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Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion

Open AccessPublished:April 20, 2020DOI:https://doi.org/10.1016/j.clcc.2020.04.003

      Abstract

      Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.

      Keywords

      Introduction

      Colorectal cancer (CRC) is a public health problem, and it is the third most common cancer in men (746,000 new cases every year) and the second in women (614,000 new cases every year), and represents the second leading cause of death by cancer worldwide.
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      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      In Spain, 41,441 cases were expected in 2015, representing the second most common tumor in both genders.
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      REDECAN Working Group
      Cancer incidence in Spain, 2015.
      It is believed that in 2035, the standardized mortality rate for colon cancer will be reduced by 12.4%, but for rectal cancer, there will be an increase of 10%, which is consistent with other European countries.
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      Global trends in colorectal cancer mortality: projections to the year 2035.
      The prognosis for metastatic CRC (mCRC) is poor, with survival rates of 15% at 5 years and a median survival of 24 to 36 months.
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      Cancer statistics, 2019.
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      FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.
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      FIRE-3 investigators
      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.
      Standard first- and second-line treatments are based on combinations of fluoropirimidines plus oxaliplatin or irinotecan, associated to an antiagiogenic monoclonal antibody or anti-epidermal growth factor receptor (EGFR), which is chosen based on the RAS mutational status, although the optimal sequence is still unknown.
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      FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.
      ,
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      • Lenz H.J.
      • et 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.
      We are facing a molecularly heterogeneous disease, with various biomarkers both prognostic and predictive of response. Only the presence of RAS activating mutations (KRAS/NRAS), present in 30% to 45% of mCRC, has proven to be a negative predictive biomarker of response to anti-EGFR.
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      • McKinnon R.A.
      • Karapetis C.S.
      Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.
      Although there are no validated predictive biomarkers of response other than RAS, there are other biomarkers of special interest. These include BRAF mutation, human epidermal growth factor receptor 2 (HER2) amplification, microsatellite instability (MSI-H), and ALK/ROS/NTRK fusion/rearrangements.
      The BRAF mutation, present in 8% to 10% of mCRC, is located in the EGFR signaling pathway, and it is a factor of poor prognosis and has specific clinical features (predominance in women, right colon, and extrahepatic involvement). Despite being a controversial issue, the evidence suggesting that it is a marker of resistance to anti-EGFR drugs is increasing.
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      • Petrelli F.
      • Coinu A.
      • et al.
      Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis.
      On the other hand, HER2, a receptor of the EGFR family, whose amplification is associated with resistance to anti-EGFR drugs, is a biomarker whose blockade at different levels is under investigation.
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
      MSI, by somatic or germline pathway, results in hypermutability and lymphocyte infiltration with sensitivity to anti-programmed cell death protein 1 (PD-1) and anti-CTLA4 therapies.
      • Overman M.J.
      • Lonardi S.
      • Wong K.Y.M.
      • et al.
      Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.
      ,
      • Le D.T.
      • Durham J.N.
      • Smith K.N.
      • et al.
      Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
      Finally, ALK, ROS, and NKTR fusions and rearrangements occur in 0.2% to 2.4% of mCRC and lead to a constitutive activation of tyrosine kinase receptors and, like BRAF mutations, they are associated with right colon tumors, elderly patients, lymph node involvement, absence of mutations in RAS, and also resistance to anti-EGFR agents.
      • Pietrantonio F.
      • Di Nicolantonio F.
      • Schrock A.B.
      • et al.
      ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.
      There is a growing number of patients with mCRC who are candidates to receive a treatment in the third line or beyond, although the optimal drug regimen and sequence are still unknown. The aim of this article is to review the scientific evidence of the available therapeutic options in the third line and beyond and to establish the therapeutic recommendations agreed upon by the Group for Digestive Tumour Therapy (TTD Group).

