To explore the efficacy and safety of an intensified treatment regimen consisting of short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with precise targeted therapy (based on RAS/BRAF status: cetuximab for wild-type, bevacizumab for mutant) and a PD-1 monoclonal antibody, compared with short-course radiotherapy followed by mFOLFOX6 chemotherapy alone, in high-risk locally advanced pMMR/MSS rectal adenocarcinoma through a prospective, randomized controlled phase III clinical study, providing high-level evidence-based medical evidence to establish a superior neoadjuvant treatment strategy for this population.
Patients with locally advanced rectal cancer (LARC) who have high-risk factors, such as low rectal cancer, clinical stage T4b, positive mesorectal fascia (MRF), and positive extramural vascular invasion (EMVI), are at extremely high risk of distant metastasis. For these LARC patients with high-risk factors, the pathological complete response (PCR) rate with neoadjuvant chemotherapy alone is relatively low, ranging from 4.3% to 13.3%. Therefore, the use of a more potent comprehensive neoadjuvant treatment regimen, including concurrent chemoradiotherapy combined with targeted therapy and immunotherapy, may offer greater benefits to these patients. For patients with high-risk LARC, this study aims to explore whether the combination of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) can improve the pathological responce rate, and achieve better long-term survival benefits. The study will investigate the efficacy and safety of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) for high-risk LARC. Based on the above theoretical and clinical needs, we conducted a preliminary phase II exploratory study (the CRIT study). This study preliminarily validated the safety and excellent preliminary efficacy of the strategy of "short-course radiotherapy (SCRT) followed by mFOLFOX6 chemotherapy combined with RAS-guided targeted therapy and a PD-1 monoclonal antibody," achieving a pathological complete response (pCR) rate of 62.1% (66.7% in the RAS/BRAF wild-type subgroup and 57.1% in the RAS/BRAF mutant subgroup), which is much higher than historical controls, suggesting that this regimen has great clinical application value. Therefore, a phase III randomized controlled trial is being conducted. Enrolled patients will be randomized into 2 groups with different treatment regimen. The control group will receive neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen. The experimental group will receive neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy (combined with targeted and immune therapy in the experimental group), patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy (combined with PD-1 monoclonal antibody and targeted drugs in the experimental group). Bevacizumab is not used in the last cycle with RAS/BRAF mutations. Surgery is performed 8-10 weeks after the completion of SCRT. If pelvic MRI indicates clinical complete response (CCR) and N0, or T1N0M0, local excision (LE) will be performed. Otherwise, total mesorectal excision (TME) will be performed. The decision regarding adjuvant chemotherapy after surgery will be made by the attending physician.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
204
Patients undergo SCRT at a dose of 5Gy × 5 fractions
Patients complete immune therapy with PD-1 monoclonal antibody for 4 cycles.
Patients complete chemotherapy with mFOLFOX6 regimen for 4 cycles.
Patients with RAS/BRAF wild-type receive targeting therapy with Cetuximab for 4 cycles.
Patients with RAS/BRAF mutations receive targeting therapy with Bevacizumab for 3 cycles. (Bevacizumab is not used in the last cycle of the bevacizumab group)
Surgery either local excition or total mesorectal excision is performed 8-10 weeks after the completion of short-course radiotherapy.
Sixth Affiliated Hospital, Sun Yat-sen University
Guangzhou, Guangdong, China
RECRUITING3 years DFS Rate
3 years Disease Free Survival Rate
Time frame: 3 years
pCR rate
pathological complete response rate
Time frame: 1 year
3 years OS rate
3 years Overall Survival Rate
Time frame: 3 years
3 years DMFS Rate
3 years Disease Metastasis Free Survival Rate
Time frame: 3 years
3 years RFS Rate
3 years Recurrence Free Survival Rate
Time frame: 3 years
R0 resection rate
R0 resection rate in participants
Time frame: 1 year
Toxicities Associated with Neoadjuvant Therapy
incidence of adverse events related to neoadjuvant therapy as assessed by CTCAE v5.0
Time frame: 1 year
CR rate
Complete response rate in participants
Time frame: 1 year
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