Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, MSI-high or MMR-deficient CRC

References

• Sung H , FerlayJ, SiegelRLet al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.71(3), 209–249 (2021).
   PubMed Web of Science ®Google Scholar
• Biller LH , SchragD. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA325(7), 669–685 (2021).
   PubMed Web of Science ®Google Scholar
• Punt CJA , KoopmanM, VermeulenL. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat. Rev. Clin. Oncol.14(4), 235–246 (2017).
   PubMed Web of Science ®Google Scholar
• Van Cutsem E , CervantesA, AdamRet al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol.27(8), 1386–1422 (2016).
   PubMed Web of Science ®Google Scholar
• National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2021. (2021). www.nccn.org/patients/guidelines/content/PDF/colon-patient.pdf
   Google Scholar
• National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.2.2021. (2021). www.nccn.org/patients/guidelines/content/PDF/rectal-patient.pdf
   Google Scholar
• Kurzawski G , SuchyJ, DebniakT, KładnyJ, LubińskiJ. Importance of microsatellite instability (MSI) in colorectal cancer: MSI as a diagnostic tool. Ann. Oncol.15(Suppl. 4), iv283–284 (2004).
   PubMedGoogle Scholar
• Phipps AI , LimburgPJ, BaronJAet al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology148(1), 77–87.e72 (2015).
   PubMed Web of Science ®Google Scholar
• Le Dung T , DurhamJN, SmithKNet al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science357(6349), 409–413 (2017).
   PubMed Web of Science ®Google Scholar
• Le DT , UramJN, WangHet al. PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med.372(26), 2509–2520 (2015).
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration . FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication (2017). www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication
   Google Scholar
• André T , ShiuK-K, KimTWet al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med.383(23), 2207–2218 (2020).
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov . Study of Pembrolizumab (MK-3475) vs standard therapy in participants with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) stage IV colorectal carcinoma (MK-3475-177/KEYNOTE-177). https://clinicaltrials.gov/ct2/show/NCT02563002
   Google Scholar
• Helwick C . Pembrolizumab doubles progression-free survival in MSI-H/dMMR metastatic colorectal cancer (2020 ). www.ascopost.com/issues/june-10-2020/pembrolizumab-doubles-progression-free-survival-in-msi-hdmmr-metastatic-colorectal-cancer
   Google Scholar
• US Food and Drug Administration . FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer (2020). www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer
   Google Scholar
• Trullas A , DelgadoJ, GenazzaniAet al. The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. ESMO Open6(3), 100–145 (2021).
   Web of Science ®Google Scholar
• European Medicines Agency . Summary of opinion (post authorisation) Keytruda (pembrolizumab). (2020). www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-keytruda-ii-91_en.pdf
   Google Scholar
• Dias S , WeltonNJ, SuttonAJ, CaldwellDM, LuG, AdesAE. Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. Med. Decis. Making33(5), 641–656 (2013).
   PubMed Web of Science ®Google Scholar
• Jansen JP , NaciH. Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers. BMC Med.11(1), 1–8 (2013).
   PubMedGoogle Scholar
• Moher D , LiberatiA, TetzlaffJ, AltmanDG, GroupP. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J. Clin. Epidemiol.62(10), 1006–1012 (2009).
   PubMed Web of Science ®Google Scholar
• Scottish Intercollegiate Guidelines Network. Search filters. www.sign.ac.uk/what-we-do/methodology/search-filters/
   Google Scholar
• Higgins JP , ThomasJ, ChandlerJet al. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, NJ, USA (2019).
   Google Scholar
• Cochrane Methods . Risk of Bias 2 (RoB 2) tool. https://methods.cochrane.org/risk-bias-2
   Google Scholar
• Jansen JP , CopeS. Meta-regression models to address heterogeneity and inconsistency in network meta-analysis of survival outcomes. BMC Med. Res. Methodol.12(1), 152–152 (2012).
   PubMedGoogle Scholar
• Dias S , WeltonNJ, CaldwellDM, AdesAE. Checking consistency in mixed treatment comparison meta-analysis. Stat. Med.29(7–8), 932–944 (2010).