      Approved Drugs for Refractory mCRC

       Trifluridine/Tipiracil

      Trifluridine/tipiracil is an oral drug consisting of trifluridine, a thymidine analogue, which incorporates to the tumoral DNA inducing DNA dysfunction, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor, responsible for trifluridine degradation, whose dosage consists of 35 mg/m2/twice daily on days 1 to 5 and 8 to 12 every 28 days. In the phase III double-blind placebo-controlled study, RECOURSE, trifluridine/tipiracil achieved a significant benefit in overall survival (OS)
      • Mayer R.J.
      • Van Cutsem E.
      • Falcone A.
      • et al.
      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      (Table 1). The tolerance profile to trifluridine/tipiracil was favorable, with grade (G) 3 to 4 neutropenia (38%) as the most relevant toxicity (only 4% were febrile neutropenia). Other G3 to 4 toxicities were rare (< 5%): nausea/vomiting, hyporexia, asthenia, and diarrhea. Despite not having a specific quality of life (QoL) assessment, the median time for the deterioration of the performance status (PS) of 0 to 1 versus ≥ 2 was significantly longer in the trifluridine/tipiracil arm (5.7 vs. 4.0 months), and 84% of the patients had a PS 0 to 1 at the end of treatment.
      • Van Cutsem E.
      • Mayer R.J.
      • Laurent S.
      • et al.
      RECOURSE Study Group
      The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer.
      Subsequently, the phase III study, TERRA, confirmed the benefits of trifluridine/tipiracil in Asian patients regardless of whether they had received biological agents or not
      • Xu J.
      • Kim T.W.
      • Shen L.
      • et al.
      Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study.
      (Table 1).
      Table 1Phase III Studies in mCRC With Regorafenib or Trifluridine/Tipiracil: Efficacy and Safety Data
      Phase III StudiesRegorafenibTrifluridine/Tipiracil
      CORRECT
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      CORRECT Study Group
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      CONCUR
      • Li J.
      • Qin S.
      • Xu R.
      • et al.
      CONCUR Investigators
      Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
      RECOURSE
      • Mayer R.J.
      • Van Cutsem E.
      • Falcone A.
      • et al.
      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      ,
      • Van Cutsem E.
      • Mayer R.J.
      • Laurent S.
      • et al.
      RECOURSE Study Group
      The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer.
      TERRA
      • Xu J.
      • Kim T.W.
      • Shen L.
      • et al.
      Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study.
      Prior Biological Therapies100% BEV

      100% Anti-EGFR
      60%100% BEV

      100% Anti-EGFR
      BEV or EGFR or Both

      55% vs. 49%
      REGOBSCREGOBSCTrifluridine/TipiracilBSCTrifluridine/TipiracilBSC
      N50525513668534266271135
      mOS, mos6.45.08.86.37.15.37.87.1
      HR 0.77

      P = .0052
      HR 0.55

      P = .0002
      HR 0.68

      P < .001
      HR 0.79

      P = .035
      mPFS, mos1.91.73.21.72.01.72.01.8
      HR 0.49

      P < .0001
      HR 0.31

      P < .0001
      HR 0.48

      P < .001
      HR 0.43

      P < .001
      ORR, %1.00.44.401.60.41.10
      P = .29P = .55
      DCR441644.114.6
      P < .001P < .001
      Abbreviations: BEV = bevacizumab; BSC = best supportive care; DCR = disease control rate; EGFR = epidermal growth factor receptor; HR = hazard ratio; mCRC = metastatic colorectal cancer; mOS = mean overall survival; mPFS = median progression-free survival; ORR = objective response rate; REGO = regorafenib.
      There is also evidence of efficacy in the real-life population. The United States expanded access program in 549 patients confirmed a safety profile similar to that of the RECOURSE study.
      • Mayer R.J.
      • Hochster H.S.
      • Cohen S.J.
      • Winkler R.
      • Makris L.
      • Grothey A.
      Safety of trifluridine/tipiracil in an open-label expanded-access program in elderly and younger patients with metastatic colorectal cancer.
      A post-hoc analysis showed no difference in treatment duration or toxicity in patients aged over 65 years. Another Italian study, including 341 patients in the Italian compassionate use program, showed an estimated progression-free survival (PFS) at 6 months of 19% and a median OS (mOS) of 6.2 months. One hundred twenty-one patients received both regorafenib and trifluridine/tipiracil, and no differences were observed in the first or second PFS and OS between the 2 sequences.
      • Cremolini C.
      • Rossini D.
      • Martinelli E.
      • et al.
      Trifluridine/tipiracil (TAS-102) in refractory metastatic colorectal cancer: a multicenter register in the frame of the Italian Compassionate Use Program.
      Other experiences of expanded use in countries such as Spain or Great Britain also obtained comparable results to those of the RECOURSE study.
      • Garcia-Alfonso P.
      • Ruiz A.
      • Carrato A.
      • et al.
      Compassionate use program with FDT-TPI (trifluridine-tipiracil) in pre-treated metastatic colorectal cancer patients: Spanish real world data.
      ,
      • O’Brien C.
      • Callaghan S.
      • Papaxoinis G.
      • et al.
      TAS 102 in refractory metastatic colorectal cancer: UK Expanded Access Programme experience.
      In terms of predictive factors of response, no differences were observed regarding age or RAS status in the RECOURSE study.
      • Van Cutsem E.
      • Mayer R.J.
      • Laurent S.
      • et al.
      RECOURSE Study Group
      The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer.
      A post hoc analysis revealed a potential relationship between the development of G3 to 4 neutropenia and OS.
      • Ohtsu A.
      • Yoshino T.
      • Falcone A.
      • et al.
      Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer.
      The Italian real world data (RWD) study showed a PS 0, a normal lactate dehydrogenase, and time from diagnosis > 18 months, which were independently associated with a greater likelihood of being progression-free at 6 months
      • Cremolini C.
      • Rossini D.
      • Martinelli E.
      • et al.
      Trifluridine/tipiracil (TAS-102) in refractory metastatic colorectal cancer: a multicenter register in the frame of the Italian Compassionate Use Program.
      (Table 2).
      Table 2Real-life Studies With Trifluridine/Tipiracil and Regorafenib in Refractory mCRC
      Trifluridine/Tipiracil
      StudyNStarting DosePSPFS, mosOS, mosToxicity G3-4, %Most Relevant Toxicity
      USA
      • Mayer R.J.
      • Hochster H.S.
      • Cohen S.J.
      • Winkler R.
      • Makris L.
      • Grothey A.
      Safety of trifluridine/tipiracil in an open-label expanded-access program in elderly and younger patients with metastatic colorectal cancer.
      54935 mg/m2/12h0-12.7NR43Neutropenia
      Italian RWD
      • Cremolini C.
      • Rossini D.
      • Martinelli E.
      • et al.
      Trifluridine/tipiracil (TAS-102) in refractory metastatic colorectal cancer: a multicenter register in the frame of the Italian Compassionate Use Program.
      34135 mg/m2/12h0: 59%

