Randomized phase-II trial of surufatinib plus FOLFOX/FOLFIRI versus FOLFOXIRI as second-line therapy for metastatic colorectal cancer.

TL;DR

In a phase-II trial, surufatinib combined with doublet chemotherapy achieved a 35.7% response rate and 19-month median overall survival in treatment-resistant metastatic colorectal cancer, but adding it to triplet chemotherapy increased toxicity without survival benefit.

What the Study Found

Metastatic colorectal cancer (mCRC) that progresses despite first-line chemotherapy presents a clinical challenge with limited options. Patients typically move to second-line regimens using either doublet chemotherapy (two drugs) or triplet chemotherapy (three drugs), sometimes paired with anti-angiogenic agents that block blood vessel growth. This phase-II trial tested whether surufatinib, an oral kinase inhibitor that blocks multiple growth pathways involved in tumor angiogenesis and immunosuppression (VEGFR1-3, FGFR1, and CSF-1R), could improve outcomes when combined with chemotherapy.

The trial randomized 57 patients across two cohorts. The doublet cohort (28 patients) received surufatinib plus either mFOLFOX6 or FOLFIRI based on their prior first-line treatment. The triplet cohort (27 patients) received surufatinib plus FOLFOXIRI. In the doublet arm, the objective response rate was 35.7%, with a median progression-free survival of 5.4 months and median overall survival of 19.0 months. Grade 3 or higher adverse events occurred in 57.1% of doublet patients, with 72% experiencing treatment delays and 14.3% discontinuing due to toxicity. These results suggested surufatinib plus doublet chemotherapy merited further investigation.

The triplet combination told a different story. The objective response rate was 39.3%, only marginally higher than the doublet arm, and median overall survival dropped to 10.9 months, nearly half that of the doublet group. Grade 3 or higher toxicity jumped to 71.4%, with 89.3% of triplet patients requiring treatment delays and 25% discontinuing entirely. The investigators concluded that the triplet combination "is not recommended for further investigation in this setting," citing both increased toxicity and inferior survival outcomes.

The survival disparity is particularly striking: despite similar response rates, patients receiving surufatinib plus triplet chemotherapy had substantially shorter overall survival. This pattern suggests either that the additional chemotherapy intensity in the triplet regimen overwhelmed the tolerability window despite surufatinib, or that treatment delays and discontinuations in this more toxic cohort compromised the intended cumulative drug exposure. The doublet approach appears to have achieved a more favorable balance between antitumor activity and tolerability.

What This Means for You

This is a negative trial for one approach and a potentially positive one for another, though with important caveats:

If you or someone you know has mCRC progressing on first-line therapy: The doublet surufatinib combination achieved response and survival outcomes that are encouraging relative to historical second-line data, though these remain preliminary findings from a small phase-II trial. If this combination advances to larger phase-III testing and maintains benefit, it could offer an alternative to current standard-of-care doublet chemotherapy alone. However, the median overall survival of 19 months remains consistent with existing second-line options, so this is an incremental improvement pathway rather than a transformative breakthrough.

On triplet chemotherapy combinations: This trial provides cautionary evidence that simply adding another active agent to an already-intensive regimen can backfire. The triplet plus surufatinib arm demonstrates that more is not always better in cancer treatment. If you are considering treatment options, toxicity and treatment adherence matter as much as theoretical drug activity on paper.

On the broader strategy of targeted agents plus chemotherapy: Surufatinib's multi-targeted mechanism blocking angiogenesis and myeloid immunosuppression is rational for colorectal cancer, but this trial shows the combination requires careful calibration with chemotherapy intensity. The doublet approach may be better tolerated because it leaves more room in the toxicity budget for surufatinib's effects.

Study Details

Sources

Xie, L., et al. (2025). Randomized phase-II trial of surufatinib plus FOLFOX/FOLFIRI versus FOLFOXIRI as second-line therapy for metastatic colorectal cancer. *Annals of Medicine*. PubMed: 42421558