   PubMed Web of Science ®Google Scholar
• Latimer NR , AbramsKR, LambertPCet al. Adjusting for treatment switching in randomised controlled trials – a simulation study and a simplified two-stage method. Stat. Methods Med. Res.26(2), 724–751 (2014).
   PubMedGoogle Scholar
• Robins JM , TsiatisAA. Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun. Stat. Theory Methods20(8), 2609–2631 (1991).
   Web of Science ®Google Scholar
• Jansen JP . Network meta-analysis of survival data with fractional polynomials. BMC Med. Res. Methodol.11(1), 1–14 (2011).
   PubMedGoogle Scholar
• Grambsch PM , TherneauTM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika81(3), 515–526 (1994).
   Web of Science ®Google Scholar
• Dias S , WeltonNJ, SuttonAJ, AdesAE. NICE DSU Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. National Institute for Health and Clinical Excellence, London, UK (2011).
   Google Scholar
• Dias S , SuttonAJ, AdesAE, WeltonNJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med. Decis. Making33(5), 607–617 (2013).
   PubMed Web of Science ®Google Scholar
• Ouwens MJNM , PhilipsZ, JansenJP. Network meta-analysis of parametric survival curves. Res. Synth. Methods1(3–4), 258–271 (2011).
   Google Scholar
• Guyot P , AdesAE, OuwensMJ, WeltonNJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan–Meier survival curves. BMC Med. Res. Methodol.12, 9 (2012).
   PubMed Web of Science ®Google Scholar
• Dempster AP . The direct use of likelihood for significance testing. Stat. Comput.7(4), 247–252 (1997).
   Web of Science ®Google Scholar
• Plummer M . JAGS: a program for analysis of Bayesian graphical models using Gibbs sampling. Proceedings of the 3rd International Workshop on Distributed Statistical Computing. Vienna, Austria, Abstract 125.10 (20–22 March 2003).
   Google Scholar
• Muller CI , SchulmannK, Reinacher-SchickAet al. Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report of the AIO Colorectal Study Group. Int. J. Colorectal Dis.23(11), 1033–1039 (2008).
   PubMed Web of Science ®Google Scholar
• Simkens LH , Van TinterenH, MayAet al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet385(9980), 1843–1852 (2015).
   PubMed Web of Science ®Google Scholar
• Goey KKH , EliasSG, Van TinterenHet al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann. Oncol.28(9), 2128–2134 (2017).
   PubMed Web of Science ®Google Scholar
• Porschen R , ArkenauHT, KubickaSet al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J. Clin. Oncol.25(27), 4217–4223 (2007).
   PubMedGoogle Scholar
• Cassidy J , ClarkeS, Diaz-RubioEet al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br. J. Cancer105(1), 58–64 (2011).
   PubMed Web of Science ®Google Scholar
• Personeni N , RimassaL, VerusioCet al. Prognostic factors in KRAS wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts) treated with biweekly cetuximab (C) plus irinotecan, fluorouracil, and leucovorin (FOLFIRI): a phase II study. J. Clin. Oncol.31(1 Suppl. 15), e14611 (2013).
   Google Scholar
• Madajewicz S , WaterhouseDM, RitchPSet al. Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer. Invest. New Drugs30(2), 772–778 (2012).
   PubMedGoogle Scholar
• Tournigand C , ChibaudelB, SamsonBet al. Improving safety in first-line metastatic colorectal cancer (MCRC) therapy with bevacizumab: modified FOLFOX7 versus XELOX2 – results of the induction phase of the GERCOR DREAM randomized phase III study. J. Clin. Oncol.33(Suppl. 3), 670 (2015).
   PubMedGoogle Scholar
• Kato S , ImaiH, GamohMet al. Intermittent withdrawal of oxaliplatin for alleviating neurotoxicity during oxaliplatin-based chemotherapy for Japanese patients with inoperable or metastatic colorectal cancer: a phase 2 multicenter study. Tohoku J. Exp. Med.245(1), 21–28 (2018).
