–Meier curves of progression-free survival (A) and overall survival (B) in the full analysis set population. The doublet cohort is shown in red and the triplet cohort in blue. Hazard ratios (HR) and 95% confidence intervals were calculated using stratified Cox proportional hazards regression. P-values are from the stratified log-rank test. Numbers at risk are displayed below each time point, with censored patients in parentheses.
Safety
All patients in both cohorts experienced at least one treatment-emergent adverse event (TEAE) of any grade. Grade 3–4 TEAEs occurred in 57.1% (16/28) of patients in the doublet cohort and 71.4% (20/28) in the triplet cohort. Serious adverse events were reported in five patients (17.9%) and eight patients (28.6%), respectively. Adverse events leading to treatment discontinuation occurred in four patients (14.3%) in the doublet cohort and seven (25.0%) in the triplet cohort.
Hematologic toxicities were more frequent and severe in the triplet cohort. Grade ≥3 neutropenia occurred in 14.3% of patients in the doublet cohort versus 42.9% in the triplet cohort. Clinically meaningful differences (≥15% absolute difference) favouring the doublet cohort were observed for any-grade thrombocytopenia (25.0% versus 46.4%) and lymphocytopenia (21.4% versus 42.9%). The triplet cohort also had higher rates of anaemia (71.4% versus 60.7%) and febrile neutropenia (10.7% versus 3.6%).
Among nonhematologic toxicities, diarrhoea (42.9% versus 17.9%) and fatigue (67.9% versus 50.0%) were more common in the triplet cohort. The triplet regimen was associated with significantly increased incidence of oxaliplatin-related hypersensitivity reactions (46.4% versus 7.1%; p ≤ 0.001) and peripheral neuropathy (32.1% versus 10.7%; p = 0.018), likely attributable to increased cumulative oxaliplatin exposure. Haemorrhage occurred in 5 patients (17.9%) in the triplet cohort (including 3 cases of gastrointestinal haemorrhage likely related to underlying cancer, 1 case of grade 1 epistaxis, and 1 case of grade 1 gingival bleeding likely related to surufatinib).
Two deaths unrelated to treatment occurred in the triplet cohort (one due to cardiac and respiratory arrest and one due to aspiration pneumonia). No treatment-related deaths occurred in either cohort. Detailed AE profiles are presented in Table 3.
Table 3.
Common treatment-emergent adverse events (TEAEs) in the safety population.
| Adverse Event, n (%) | Doublet Cohort (n = 28) |
Triplet Cohort (n = 28) |
||
|---|---|---|---|---|
| Any Grade | Grade 3–4 | Any Grade | Grade 3–4 | |
| TEAE | 28 (100) | 16 (57.1) | 28 (100) | 20 (71.4) |
| TEAE leading to treatment discontinuation | 4 (14.3) | 4 (14.3) | 7 (25.0) | 7 (25.0) |
| TEAE leading to death | 0 | 0 | 2 (7.1) | 2 (7.1) |
| Hematologic | ||||
| Leukopenia | 28 (100) | 1 (3.6) | 28 (100) | 12 (42.9) |
| Neutropenia | 28 (100) | 4 (14.3) | 28 (100) | 12 (42.9) |
| Febrile neutropenia | – | 1 (3.6) | – | 3 (10.7) |
| Lymphocytopenia | 6 (21.4) | 0 | 12 (42.9) | 1 (3.6) |
| Thrombocytopenia | 7 (25.0) | 1 (3.6) | 13 (46.4) | 3 (10.7) |
| Anemia | 17 (60.7) | 1 (3.6) | 20 (71.4) | 2 (7.1) |
| Nonhematologic | ||||
| Diarrhea | 5 (17.9) | 0 | 12 (42.9) | 3 (10.7) |
| Fatigue | 14 (50.0) | 3 (10.7) | 19 (67.9) | 8 (28.6) |
| Elevated lactate dehydrogenase | 12 (42.9) | 0 | 11 (39.3) | 0 |
| Nausea | 12 (42.9) | 1 (3.6) | 15 (53.6) | 3 (10.7) |
| Anorexia | 9 (32.1) | 0 | 13 (46.4) | 1 (3.6) |
| Mucositis | 7 (25.0) | 1 (3.6) | 8 (28.6) | 3 (10.7) |
| Vomiting | 10 (35.7) | 0 | 11 (39.3) | 0 |
| Hypothyroidism | 9 (32.1) | 0 | 8 (28.6) | 0 |
| Constipation | 9 (32.1) | 0 | 8 (28.6) | 0 |
| Oxaliplatin-related hypersensitive reaction | 2 (7.1) | 0 | 13 (46.4) | 0 |
| Elevated alanine transaminase | 7 (25.0) | 0 | 8 (28.6) | 0 |
| Peripheral Neuropathy | 3 (10.7) | 0 | 9 (32.1) | 2 (7.1) |
| Hypoalbuminemia | 6 (21.4) | 0 | 8 (28.6) | 0 |
| Elevated aspartate aminotransferase | 6 (21.4) | 0 | 6 (21.4) | 0 |
| Hand-food syndrome | 8 (28.6) | 0 | 8 (28.6) | 0 |
| Hypertension | 13 (46.4) | 1 (3.6) | 13 (46.4) | 0 |
| Proteinuria | 4 (14.3) | 0 | 2 (7.1) | 0 |
| Hemorrhagea | 0 | 0 | 5 (17.9) | 1 (3.6) |
Abbreviations: TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.
