SBRT Followed by PD-1 Inhibitor, Bevacizumab and TAS-102 as Third-Line Therapy for Recurrent/Metastatic Colorectal Cancer
brief summary
This phase II trial studies how well stereotactic body radiotherapy (SBRT) followed by a combination of an immune checkpoint inhibitor (sintilimab), bevacizumab, and trifluridine/tipiracil (TAS-102) works as third-line treatment for patients with recurrent or metastatic colorectal cancer (mCRC) that has progressed after at least two prior lines of systemic therapy. The study will enroll 58 participants at Zhongshan Hospital, Fudan University. Participants will be randomly assigned (1:1) to either the experimental group or the control group. Those in the experimental group will receive SBRT to lung or liver metastases, followed one week later by sintilimab (200 mg every 2 weeks), bevacizumab (5 mg/kg every 2 weeks), and TAS-102 (35 mg/m² twice daily on days 1-5 every 2 weeks). Those in the control group will receive the investigator's choice of standard third-line therapy (such as TAS-102 alone or with bevacizumab, regorafenib, or fruquintinib). The main purpose is to see whether the new combination extends the time without the cancer growing or spreading (progression-free survival, PFS). Other goals include measuring overall survival, tumor response rates, local control of treated tumors, abscopal (out-of-field) effects, safety, quality of life, and exploring biomarkers that might predict treatment response. The study is expected to take 24 months to complete (12 months for enrollment and 12 months for follow-up). Results will help determine if adding SBRT and immunotherapy to standard chemotherapy and anti-angiogenic therapy is a beneficial option for patients with refractory mCRC.
detailed description
Background and Rationale Colorectal cancer (CRC) is the third most common malignancy worldwide. Approximately 40-50% of patients develop metastatic disease (mCRC). For patients who progress after first- and second-line systemic therapy (including fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF or anti-EGFR antibodies where indicated), third-line treatment options remain limited. Currently approved agents such as regorafenib, fruquintinib, and trifluridine/tipiracil (TAS-102) provide modest benefit, with median progression-free survival (PFS) of approximately 2-3 months and objective response rates below 5%. Moreover, the vast majority (90-95%) of mCRC patients have microsatellite stable (MSS) or proficient mismatch repair (pMMR) tumors, which are largely unresponsive to immune checkpoint inhibitor monotherapy.
Preclinical and emerging clinical evidence suggests that stereotactic body radiotherapy (SBRT) can induce immunogenic cell death, remodel the tumor immune microenvironment, and synergize with immune checkpoint inhibitors. Additionally, bevacizumab (anti-VEGF) has immunomodulatory effects, including reducing regulatory T cells and M2-type tumor-associated macrophages, and promoting dendritic cell maturation. The phase III SUNLIGHT trial demonstrated that adding bevacizumab to TAS-102 significantly improved overall survival (10.8 vs. 7.5 months) and PFS (5.6 vs. 2.4 months) in refractory mCRC. Therefore, combining SBRT with PD-1 inhibitor, bevacizumab, and TAS-102 may further enhance antitumor immunity and improve clinical outcomes in MSS/pMMR mCRC patients.
Study Design This is a prospective, single-center, randomized, open-label, phase II trial. A total of 58 eligible patients will be randomized 1:1 to either the experimental arm or the control arm. Randomization will be performed using a computer-generated random sequence. No blinding is applied.
Interventions
* Experimental arm: Patients will first receive SBRT to metastatic lung or liver lesions. SBRT is delivered using image-guided radiotherapy. The fractionation schedule is tailored to tumor location, with a biologically effective dose (BED) ≥94 Gy, completed within 1-2 weeks. One week after completion of SBRT, patients start systemic therapy: sintilimab (200 mg intravenously every 2 weeks), bevacizumab (5 mg/kg intravenously every 2 weeks), and TAS-102 (35 mg/m² orally twice daily on days 1-5 of each 14-day cycle). Treatment continues until disease progression, unacceptable toxicity, patient withdrawal, or other protocol-specified discontinuation criteria. * Control arm: Patients receive investigator's choice of standard-of-care third-line therapy for mCRC, which may include TAS-102 monotherapy, TAS-102 plus bevacizumab, regorafenib, or fruquintinib, according to local clinical practice and Chinese Society of Clinical Oncology (CSCO) guidelines.
official title
A Phase II Clinical Study on the Efficacy of Stereotactic Body Radiation Therapy Sequential Combined With Bevacizumab and Trifluridine/Tipiracil in the Treatment of Recurrent Metastatic Colorectal Cancer(BEST)