   PubMedGoogle Scholar
• Schmoll H , GarlippB, JunghanssCet al. FOLFOX/bevacizumab (beva) +/- irinotecan in advanced colorectal cancer (CRC): a randomized phase II trial (AIO KRK 0209, CHARTA). Ann. Oncol.27(Suppl. 6), VI560 (2016).
   Google Scholar
• Hans-Joachim S , BenjaminG, ChristianJet al. FOLFOX/bevacizumab 1/2 irinotecan in advanced colorectal cancer (AIO) ‘cHARTA’: final results and multivariate prognostic factor analysis. Ann. Oncol.28(Suppl. 3), III152 (2017).
   Google Scholar
• Meinert F , CygonF, SteinAet al. CHARTA: FOLFOX/bevacizumab +/- irinotecan in advanced colorectal cancer; a multivariate analysis of prognostic and predictive factors. Oncol. Res. Treat.40, 162 (2017).
   Google Scholar
• Meinert F , SchmollH, GarlippBet al. CHARTA: FOLFOX/bevacizumab +/- irinotecan in advanced colorectal cancer – long term outcome. Oncol. Res. Treat.41, 245 (2018).
   Google Scholar
• Schmoll H , GarlippB, JunghanssCet al. CHARTA: FOLFOX + bevacizumab +/- irinotecan in advanced colorectal cancer (CRC) – final results of the randomized phase II trial of the AIO (KRK 0209). J. Clin. Oncol.35(4), 658 (2017).
   Google Scholar
• Stein A , MeinertF, CygonFet al. ‘CHARTA’ – FOLFOX/bevacicumab vs FOLFOXIRI/bevacicumab in advanced colorectal cancer – final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO. Oncol. Res. Treat.35(15), 3533 (2018).
   Google Scholar
• Goring S , JansenJP. PNS308 Methodological approaches for incorporating investigators’ choice comparator arms into network meta-analyses. Value Health22, S815–S816 (2019).
   Google Scholar
• Van Cutsem E , KohneCH, HitreEet al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med.360(14), 1408–1417 (2009).
   PubMed Web of Science ®Google Scholar
• Van Cutsem E , KohneCH, LangIet al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol.29(15), 2011–2019 (2011).
   PubMed Web of Science ®Google Scholar
• Bokemeyer C , Van CutsemE, RougierPet al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur. J. Cancer48(10), 1466–1475 (2012).
   PubMed Web of Science ®Google Scholar
• Anonymous . Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer. Clin. Adv. Hematol. Oncol.8(3), 7–8 (2010).
   Google Scholar
• Guren TK , ThomsenM, KureEHet al. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br. J. Cancer116(10), 1271–1278 (2017).
   PubMed Web of Science ®Google Scholar
• Tveit KM , GurenT, GlimeliusBet al. Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group. J. Clin. Oncol.29(4), 365 (2011).
   Google Scholar
• Tveit KM , GurenT, GlimeliusBet al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J. Clin. Oncol.30(15), 1755–1762 (2012).
   PubMed Web of Science ®Google Scholar
• Bokemeyer C , BondarenkoI, HartmannJTet al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann. Oncol.22(7), 1535–1546 (2011).
   PubMed Web of Science ®Google Scholar
• Bokemeyer C , BondarenkoI, MakhsonAet al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol.27(5), 663–671 (2009).
   PubMed Web of Science ®Google Scholar
• Bokemeyer C , KohneCH, CiardielloFet al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur. J. Cancer51(10), 1243–1252 (2015).
   PubMed Web of Science ®Google Scholar
• Qin S , LiJ, WangLet al. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J. Clin. Oncol.36(30), 3031–3039 (2018).
   PubMed Web of Science ®Google Scholar
• Qin S , GuoW, XuJMet al. Final overall survival (OS) analysis of first-line (1L) FOLFOX-4 +/- cetuximab (cet) in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 3 TAILOR trial. J. Clin. Oncol.36(15), 3521 (2018).
