433P A phase Ib/II clinical trial of tolerability, safety and efficacy of regorafenib in combination with toripalimab (a PD-1 antibody) in patients with relapsed or metastatic colorectal cancer

Wang, F.; He, M-M.; Yao, Y-C.; Zq, Wang; Jin, Ying; Fh, Wang; Qiu, M-Z.; Lv, Z-D.; Ds, Wang; Hy, Luo; Yh, Li; Ds, Zhang; Xu, Rui‐hua

doi:10.1016/j.annonc.2020.08.544

Cited by 9 publications

(6 citation statements)

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“…The toxicity profile of this study was generally tolerable and was comparable with previous studies evaluating the same strategy; the incidence of TRAEs was also similar to conventional treatment such as regorafenib single agent or TAS-102 [ 3 , 4 , 17 , 18 , 26 ]. Thus, the combination of ICIs with regorafenib could be safely applied in patients with chemotherapy refractory MSS colorectal cancer.…”

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

“…Several previous studies with small sample sizes have evaluated the efficacy of ICIs combined with regorafenib in MSS colorectal cancer [ 17 , 18 , 26 ]. The results of our study were comparable with the REGOMUNE (NCT03475953) and the REGOTORI study (NCT03946917) [ 18 , 26 ]. However, in the phase Ib REGONIVO trial (NCT03406871), an ORR of 33% and a DCR of 88% were reported in 24 patients with MSS colorectal cancer, which was higher than the responses reported in other studies [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

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Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study

Yang

Han

et al. 2021

Cancer Immunol Immunother

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Background Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. Methods We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). Results Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07–3.69, P = 0.03) and neutrophil–lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00–7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). Conclusion The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study

Yang

Han

et al. 2021

Cancer Immunol Immunother

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“…e OS of 39 patients was 15.5 months, and the median duration of response (DOR) was 9.6 months, suggesting that the antitumor efficacy of the regimen was long-lasting. ORR was up to 30% in patients without liver metastasis [15]. REGOMUNE was a study on the combination of avelumab and regorafenib treating third-line and above MSS advanced colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer

Tao

Zhang

et al. 2021

Journal of Oncology

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Background. The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods. We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results. The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment ( p = 0.005 ). Lung metastasis was a negative factor in combined therapy ( p = 0.032 ). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy ( p = 0.034 ). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 ( p = 0.034 ). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions. Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

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“…The combination of a PD-1 inhibitor with angiogenesis agents might have a potential in tumor control, as suggested by the REGONIVO study. Despite of that, the immunotherapy-based options for mCRC harboring MSS phenotype remain dismal (12,13), with PFS around 3-4months in China and even worldwide (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Fruquintinib in Combination With PD-1 Inhibitors in Patients With Refractory Non-MSI-H/pMMR Metastatic Colorectal Cancer: A Real-World Study in China

et al. 2022

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BackgroundFruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients.MethodsA total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated.ResultsAmong the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported.ConclusionsFruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.

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433P A phase Ib/II clinical trial of tolerability, safety and efficacy of regorafenib in combination with toripalimab (a PD-1 antibody) in patients with relapsed or metastatic colorectal cancer

Cited by 9 publications

References 0 publications

Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study

Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study

Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer

Fruquintinib in Combination With PD-1 Inhibitors in Patients With Refractory Non-MSI-H/pMMR Metastatic Colorectal Cancer: A Real-World Study in China

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