Surufatinib and sintilimab in combination with capecitabine for previously treated metastatic small bowel adenocarcinoma or appendiceal carcinoma: A single-arm, single-center, phase Ib/II trial

BACKGROUND: Small bowel adenocarcinoma (SBA) and appendiceal carcinoma are rare malignancies, highlighting the urgent need for prospective research to guide second-line and subsequent treatments. Previous studies suggest a synergistic benefit of combining anti-angiogenic therapy with immunotherapy in gastrointestinal tumors. This trial aims to evaluate the efficacy and safety of surufatinib, a multi-target tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1, and CSF-1R, in combination with sintilimab and capecitabine for advanced SBA and appendiceal carcinoma. METHODS: This ongoing single-center, single-arm, Phase Ib/II trial enrolls patients (pts) with advanced SBA or appendiceal carcinoma who have progressed on at least one prior line of therapy. The Phase Ib dose-escalation component follows a 3+3 design, with patients receiving surufatinib 200 mg/day (dose level 1; DL1) or 250 mg/day (DL2) orally on days 1-21, combined with sintilimab (200 mg IV, day 1) and capecitabine (1000 mg/m2 orally twice daily, days 1-14), administered in 21-day cycles. The primary Phase Ib objective is to assess dose-limiting toxicities (DLTs) and establish the recommended Phase II dose (RP2D). RESULTS: The data cutoff for the current analysis was December 31, 2024, nine patients (median age: 61 years) were enrolled, including three in the 200 mg surufatinib cohort and six in the 250 mg cohort. Of these, 8 (88.9%) were female, 5 (55.6%) were SBA, 8 (88.9%) had peritoneal metastases, and 4 (44.4%) had multi-organ metastases. All patients were pMMR, and 77.8% had undergone primary tumor resection. 4 patients had failed a prior first-line treatment, and 5 had failed a prior second-line or later treatment. No DLTs were observed, surufatinib at 250 mg was determined to be the RP2D. Among the 9 patients evaluable for tumor response, 1 achieved partial response (PR), 2 achieved stable disease (SD) and 6 experienced progressive disease (PD). With a median follow-up of 21.27 months, the mPFS was 2.63 months while the mOS was 6.6 months. All treatment-emergent adverse events (TEAEs) were Grade 1-2, with ≥30% incidence of asthenia, abdominal distension, elevated ALT/AST, decreased appetite, abdominal pain, and thrombocytopenia. No serious adverse events or cases with fatal outcome were reported. CONCLUSIONS: The combination of surufatinib, sintilimab, and capecitabine, demonstrates acceptable tolerability and promising activity in SBA and appendiceal carcinoma who have failed at least one line of prior therapy. The trial is ongoing with continued investigation. Clinical trial information: NCT05472948.