   Google Scholar
• Qin S , XuJ, WangLet al. First-line FOLFOX-4 +/- cetuximab in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC): the open-label, randomized phase 3 TAILOR trial. Ann. Oncol.27 (Suppl. 2), II141 (2016).
   Google Scholar
• Qin S , XuJ, WangLet al. Impact of tumor epidermal growth factor receptor (EGFR) status on the outcomes of first-line FOLFOX-4 +/- cetuximab in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the randomized phase 3 TAILOR trial. Ann. Oncol.27(Suppl. 6), VI174 (2016).
   Google Scholar
• Xu J , YeLC, RenL, WeiY. A randomized, controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. Ann. Oncol.23(Suppl. 9), IX190 (2012).
   Google Scholar
• Ye LC , ZhuD, RenLet al. Tumor response and secondary resectability of colorectal liver metastases following cetuximab with chemotherapy: a randomized, controlled study. Ann. Oncol.xi37 23 (2012).
   Google Scholar
• Ye LC , LiuTS, RenLet al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J. Clin. Oncol.31(16), 1931–1938 (2013).
   PubMed Web of Science ®Google Scholar
• Innocenti F , OuFS, QuXet al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J. Clin. Oncol.37(14), 1217–1227 (2019).
   PubMed Web of Science ®Google Scholar
• Lenz HJ , OuFS, VenookAPet al. Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: results from CALGB/SWOG 80405 (Alliance). J. Clin. Oncol.37(22), 1876 (2019).
   PubMed Web of Science ®Google Scholar
• Venook AP , NiedzwieckiD, LenzHJet al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA317(23), 2392–2401 (2017).
   PubMed Web of Science ®Google Scholar
• Uetake H , EmiY, YamanakaTet al. A randomized phase II study of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab for previously untreated, liver limited metastatic colorectal cancer that is unsuitable for resection (ATOM trial). J. Clin. Oncol.36(4), 734 (2018).
   Google Scholar
• Oki E , EmiY, YamanakaTet al. Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial). Br. J. Cancer121(3), 222–229 (2019).
   PubMed Web of Science ®Google Scholar
• Heinemann V , Von WeikersthalLF, DeckerTet al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol.15(10), 1065–1075 (2014).
   PubMed Web of Science ®Google Scholar
• Modest DP , Von WeikersthalLF, StintzingSet al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). Ann. Oncol.24, iv22–iv23 (2013).
   Google Scholar
• Stintzing S , FischerVon Weikersthal L, DeckerTet al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer – subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann. Oncol.23(7), 1693–1699 (2012).
   PubMed Web of Science ®Google Scholar
• Stintzing S , ModestDP, RossiusLet al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol.17(10), 1426–1434 (2016).
   PubMed Web of Science ®Google Scholar
• Stintzing S , JungA, RossiusLet al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Eur. J. Cancer49, S8–S9 (2013).
   PubMed Web of Science ®Google Scholar
• Stintzing S , JungA, RossiusLet al. Mutations within the EGFR signaling pathway: influence on efficacy in FIRE-3 – a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. J. Clin. Oncol.32(3), 445 (2014).
   Google Scholar
• Guan ZZ , XuJM, LuoRCet al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin. J. Cancer30(10), 682–689 (2011).
   PubMedGoogle Scholar
• Hurwitz H , FehrenbacherL, NovotnyWet al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med.350(23), 2335–2342 (2004).
   PubMed Web of Science ®Google Scholar
• Hurwitz H , FehrenbacherL, NovotnyW. Bevacizumab in combination with irinotecan plus fluorouracil plus leucovorin chemotherapy prolongs survival but increases adverse events in people with metastatic colorectal cancer. Cancer Treat. Rev.30(8), 715–720 (2004).
   PubMedGoogle Scholar
• Hurwitz HI , YiJ, InceW, NovotnyWF, RosenO. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist14(1), 22–28 (2009).
   PubMed Web of Science ®Google Scholar
• Passardi A , NanniO, TassinariDet al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann. Oncol.26(6), 1201–1207 (2015).