a. In the triplet cohort, three cases of gastrointestinal hemorrhage (one grade 3) were considered tumor-related; one case of grade 1 epistaxis and one case of grade 1 gingival bleeding were considered related to surufatinib.
Discussion
The SYLT-020 trial met its primary endpoint, achieving a confirmed ORR exceeding 35% in both cohorts. The doublet regimen (surufatinib plus mFOLFOX6 or FOLFIRI) showed promising efficacy and a favourable safety profile as second-line treatment of mCRC, with a confirmed ORR of 35.7%, median PFS of 5.4 months and median OS of 19.0 months. Contrary to our hypothesis that adding a third chemotherapeutic agent (despite potential acquired resistance from first-line exposure) would enhance synergistic efficacy, the triplet regimen (FOLFOXIRI plus surufatinib) demonstrated similar ORR and PFS but significantly inferior OS compared to doublet regimen plus surufatinib. Patients in the triplet cohort experienced higher treatment-related toxicity, lower treatment completion rates, fewer chemotherapy cycles, and reduced receipt of subsequent systemic therapies. To our knowledge, this is the first prospective trial to evaluate surufatinib combined with doublet or triplet chemotherapy in the second-line setting in mCRC.
Compared with historical data from phase 3 trials of chemotherapy doublets combined with anti-VEGF or VEGFR-targeted monoclonal antibodies (e.g. bevacizumab, aflibercept, and ramucirumab; ORR range: 5%–22.7%; median PFS range: 5.7–7.3 months, and median OS range: 11.2–13.5 months) [4–7], the ORR and median OS in the doublet cohort of SYLT-020 trial were numerically superior. Although median PFS was comparable, these findings are encouraging. Despite the inherent limitations of cross-trial comparisons, these data collectively support the potential of combining surufatinib with doublet chemotherapy in the second-line mCRC.
Unlike monoclonal anti-VEGF/VEGFR antibodies, surufatinib inhibits not only VEGFR1–3 but also FGFR1 and CSF-1R. FGFR alterations occur in approximately 5% of colorectal cancers and are associated with worse prognosis [14]. Upregulation of FGF/FGFR signalling has been implicated in resistance to anti-VEGF therapy, with FGFR1 alterations linked to shorter PFS in patients treated with bevacizumab [15,16]. CSF-1R is essential for the survival and function of M2-polarized tumour-associated macrophages (TAMs), which promote tumour growth, immune evasion, and metastasis in CRC [17]. Chemotherapy-induced tumour damage can upregulate tumour-derived CSF1, enhancing TAM infiltration and providing survival signals to residual tumour cells. Anti-angiogenic agents may further increase VEGF production by TAMs. Thus, the multi-target inhibition of angiogenesis (via VEGFR and FGFR1) and CSF-1R by surufatinib may more effectively counteract these resistance mechanisms and enhance chemotherapy sensitivity compared with anti-VEGF or anti-VEGFR antibodies alone [18].
A post hoc analysis by Fornaro et al. evaluated second-line FOLFOXIRI (n = 32) versus irinotecan- or oxaliplatin-based doublets (n = 52) after first-line FOLFOXIRI, reporting higher ORR (38% versus 28%), longer PFS (8.2 versus 6.3 months; p = 0.003, HR =0.61), and longer OS (19.3 versus 14.0 months; p = 0.02, HR =0.57) with the triplet regimen [24]. In contrast, SYLT-020 showed comparable ORR and PFS between the triplet and doublet arms, with worse OS in the triplet cohort. Several factors may explain this discrepancy. First, the median interval from the end of first-line therapy to second-line initiation was shorter in our triplet cohort (1.68 months) due to the inclusion criterion of progression within 6 months, compared with 5.6 months in Fornaro et al. [24]. A pooled analysis has shown a positive correlation between oxaliplatin-free interval and PFS upon oxaliplatin reintroduction [25]. S, adding surufatinib to FOLFOXIRI likely exacerbated toxicity, resulting in lower treatment completion rates, fewer chemotherapy cycles, and reduced use of subsequent therapies, thereby impairing long-term efficacy, particularly OS. Furthermore, surufatinib’s toxicity profile, driven by inhibition of VEGFR, FGFR1, and CSF-1R, probably compromised patient tolerance to this intensified triplet regimen. As noted by Lu et al. [26] insufficient kinase selectivity can produce off-target effects and additive toxicities, limiting the deliverability and therapeutic index of combination regimens. These findings underscore the importance of careful TKI selection and improve selectivity in future multi-targeted agents.
