Advertisement

Final results of the CAVE trial in RAS wild type metastatic colorectal cancer patients treated with cetuximab plus avelumab as rechallenge therapy: Neutrophil to lymphocyte ratio predicts survival

Published:January 16, 2022DOI:https://doi.org/10.1016/j.clcc.2022.01.005

      Abstract

      Background

      High neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic factor in metastatic colorectal cancer (mCRC). Here we provide final results of CAVE mCRC trial, of cetuximab plus avelumab rechallenge in chemo-refractory mCRC patients and investigated the predictive role of NLR.

      Methods

      All the 77 patients enrolled were included in the analysis. A cut-off of 3 was used to correlate baseline NLR with with overall survival (OS) and with progression free survival (PFS), in intention to treat (ITT) and in circulating tumor DNA (ctDNA) RAS/BRAF Wild Type (WT) patients.

      Results

      In ITT population, NLR <3 (49%) group had median overall survival (mOS) of 17.8 months, vs. 8.9 months in NLR ≥ 3 group (51%) [HR 0.50, (CI 95% 0.3-0.8), P = .006]. Median progression free survival (mPFS) was 3.9 months in NLR <3 group and 3.5 months in NLR≥3 [HR 0.79, (CI 95% 0.5-1.24), P = .3]. In ctDNA RAS/BRAF WT population, mOS was 22 months in NLR <3 group (48%), vs. 8.9 months in NLR ≥3 group (52%), [HR 0.38, (CI 95% 0.19-0.75), P = .005]. A trend towards increased mPFS was observed in patients with NLR <3 versus NLR ≥3: 5.3 vs. 3.6 months [HR: 0.79, (CI 95% 0.44-1.4), P = .43]. In contrast, NLR did not correlate either with PFS or OS in ctDNA RAS/BRAF mutated patients.

      Conclusion

      In the exploratory analysis of the CAVE mCRC trial, baseline NLR <3 significantly correlated with improved survival and may represent a potential predictive biomarker of cetuximab plus avelumab rechallenge activity in ctDNA RAS/BRAF WT patients, that must be confirmed in randomized studies.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Colorectal Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Di Nicolantonio F.
        • Vitiello P.P.
        • Marsoni S.
        • et al.
        Precision oncology in metastatic colorectal cancer — from biology to medicine.
        Nat Rev Clin Oncol. 2021; 18: 506-525https://doi.org/10.1038/s41571-021-00495-z
        • Martinelli E
        • Ciardiello D
        • Martini G
        • et al.
        Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives.
        Ann Oncol. 2020; 31: 30-40https://doi.org/10.1016/j.annonc.2019.10.007
        • Mauri G
        • Pizzutilo EG
        • Amatu A
        • et al.
        Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: systematic review of different strategies.
        Cancer Treat Rev. 2019; 73: 41-53https://doi.org/10.1016/j.ctrv.2018.12.006
        • Ciardiello D
        • Martini G
        • Famiglietti V
        • et al.
        Biomarker-guided anti-egfr rechallenge therapy in metastatic colorectal cancer.
        Cancers. 2021; 13https://doi.org/10.3390/cancers13081941
        • Martinelli E
        • Martini G
        • Famiglietti V
        • et al.
        Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: the phase II single-arm clinical CAVE trial [published online ahead of print, August 12, 2021].
        JAMA Oncol. 2021; https://doi.org/10.1001/jamaoncol.2021.2915
        • Ciardiello D
        • Vitiello PP
        • Cardone C
        • et al.
        Immunotherapy of colorectal cancer: challenges for therapeutic efficacy.
        Cancer Treat Rev. 2019; 76: 22-32https://doi.org/10.1016/j.ctrv.2019.04.003
        • André T
        • Shiu KK
        • Kim TW
        • et al.
        Pembrolizumab in microsatellite-instability-high advanced colorectal cancer.
        N Engl J Med. 2020; 383: 2207-2218https://doi.org/10.1056/NEJMoa2017699
        • Overman MJ
        • McDermott R
        • Leach JL
        • et al.
        Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicenter, phase II study [published correction appears in Lancet Oncol. September, 2017;18(9):e510].
        Lancet Oncol. 2017; 18: 1182-1191https://doi.org/10.1016/S1470-2045(17)30422-9
        • Fasano M
        • Della Corte CM
        • Di Liello R
        • et al.
        Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer.
        ESMO Open. 2020; 5e000753https://doi.org/10.1136/esmoopen-2020-000753
        • Srivastava RM
        • Lee SC
        • Andrade Filho PA
        • et al.
        Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.
        Clin Cancer Res. 2013; 19: 1858-1872https://doi.org/10.1158/1078-0432.CCR-12-2426
        • Trivedi S
        • Srivastava RM
        • Concha-Benavente F
        • et al.
        Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients.
        Clin Cancer Res. 2016; 22: 5229-5237https://doi.org/10.1158/1078-0432.CCR-15-2971
        • Greten FR
        • Grivennikov SI.
        Inflammation and cancer: triggers, mechanisms, and consequences.
        Immunity. 2019; 51: 27-41https://doi.org/10.1016/j.immuni.2019.06.025
        • el-Hag A
        • Clark RA.
        Immunosuppression by activated human neutrophils. Dependence on the myeloperoxidase system.
        J Immunol. 1987; 139: 2406-2413
        • Templeton AJ
        • McNamara MG
        • Šeruga B
        • et al.
        Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.
        JNCI: Journal of the National Cancer Institute. 2014; 106https://doi.org/10.1093/jnci/dju124
        • Dell'Aquila E
        • Cremolini C
        • Zeppola T
        • et al.
        Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.
        Ann Oncol. 2018; 29: 924-930https://doi.org/10.1093/annonc/mdy004
        • Capone M
        • Giannarelli D
        • Mallardo D
        • et al.
        Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab.
        J Immunother Cancer. 2018; 6 (Published 2018 Jul 16): 74https://doi.org/10.1186/s40425-018-0383-1
        • Jin J
        • Yang L
        • Liu D
        • et al.
        Association of the neutrophil to lymphocyte ratio and clinical outcomes in patients with lung cancer receiving immunotherapy: a meta-analysis.
        BMJ Open. 2020; 10e035031https://doi.org/10.1136/bmjopen-2019-035031
        • Vitiello PP
        • De Falco V
        • Giunta EF
        • et al.
        Clinical Practice Use of Liquid Biopsy to Identify RAS/BRAF Mutations in Patients with Metastatic Colorectal Cancer (mCRC): A Single Institution Experience.
        Cancers (Basel). 2019; 11 (Published 2019 Oct 8): 1504https://doi.org/10.3390/cancers11101504
        • Proctor M.
        • McMillan D.
        • Morrison D.
        • et al.
        A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer.
        Br J Cancer. 2012; 107: 695-699https://doi.org/10.1038/bjc.2012.292
        • Walsh SR
        • Cook EJ
        • Goulder F
        • Justin TA
        • Keeling NJ.
        Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer.
        J Surg Oncol. 2005; 91: 181-184https://doi.org/10.1002/jso.20329
        • Haram A
        • Boland MR
        • Kelly ME
        • Bolger JC
        • Waldron RM
        • Kerin MJ.
        The prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review.
        J Surg Oncol. 2017; 115: 470-479https://doi.org/10.1002/jso.24523
        • Grothey A.
        • Van Cutsem E.
        • Sobrero A.
        • et al.
        Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicenter, randomized, placebo-controlled, phase III trial.
        Lancet. 2013; 381: 303-312https://doi.org/10.1016/s0140-6736(12)61900-x
        • Li J.
        • Qin S.
        • Xu R.
        • et al.
        Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomized, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2015; 16: 619-629
        • Mayer R.J.
        • Van Cutsem E.
        • Falcone A.
        • et al.
        Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer.
        N. Engl. J. Med. 2015; 372: 1909-1919https://doi.org/10.1056/nejmoa1414325
        • Wang C
        • Fakih M.
        Targeting MSS colorectal cancer with immunotherapy: are we turning the corner? [published online ahead of print, May 31, 2021].
        Expert Opin Biol Ther. 2021; : 1-11https://doi.org/10.1080/14712598.2021.1933940
      1. Association of tumor mutational burden with outcomes in patients with advanced solid tumors treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase II KEYNOTE-158 study. Lancet Oncol. 2020;21:1353-1365. doi:10.1016/S1470-2045(20)30445-9