   PubMed Web of Science ®Google Scholar
• Stathopoulos GP , BatziouC, TrafalisDet al. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology78(5–6), 376–381 (2010).
   PubMed Web of Science ®Google Scholar
• Falcone A , RicciS, BrunettiIet al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J. Clin. Oncol.25(13), 1670–1676 (2007).
   PubMed Web of Science ®Google Scholar
• Masi G , VasileE, LoupakisFet al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J. Natl Cancer Inst.103(1), 21–30 (2011).
   PubMedGoogle Scholar
• Maiello E , DiMaggio G, CordioSet al. Bevacizumab in combination with either FOLFOX-4 or XELOX-2 in first-line treatment of patients with metastatic colorectal cancer: a multicenter randomized phase II Trial of the Gruppo Oncologico dell’Italia Meridionale (GOIM 2802). Clin. Colorectal Cancer19(2), 109–115 (2020).
   PubMedGoogle Scholar
• Maiello E , DiMaggio G, CordioSet al. Bevacizumab (B)+ bi-weekly capecitabine (C) and oxaliplatin (O) (XELOX2) or FOLFOX4 in first-line treatment of metastatic colorectal cancer (mCRC): final results of a multicenter randomized phase II trial of the Gruppo Oncologico dell’Italia Meridionale (GOIM protocol 2802). J. Clin. Oncol.36(15), 3542 (2018).
   Google Scholar
• Andre T , ShiuK-K, KimTWet al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 Study. J. Clin. Oncol.38(Suppl. 18), LBA4–LBA4 (2020).
   Web of Science ®Google Scholar
• A phase III study of pembrolizumab (MK-3475) vs. chemotherapy in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) stage IV colorectal carcinoma (KEYNOTE-177). Clinical Study Report. Merck Sharp & Dohme Corp., NJ, USA (2020).
   Google Scholar
• Ychou M , RivoireM, ThezenasSet al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann. Surg. Oncol.20(13), 4289–4297 (2013).
   PubMed Web of Science ®Google Scholar
• Gruenberger T , BridgewaterJ, ChauIet al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann. Oncol.26(4), 702–708 (2015).
   PubMed Web of Science ®Google Scholar
• Schwartzberg L , RiveraF, KarthausMet al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol.32(21), 2240–2247 (2014).
   PubMed Web of Science ®Google Scholar
• Karthaus M , SchwartzbergL, RiveraFet al. Updated overall survival (OS) analysis of novel predictive KRAS/NRAS mutations beyond KRAS exon 2 in PEAK: a 1st-line phase 2 study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) in metastatic colorectal cancer (mCRC). Eur. J. Cancer49, S516 (2013).
   Web of Science ®Google Scholar
• Rivera F , KarthausM, HechtJRet al. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int. J. Colorectal Dis.32(8), 1179–1190 (2017).
   PubMed Web of Science ®Google Scholar
• Bennett L , ZhaoZ, BarberBet al. Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment. Br. J. Cancer105(10), 1495–1502 (2011).
   PubMed Web of Science ®Google Scholar
• Douillard J , SienaS, CassidyJet al. Final results from PRIME: randomized phase III study of panitumumab (pmab) with FOLFOX4 for first line metastatic colorectal cancer (mCRC). J. Clin. Oncol.29(15), 3510 (2011).
   PubMedGoogle Scholar
• Douillard JY , SienaS, CassidyJet al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann. Oncol.25(7), 1346–1355 (2014).
   PubMed Web of Science ®Google Scholar
• Douillard JY , SienaS, CassidyJet al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J. Clin. Oncol.28(31), 4697–4705 (2010).
   PubMed Web of Science ®Google Scholar
• Udar N , Lofton-DayC, DongJet al. Clinical validation of the next-generation sequencing-based extended RAS panel assay using metastatic colorectal cancer patient samples from the phase 3 PRIME study. J. Cancer Res. Clin. Oncol.144(10), 2001–2010 (2018).