This study has several limitations. First, the SYLT-020 trial was an open-label study without blinding of investigators and participants, which inherently carries a risk of performance and assessment bias. The implementation of standardized protocols, blinded central radiology review, blinded data analysis, and patient education may have effectively mitigated potential biases. Second, the small sample size and absence of a standard-of-care control arm reflect the trial’s design as a preliminary feasibility assessment of surufatinib combined with either doublet or triplet chemotherapy regimens. Consequently, no formal statistical comparisons between arms were planned; all inter-arm observations were exploratory and descriptive only. Additionally, the triplet cohort used surufatinib rather than a large-molecule anti-angiogenic monoclonal antibody (e.g. bevacizumab, aflibercept, or ramucirumab), which generally exhibits a more favourable toxicity profile than small-molecule TKIs and may offer better tolerability and efficacy when combined with triplet chemotherapy [27]. Lastly, tumour tissue biomarker analyses were not performed, including immunohistochemistry for VEGFR, FGFR1, and CSF-1R expression or evaluation of tumour-associated macrophage infiltration, which might serve as potential predictors of response to surufatinib [28,29]. However, well-validated tissue-based predictive biomarkers for surufatinib are currently lacking [19,20]. In the future, supplementary multi-omics testing of tumour tissue may be prioritized to further explore potential efficacy-related biomarkers.
Conclusions
Surufatinib combined with doublet chemotherapy (mFOLFOX6 or FOLFIRI) demonstrated promising clinical efficacy and an acceptable safety profile as second-line treatment in patients with mCRC. These preliminary results support further evaluation of this combination in a larger, randomized, controlled, phase-III trial comparing it with standard second-line anti-VEGF monoclonal antibody therapy plus FOLFOX or FOLFIRI [4–7], ideally incorporating biomarker-guided stratification. In contrast, the triplet regimen (FOLFOXIRI) combined with surufatinib showed no efficacy advantage and was associated with substantially increased toxicity. This combination is strongly discouraged for further development or routine clinical use in second-line setting.
Supplementary Material
Acknowledgments
The authors thank all patients and their families for participating in the SYLT-020 trial, as well as the investigators, study coordinators, and staff at the participating centers for their dedication in patient enrollment, trial conduct, and data collection. We also thank Caron Modeas (Evolved Editing, LLC) for editorial assistance and Shaowei Lin (School of Public Health, Fujian Medical University) for statistic assistance. Liyu Su: investigation, data curation, formal analysis, methodology, visualization, writing – original draft, writing – review and editing. Peicheng Lin: investigation, formal analysis, methodology, visualization, writing – original draft, writing – review and editing. Yi Yin: investigation, data curation, formal analysis, methodology, visualization, writing – original draft, writing – review and editing. Zaisheng Ye: investigation, writing – review and editing. Changhua Zhuo: investigation, writing – review and editing. Shenghong Wei: investigation, writing – review and editing. Shichao Yu: investigation, writing – review and editing. Jinluan Li: investigation, writing – review and editing. Yanni Hong: investigation, writing – review and editing. Liang Zheng: investigation, writing – review and editing. Shen Zhao: investigation, writing – review and editing. Ying Chen: writing – review and editing. Hui Li: conceptualization, project administration, supervision. Rongbo Lin: conceptualization, project administration, supervision.
Funding Statement
This work was supported by the Joint Funds for the Innovation of Science and Technology, Fujian Province under Grant No. 2023Y9420 and Grant No. 2023Y0057, the Fujian Cancer Hospital High-level Talent Training Project under Grant No. 2023YNG06, in-hospital project No. 4001024, and the Fujian Provincial Health Commission Youth Scientific Research Project under Grant No. 2024QNA056.
Authors contributions statement
CRediT: Liyu Su: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing; Peicheng Lin: Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing; Yi Yin: Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing; Zaisheng Ye: Investigation, Writing – review & editing; Changhua Zhuo: Investigation, Writing – review & editing; Shenghong Wei: Investigation, Writing – review & editing; Shichao Yu: Investigation, Writing – review & editing; Yanni Hong: Investigation, Writing – review & editing; Liang Zheng: Investigation, Writing – review & editing; Shen Zhao: Investigation, Writing – review & editing; Ying Chen: Writing – review & editing; Hui Li: Conceptualization, Project administration, Supervision; Rongbo Lin: Conceptualization, Funding acquisition, Project administration, Supervision.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, Rongbo Lin.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, Rongbo Lin.