        • Marcus L
        • Fashoyin-Aje LA
        • Donoghue M
        • et al.
        FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid tumors.
        Clin Cancer Res. 2021; 27: 4685-4689https://doi.org/10.1158/1078-0432.CCR-21-0327
        • Rousseau B
        • Foote MB
        • Maron SB
        • et al.
        The spectrum of benefit from checkpoint blockade in hypermutated tumors.
        N Engl J Med. 2021; 384: 1168-1170https://doi.org/10.1056/NEJMc2031965
        • Patel SP
        • Kurzrock R.
        PD-L1 Expression as a predictive biomarker in cancer immunotherapy.
        Mol Cancer Ther. 2015; 14: 847-856https://doi.org/10.1158/1535-7163.MCT-14-0983
        • Gomez-Roca C
        • Yanez E
        • Im S-A
        • 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.
        JCO. 2021; 39 (94-94)https://doi.org/10.1200/JCO.2021.39.3_suppl.94
        • Colotta F
        • Allavena P
        • Sica A
        • Garlanda C
        • Mantovani A.
        Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
        Carcinogenesis. 2009; 30: 1073-1081https://doi.org/10.1093/carcin/bgp127
        • de Wit R
        • Wülfing C
        • Castellano D
        • et al.
        Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study [published online ahead of print, August 24, 2021].
        ESMO Open. 2021; 6100241https://doi.org/10.1016/j.esmoop.2021.100241
        • Faria SS
        • Fernandes Jr, PC
        • Silva MJ
        • et al.
        The neutrophil-to-lymphocyte ratio: a narrative review.
        E cancer Med Sci. 2016; 10 (Published 2016 Dec 12): 702https://doi.org/10.3332/ecancer.2016.702
        • Coffelt S.
        • Kersten K.
        • Doornebal C.
        • et al.
        IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
        Nature. 2015; 522 (DOI:): 345-348https://doi.org/10.1038/nature14282
        • Ménétrier-Caux C.
        • Ray-Coquard I.
        • Blay JY.
        • et al.
        Lymphopenia in Cancer Patients and its Effects on Response to Immunotherapy: an opportunity for combination with Cytokines?.
        J Immunotherapy Cancer. 2019; 7 (DOI:): 85https://doi.org/10.1186/s40425-019-0549-5