Original Research| Volume 169, P93-102, July 2022

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A phase I/Ib study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer


      • Mismatch repair proficient (pMMR) colon cancer (CRC) is unresponsive to immunotherapy.
      • Regorafenib (REGO) may enhance the antitumor activity of nivolumab (NIVO).
      • The dose-limiting toxicity of REGO/NIVO was rash.
      • REGO/NIVO showed limited anticancer activity in pMMR CRC.
      • REGO/NIVO showed anticancer activity in non-liver or lung metastatic pMMR CRC.



      In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC.


      This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS).


      A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively.


      Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC.

      Trial Registration identifier: NCT03712943.


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        • Gabrilovich D.I.
        • Chen H.L.
        • Girgis K.R.
        • Cunningham H.T.
        • Meny G.M.
        • Nadaf S.
        • et al.
        Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells.
        Nat Med. 1996; 2: 1096-1103
        • Terme M.
        • Pernot S.
        • Marcheteau E.
        • Sandoval F.
        • Benhamouda N.
        • Colussi O.
        • et al.
        VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer.
        Cancer Res. 2013; 73: 539-549
        • Gabrilovich D.
        • Ishida T.
        • Oyama T.
        • Ran S.
        • Kravtsov V.
        • Nadaf S.
        • et al.
        Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo.
        Blood. 1998; 92: 4150-4166
        • Yuan J.
        • Zhou J.
        • Dong Z.
        • Tandon S.
        • Kuk D.
        • Panageas K.S.
        • et al.
        Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab.
        Cancer Immunol Res. 2014; 2: 127-132
        • Sabatino M.
        • Kim-Schulze S.
        • Panelli M.C.
        • Stroncek D.
        • Wang E.
        • Taback B.
        • et al.
        Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy.
        J Clin Oncol. 2009; 27: 2645-2652
        • Abou-Elkacem L.
        • Arns S.
        • Brix G.
        • Gremse F.
        • Zopf D.
        • Kiessling F.
        • et al.
        Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model.
        Mol Cancer Ther. 2013; 12: 1322-1331
        • Hoff S.
        • Grunewald S.
        • Rose L.
        • Zopf D.
        Immunomodulation by regorafenib alone and in combination with anti PD1 antibody on murine models of colorectal cancer.
        ESMO 2017 Congress, Madrid, Spain2017
        • Grothey A.
        • Van Cutsem E.
        • Sobrero A.
        • Siena S.
        • Falcone A.
        • Ychou M.
        • et al.
        Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
        Lancet. 2013; 381: 303-312
        • Overman M.J.
        • McDermott R.
        • Leach J.L.
        • Lonardi S.
        • Lenz H.J.
        • Morse M.A.
        • et al.
        Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
        Lancet Oncol. 2017; 18: 1182-1191
        • Bekaii-Saab T.S.
        • Ou F.S.
        • Ahn D.H.
        • Boland P.M.
        • Ciombor K.K.
        • Heying E.N.
        • et al.
        Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.
        Lancet Oncol. 2019; 20: 1070-1082
        • Fukuoka S.
        • Hara H.
        • Takahashi N.
        • Kojima T.
        • Kawazoe A.
        • Asayama M.
        • et al.
        Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603).
        J Clin Oncol. 2020; 38: 2053-2061
        • Tumeh P.C.
        • Hellmann M.D.
        • Hamid O.
        • Tsai K.K.
        • Loo K.L.
        • Gubens M.A.
        • et al.
        Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC.
        Cancer Immunol Res. 2017; 5: 417-424
        • Yu J.
        • Green M.D.
        • Li S.
        • Sun Y.
        • Journey S.N.
        • Choi J.E.
        • et al.
        Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.
        Nat Med. 2021; 27: 152-164
        • Wang C.
        • Sandhu J.
        • Ouyang C.
        • Ye J.
        • Lee P.P.
        • Fakih M.
        Clinical response to immunotherapy targeting programmed cell death receptor 1/programmed cell death ligand 1 in patients with treatment-resistant microsatellite stable colorectal cancer with and without liver metastases.
        JAMA Netw Open. 2021; 4e2118416
        • Fakih M.
        • Raghav K.
        • Chang D.
        • Bendell J.
        • Larson T.
        • Cohn A.
        • et al.
        Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC).
        in: ASCO annual meeting. Chicago IL 2021. 2021
        • Barzi A.
        • Azad N.
        • Yang Y.
        • Tsao-Wei D.
        • Rehman R.
        • Zhang W.
        • et al.
        Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC).
        in: ASCO gastrointestinal cancers symposium. San francisco, CA2022. 2022
        • Lee J.C.
        • Mehdizadeh S.
        • Smith J.
        • Young A.
        • Mufazalov I.A.
        • Mowery C.T.
        • et al.
        Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis.
        Sci Immunol. 2020; 5
        • Gomez-Roca C.
        • Yanez E.
        • Im S.
        • Alvarez E.
        • Senellart H.
        • Doherty M.
        • et al.
        LEAP-005: a phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—results from the colorectal cancer cohort.
        in: Gastrointestinal cancers symposium. Virtual Meeting2021. 2021
        • Guo Y.
        • Zhang W.
        • Ying J.
        • Zhang Y.
        • Pan Y.
        • Qiu W.
        • et al.
        Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
        in: ASCO annual meeting. Chicago, IL 2021. 2021
        • Kim R.D.
        • Chung V.
        • Alese O.B.
        • El-Rayes B.F.
        • Li D.
        • Al-Toubah T.E.
        • et al.
        A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer.
        JAMA Oncol. 2020; 6: 888-894
        • Fuchs C.S.
        • Doi T.
        • Jang R.W.
        • Muro K.
        • Satoh T.
        • Machado M.
        • et al.
        Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
        JAMA Oncol. 2018; 4e180013
        • Tumeh P.C.
        • Harview C.L.
        • Yearley J.H.
        • Shintaku I.P.
        • Taylor E.J.
        • Robert L.
        • et al.
        PD-1 blockade induces responses by inhibiting adaptive immune resistance.
        Nature. 2014; 515: 568-571
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • Bartlett B.R.
        • Kemberling H.
        • Eyring A.D.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Cousin S.
        • Cantarel C.
        • Guegan J.P.
        • Gomez-Roca C.
        • Metges J.P.
        • Adenis A.
        • et al.
        Regorafenib-avelumab combination in patients with microsatellite stable colorectal cancer (REGOMUNE): a single-arm, open-label, phase II trial.
        Clin Cancer Res. 2021; 27: 2139-2147
        • Sharma P.
        • Hu-Lieskovan S.
        • Wargo J.A.
        • Ribas A.
        Primary, adaptive, and acquired resistance to cancer immunotherapy.
        Cell. 2017; 168: 707-723
        • Ling A.
        • Edin S.
        • Wikberg M.L.
        • Oberg A.
        • Palmqvist R.
        The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues.
        Br J Cancer. 2014; 110: 2551-2559
        • Salama P.
        • Phillips M.
        • Grieu F.
        • Morris M.
        • Zeps N.
        • Joseph D.
        • et al.
        Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.
        J Clin Oncol. 2009; 27: 186-192
        • Saito T.
        • Nishikawa H.
        • Wada H.
        • Nagano Y.
        • Sugiyama D.
        • Atarashi K.
        • et al.
        Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.
        Nat Med. 2016; 22: 679-684