Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

Abstract

BACKGROUND The effectiveness of regorafenib plus programmed cell death-1 (PD-1) inhibitor in treating microsatellite stable (MSS) metastatic colorectal cancer (mCRC) remains controversial. AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response. METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020. During a 4-wk treatment cycle, regorafenib was performed for 3 continuous weeks. PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib. We reviewed tumor response, progression-free survival (PFS), overall survival, and treatment-related adverse events (TRAEs) and evaluated association between platelet-to-lymphocyte ratio (PLR) and outcomes in this retrospective study. RESULTS Stable disease and progressive disease were found in 18 (60.0%) and 12 (40.0%) patients, respectively. The disease control rate was 60.0%. The median follow-up time was 12.0 mo, and median PFS was 3.4 mo [95% confidence interval (CI): 2.2-4.6 mo]. Of the 12 patients with progressive disease, 10 (83.3%) had liver metastasis before starting the combined treatment. Among the 18 patients with SD, 10 (55.6%) did not have liver metastases. One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo. The liver metastasis, the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome. The median PFS in the low-PLR group was 4.2 mo (95%CI: 3.5-4.9 mo), compared with 2.8 mo (95%CI: 1.4-4.2 mo) in the high-PLR group ( P = 0.005). The major TRAEs included hand-foot syndrome (33.3%), hypertension (23.3%), malaise (20.0%), and gastrointestinal reaction (16.7%). The incidence of grade 3 TRAEs was 13.3% (4/30), which comprised abnormal capillary proliferation ( n = 1), transaminase elevation ( n = 1), and hand-foot syndrome ( n = 2). No grade 4 or higher toxicity was observed. CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC. The PLR might be a prediction of the patient response to this therapy.

Effectiveness of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in patients with advanced or metastatic colorectal carcinoma with either mismatch repair proficient or metastatic microsatellite stable disease: A systematic review and meta‑analysis

“…In clinical settings, TKIs, such as regorafenib and fruquintinib, are often used as anti-angiogenic pharmaceuticals. These medications have been incorporated into the therapeutic regimen for CRC (28)(29)(30). Yang et al (30) assessed the combined use of ICIs with regorafenib for treating patients with advanced or metastatic MSS CRC.…”

“…Moreover, this is consistent with previous clinical studies in terms of therapeutic effect (16-18), and the therapeutic effect of TKI + ICI combination therapy provides evidential support for ICIs combined with anti-VEGF therapy for patients with advanced or metastatic MSS/pMMR CRC. In terms of the potential mechanism of the combination therapy, VEGFR and EGFR signaling pathways are related; therefore, the combination of anti-VEGF and ICIs can block several VEGFR-and EGFR-mediated signaling pathways in addition to immunosuppression, thereby inhibiting tumor angiogenesis (25,29). This would circumvent resistance to immunotherapy interventions demonstrated by MSS/pMMR mCRC.…”

Regorafenib in patients with pretreated advanced melanoma: a single-center case series

“…Our retrospective analysis of the clinical outcome of 27 pretreated advanced melanoma patients who were treated with REGO (including monotherapy and combination strategies) represents, to the best of our knowledge, the first experience with this multitargeted kinase inhibitor in this specific patient population. The interest to explore the potential therapeutic activity of REGO in advanced melanoma was sparked by results suggesting that REGO could overcome resistance to anti-PD-1 checkpoint blockade in immunotherapy refractory cancers such as mismatch repair proficient (microsatellite stable) colorectal cancer and gastric cancers [26][27][28][29]. Potential synergy between REGO and PD-1/-ligand-1targeted immune therapy has also been suggested for melanoma [30].…”

RNA Expression-Based Analysis to Predict Response in Patients with Metastatic Mismatch Repair Proficient Colorectal Cancer Treated with Regorafenib and Nivolumab

“…Identification of biomarkers that predict treatment benefit may assist in se-lecting patients for this strategy. Previous studies have linked liver metastasis, cytotoxic T cells, Tregs, tumorassociated macrophages, plasma levels of biomarkers of vascular biology, circulating tumor DNA, neutrophil-tolymphocyte ratio, gut microbiome, etc., with treatment response [6,9,10,[12][13][14][15]. However, predictive biomarkers for anti-angiogenesis and immunotherapies have been challenged by the limited studies and the inconsistent results.…”

“…The combination of regorafenib with PD-1 targeting for patients with refractory CRC has been evaluated in both prospective and retrospective settings [4][5][6][7][8][9][10][11][12][13][14][15]. The treatment efficacy in different studies among different patient populations varies greatly.…”