   PubMedGoogle Scholar
• Peeters M , DouillardJY, SienaSet al. Impact of post-protocol anti-epidermal growth factor receptor therapy on survival in wild-type KRAS/NRAS metastatic colorectal cancer: data from the PRIME study. Eur. J. Cancer49, S17 (2013).
   PubMedGoogle Scholar
• Anonymous . Panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line treatment in metastatic colorectal cancer. Clin. Adv. Hematol. Oncol.8(3), 9–10 (2010).
   Google Scholar
• Souglakos J , AndroulakisN, SyrigosKet al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br. J. Cancer94(6), 798–805 (2006).
   PubMed Web of Science ®Google Scholar
• Vamvakas L , AthanasiadisA, KarampeazisAet al. Clinical outcome of elderly patients with metastatic colorectal cancer treated with FOLFOXIRI versus FOLFIRI: subgroup analysis of a randomized phase III trial from the Hellenic Oncology Research Group (HORG). Crit. Rev. Oncol. Hematol.76(1), 61–70 (2010).
   PubMed Web of Science ®Google Scholar
• Hochster HS , HartLL, RamanathanRKet al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J. Clin. Oncol.26(21), 3523–3529 (2008).
   PubMed Web of Science ®Google Scholar
• Falcone A , CremoliniC, MasiGet al. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): results of the phase III TRIBE trial by GONO group. J. Clin. Oncol.31(15), 3505(2013).
   Google Scholar
• Loupakis F , CremoliniC, MasiGet al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med.371(17), 1609–1618 (2014).
   PubMed Web of Science ®Google Scholar
• Cremolini C , LoupakisF, MasiGet al. Folfoxiri/bevacizumab versus folfiri/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer: results of phase III tribe trial by GONO group. Ann. Oncol.24, 21 (2013).
   Google Scholar
• Cremolini C , LoupakisF, AntoniottiCet al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann. Oncol.26(6), 1188–1194 (2015).
   PubMed Web of Science ®Google Scholar
• Cremolini C , LoupakisF, LonardiSet al. Subgroup analyses in RAS mutant, BRAF mutant and ‘allwt’ metastatic colorectal cancer patients treated with folfoxiri plus bevacizumab (BEV) or folfiri plus BEV in the tribe study. Ann. Oncol.25(Suppl. 2), II107 (2014).
   Google Scholar
• Cremolini C , LoupakisF, AntoniottiCet al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as initial treatment for metastatic colorectal cancer (TRIBE study): updated survival results and final molecular subgroups analyses. Ann. Oncol.26, iv109 (2015).
   Google Scholar
• Sastre J , VieitezJM, Gomez-EspañaMAet al. Randomized phase III study comparing FOLFOX + bevacizumab versus FOLFOXIRI + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥3 baseline circulating tumor cells (bCTCs). J. Clin. Oncol.37(Suppl. 15), 3507 (2019).
   PubMedGoogle Scholar
• Cohen R , PudlarzT, DelattreJ-F, ColleR, AndréT. Molecular targets for the treatment of metastatic colorectal cancer. Cancers12(9), 2350 (2020).
   PubMed Web of Science ®Google Scholar
• Lai E , LisciaN, DonisiCet al. Molecular-biology-driven treatment for metastatic colorectal cancer. Cancers12(5), 1214 (2020).
   PubMed Web of Science ®Google Scholar
• Benson AB , VenookAP, Al-HawaryMMet al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc. Netw.19(3), 329–359 (2021).
   PubMed Web of Science ®Google Scholar
• Zhao P , LiL, JiangX, LiQ. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J. Hematol. Oncol.12(1), 54 (2019).
   PubMed Web of Science ®Google Scholar
• Calu V , IonescuA, StancaLet al. Key biomarkers within the colorectal cancer related inflammatory microenvironment. Sci. Rep.11(1), 7940 (2021).
   PubMed Web of Science ®Google Scholar
• Hameed Y , UsmanM, LiangS, EjazS. Novel diagnostic and prognostic biomarkers of colorectal cancer: capable to overcome the heterogeneity-specific barrier and valid for global applications. PLoS ONE16(9), e0256020 (2021).
   PubMed Web of Science ®Google Scholar