Regorafenib and metronomic capecitabine, cyclophosphamide, and aspirin in refractory metastatic colorectal cancer: results from the REPROGRAM-01 single-arm phase II trial

Background: Treatment of chemotherapy-resistant metastatic colorectal cancers (mCRCs) is still an unmet medical need. Combining regorafenib, an antiangiogenic multikinase inhibitor with metronomic chemotherapy and aspirin may enhance efficacy to circumvent the tumor microenvironment and offer better clinical outcomes. REPROGRAM-01 was a signal-seeking phase II study assessing the efficacy and safety of multimodal metronomic chemotherapy combined with regorafenib (NCT04534218). Patients and methods: mCRC patients involved were previously exposed to conventional chemotherapies, bevacizumab, anti-epidermal growth factor receptor (anti-EGFR) if RAS wild type, and pembrolizumab if deficient mismatch repair disease. Regorafenib (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day) was combined with multimodal metronomic chemotherapy including capecitabine (625 mg/m2 twice daily continuously) and cyclophosphamide (50 mg daily) for 6 months plus aspirin (75 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), safety, and evaluation of exploratory biomarkers. Results: Forty-eight patients were included. No unexpected serious adverse event was reported and 10 patients discontinued regorafenib for toxicity. The most common grade 3 and 4 toxicities involved palmoplantar erythrodysesthesia (14.6%), diarrhea (6.3%), hypertension (4.2%), and lymphopenia (4.2%). The best ORR was 4.2% [95% confidence interval (CI) 0.8% to 12.5%]. The trial was negative on the primary endpoint aiming to achieve an ORR of 15%, compared with 4% for null hypothesis. Median PFS and OS were 4.7 months (95% CI 3.7-5.9 months) and 9.5 months (95% CI 7.2-14.9 months), respectively. The PFS rates at 6 months and 12 months were 32.5% and 6.5%, respectively. A decrease of NPY methylated circulating tumor DNA >50% occurred in 16 out of the 26 assessable patients, leading to a median PFS of 5.5 months (95% CI 3.7-9.5 months) versus 3.6 (95% CI 1.8-9.6 months). A median PFS of 7.2 months (95% CI 3.7-11.6 months) was achieved in patients with decreasing angiopoietin-2 (ANG2) levels compared with 3.9 months (95% CI 1.3-19.4 months) in ANG2 nonresponding patients. Conclusions: According to the REPROGRAM-01 study, combining multimodal metronomic chemotherapy with regorafenib would double the number of patients who could benefit from regorafenib treatment without increasing toxicities.