Surufatinib + FOLFOXIRI Shows Better Outcomes As Second-Line Therapy In mCRC

The combination of three active agents (oxaliplatin, irinotecan, and 5-FU/leucovorin) has demonstrated synergistic effects against tumor growth and may potentially overcome resistance seen with the standard doublet combinations (FOLFOX/FOLFIRI) for metastatic colorectal cancer (mCRC).

In a previous phase II study, the investigation of FOLFOXIRI as a second-line treatment for mCRC revealed promising outcomes, with an observed overall response rate (ORR) of 25%, disease control rate (DCR) of 71%, and median progression-free survival (mPFS) of 5.7 months. This was in contrast to the doublet chemotherapy regimen (ORR 4-15%, mPFS 2.5-4.2 months) reported in the V308 study (Tournigand C, J Clin Oncol 2004).

Surufatinib, a small-molecule kinase inhibitor targeting VEGFR1-3, FGFR, and CSF-1R, has gained approval for patients (pts) with neuroendocrine tumors (NET) in China. Preclinical studies have shown that combining surufatinib with chemotherapy enhances its effectiveness by modulating the tumor microenvironment. In this study, researchers aimed to assess the efficacy and safety of combining surufatinib with chemotherapy and explored the differences between doublet and triplet chemotherapy in combination with surufatinib for treating mCRC.

This open-label, two-arm, phase II trial enrolled mCRC pts who have progressed after receiving standard first-line doublet chemotherapy. Patients were randomly assigned (1:1) to receive either surufatinib (250 mg, once daily) in combination with mFOLFOX6/FOLFIRI (depending on their first-line treatment) in arm A, or in combination with FOLFOXIRI in arm B. Treatment was administered every two weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR as per RECIST 1.1 criteria, and secondary endpoints included progression-free survival (PFS), DCR, overall survival (OS), and safety. Researchers used the Simon 2-stage design, with each arm planning to enroll 15 pts in stage 1 and an additional 13 pts in stage 2. If more than 2 out of 15 pts experience a partial response (≥PR) in stage 1, the arm will proceed to stage 2.

As of the data cutoff date on January 31, 2023, both arms have completed enrollment in stage 1, with 15 pts in each arm. All 30 pts in arm A and arm B of stage 1 were eligible for efficacy analysis. The median age was 63/60 years, and 67/80% were male. About 40/47% had an ECOG performance status of 1, and 73/60% had two or more metastatic sites. The ORR was 33.3% (5/15; 5PR) in arm A and 40% (6/15; 6PR) in arm B, while DCR was 86.7% and 80%, respectively. Median PFS and OS results have not yet matured. In arm B, two pts experienced severe adverse events (SAEs), including one grade 4 gastrointestinal hemorrhage, one grade 4 heart failure, and one SAE (resulting in death due to expectoration) was observed in arm A. The frequency of grade 3/4 treatment-emergent adverse events (TEAEs) was 66.7% in arm A and 73.3% in arm B. The most common TEAEs included lymphopenia, vomiting, anemia, hypertension, and diarrhea.

The combination of surufatinib with either mFOLFOX6/FOLFIRI or FOLFOXIRI as a second-line treatment has demonstrated promising anti-tumor activity and an acceptable safety profile in mCRC pts. The trial is ongoing, and additional data will be analyzed and reported.

Source: https://www.annalsofoncology.org/article/S0923-7534(23)00353-8/fulltext

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04734249

Lin, R., Li, H., Chen, X., Zheng, L., Hong, Y., Su, L., Li, C., Zheng, S., Su, L. Surufatinib plus doublet (FOLFOX/FOLFIRI) or triplet (FOLFOXIRI) chemotherapy as second-line therapy in metastatic colorectal cancer (mCRC): First-stage results of a randomized, open-label phase II trial. https://doi.org/10.1016/j.annonc.2023.04.211