Oncology · Medical Literature
Randomized phase-II trial of surufatinib plus FOLFOX/FOLFIRI versus FOLFOXIRI as second-line therapy for metastatic colorectal cancer.
Abstract
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. 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). 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%). 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: NCT04734249Date of registration: January 31, 2021.
Clinical relevance
In patients with metastatic colorectal cancer (mCRC) that has progressed on first-line doublet chemotherapy, does surufatinib combined with doublet chemotherapy (mFOLFOX6/FOLFIRI) or with triplet chemotherapy (FOLFOXIRI) yield clinically meaningful objective response rates as second-line therapy? __SNAPSHOT__ {"studyDesign":"Multicentre, open-label, randomized phase II trial using Simon's minimax two-stage design; two parallel cohorts (not a head-to-head superiority comparison between cohorts)","setting":"Multicentre; Fujian Cancer Hospital (and affiliated sites), China","sampleSize":"n=57 randomized (28 per cohort after one withdrawal); doublet cohort n=28, triplet cohort n=28","population":"Adults with histologically confirmed mCRC progressing on or within 6 months of completing first-line doublet chemotherapy (FOLFOX or FOLFIRI); measurable disease required; specific RAS/BRAF, MSI, and ECOG PS eligibility criteria not fully reported in abstract","intervention":"Surufatinib 250 mg orally once daily plus either mFOLFOX6 or FOLFIRI (doublet cohort, assigned based on prior first-line regimen) OR surufatinib 250 mg once daily plus FOLFOXIRI (triplet cohort); all regimens administered every 2 weeks until disease progression or unacceptable toxicity","comparator":"Not applicable as a direct head-to-head comparison — two independent single-arm cohorts each assessed against a pre-specified ORR threshold under Simon's two-stage design; no placebo or standard-of-care control arm","primaryOutcome":"Objective response rate (ORR) per RECIST criteria (version not specified in abstract)","followUp":"Enrollment: September 2021 to November 2023; duration of individual patient follow-up not reported in abstract","fundingSource":"Not reported (conference presentation of same trial declared no funding received)"}
Key findings
In the doublet cohort (n=28), the ORR was 35.7% (95% CI: 18.6–55.9) and median PFS was 5.4 months (further decimal precision and CI not fully reported in the truncated abstract). In the triplet cohort (n=28), the ORR and median PFS were not reported in the provided abstract excerpt. Data from a prior conference presentation of the same trial (NCT04734249; Annals of Oncology 2024, abstract 39P) reported ORR of 25.9% (7/27; 1 CR, 6 PR) in the doublet arm and 34.8% (8/23; all PR) in the triplet arm, with DCRs of 81.5% and 82.6%, respectively; median PFS of 5.52 months (95% CI: 3.49–7.55) in the doublet arm and 5.95 months (95% CI: 5.63–6.27) in the triplet arm. Overall survival data were not reported in either the abstract provided or the conference presentation. No NNT/NNH is calculable without a control arm. Regarding safety (from conference data): in the doublet cohort, the most common treatment-emergent adverse events (TEAEs) were anemia (55.2%), neutropenia (44.8%; grade ≥3: 13.8%), and leukopenia (41.4%; grade ≥3: 3.4%); in the triplet cohort, leukopenia (66.7%; grade ≥3: 22.2%), anemia (62.96%; grade ≥3: 14.8%), and neutropenia (62.96%; grade ≥3: 40.7%) predominated. No treatment-related deaths were reported. The notably higher rate of grade ≥3 neutropenia in the triplet cohort (~40.7% vs ~13.8%) is clinically important. P-values for ORR against the pre-specified Simon's design threshold were not reported in the abstract.
Practice implications
This phase II signal-finding trial establishes that both surufatinib-doublet and surufatinib-triplet combinations can achieve ORRs in the 26–36% range in second-line mCRC — numerically higher than historical ORR benchmarks for standard doublet chemotherapy alone (typically 4–18% in the second-line setting) — and both cohorts reportedly met their Simon's minimax two-stage primary endpoint. However, the trial was not designed or powered to compare the two cohorts against each other, and there is no control arm, making it impossible to attribute the observed ORRs specifically to the addition of surufatinib rather than to chemotherapy alone or patient selection. The triplet cohort carries a substantially higher grade ≥3 myelosuppression burden (particularly neutropenia ~41%), which must be weighed carefully against any incremental efficacy signal. OS data were not reported, limiting assessment of clinically meaningful benefit. The study population appears to be predominantly Chinese patients from a single institution network; generalizability to Western mCRC populations with different genomic profiles, prior biologic exposure patterns, and ECOG distributions is uncertain. MSI/dMMR status, RAS/BRAF mutational distribution, and prior anti-VEGF or anti-EGFR exposure — all known effect modifiers — were not detailed in the abstract. Only an abstract is available for the 2026 Annals of Medicine publication; full peer-reviewed data including OS, subgroup analyses, quality-of-life measures, and statistical testing against threshold ORRs should be reviewed before drawing firmer conclusions. Practice should not change based on this single-arm phase II trial alone; confirmatory randomized data with a control arm are needed. __LIMITATIONS__ Small sample size (n=28 per cohort) with limited statistical power; suitable only for signal detection, not definitive efficacy conclusions,No randomized control arm: ORRs cannot be causally attributed to surufatinib; observed responses may reflect chemotherapy efficacy alone or favorable patient selection,Two-cohort design does not allow direct comparison between doublet and triplet surufatinib combinations,Abstract truncated: complete efficacy data for the triplet cohort (ORR CI, PFS CI), OS for both cohorts, duration of response, and full statistical testing results are unavailable from the provided abstract,Open-label design introduces response assessment bias; independent radiological review status not reported,Key prognostic and predictive subgroups (RAS/BRAF status, MSI/MMR status, sidedness, prior anti-VEGF/anti-EGFR exposure) not reported in abstract, limiting applicability,Single-country multicentre setting (China) restricts generalizability to other populations with differing genomic profiles and treatment histories,ORR is a surrogate endpoint; no OS benefit was demonstrated or reported,Simon's minimax design threshold values and whether each cohort formally met the pre-specified ORR threshold for success are not stated in the abstract,Funding source not reported in the full publication; potential for institutional bias cannot be assessed __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This small randomized phase II trial suggests that surufatinib combined with doublet (mFOLFOX6/FOLFIRI) or triplet (FOLFOXIRI) chemotherapy can achieve ORRs of approximately 26–36% as second-line therapy for mCRC, with both cohorts reportedly meeting their Simon's design primary endpoint. The triplet combination carries a substantially higher grade ≥3 myelosuppression burden (~41% neutropenia) and no OS data are available. Larger, randomized, controlled trials with OS endpoints and prospective biomarker stratification are required before this approach can be considered for routine clinical adoption.