      1: 39%

      2: 2%
      2.46.247Neutropenia
      Spain
      • Garcia-Alfonso P.
      • Ruiz A.
      • Carrato A.
      • et al.
      Compassionate use program with FDT-TPI (trifluridine-tipiracil) in pre-treated metastatic colorectal cancer patients: Spanish real world data.
      63635 mg/m2/12h0: 33%

      1: 67%
      NRNR57Neutropenia (42%)

      Febrile neutropenia (1.3%)

      Anemia (15%)
      UK
      • O’Brien C.
      • Callaghan S.
      • Papaxoinis G.
      • et al.
      TAS 102 in refractory metastatic colorectal cancer: UK Expanded Access Programme experience.
      7835 mg/m2/12h1NR6.639Neutropenia
      Regorafenib
      StudyNStarting Dose < 160 mg/dPSPFS, mosOS, mosToxicity G3-4, %Most Relevant Toxicity
      REBECCA
      • Adenis A.
      • de la Fouchardiere C.
      • Paule B.
      • et al.
      Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program.
      65420%0-1: 90%

      > 1: 10%
      2.75.656Fatigue 14.5%, PPE 9%, HBP 5%, diarrhea 4%, anorexia 3%
      CONSIGN
      • Van Cutsem E.
      • Martinelli E.
      • Cascinu S.
      • et al.
      Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study.
      2.8720%0: 47%

      1: 53%
      2.7NA57HBP 15%, PPE 14%, fatigue 13%, diarrhoea 5%,
      CORRELATE
      • O’Connor J.M.
      • Ducreux M.
      • Petersen L.N.
      • et al.
      Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study.
      1.03730%0-1: 87%

      > 1: 13%
      2.87.636Fatigue 10%, HBP 8%, PPE 7%
      RECORA
      • Schulz H.
      • Janssen J.
      • Strauss U.P.
      • et al.
      Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: final results of the prospective multicentre non-interventional RECORA study.
      46146%0-1: 81%

      > 1: 19%
      3.15.857Mucositis 13%, diarrhea 23%, HBP 7%, hand-foot syndrome 19%, asthenia 15 %
      Abbreviations: G = grade; HBP = high blood pressure; mCRC = metastatic colorectal cancer; NA = not applicable; NR = not reported; OS = overall survival; PFS = progression-free survival; PS = performance status; PPE = palmar-plantar erythrodysesthesia.
      A recent analysis of the RECOURSE
      • Tabernero J.
      • Sobrero A.F.
      • Borg C.
      • et al.
      Exploratory analysis of the effect of FTD/TPI in patients treated in RECOURSE by prognostic factors.
      compared patients with good prognostic characteristics (GPCs), defined as low tumor burden (< 3 metastatic sites), indolent disease (≥ 18 months since diagnosis of first metastasis), Eastern Cooperative Oncology Group PS 0 to 1, and no liver metastasis and patients with poor prognostic characteristics (PPCs), defined as high tumor burden and/or aggressive disease. When treated in late-line mCRC, patients with GPCs showed a median OS of 9.3 months versus 5.3 months in patients with PPCs (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.37-0.57; P < .0001); regardless of age (≥ 65 vs. < 65 years), Eastern Cooperative Oncology Group PS (0-1), KRAS status (mutant vs. wild-type [wt]), and liver metastasis (yes/no). No liver metastasis was the best prognostic factor: mOS in such patients treated with trifluridine/tipiracil was 16.4 months and 7.6 months in the GPC (n = 97) and PPC (n = 35) groups, respectively (HR, 0.42; 95% CI, 0.24-0.74; P < .0019).

       Regorafenib

      Regorafenib is an oral tyrosine kinase inhibitor that blocks several protein kinases involved in tumor angiogenesis (VEGFR1-3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF) and tumoral microenvironment (PDGFR and FGFR); the dosage consists of 160 mg/day for 21 days in 28-day cycles.
      The randomised, double-blind phase III study, CORRECT, comparing regorafenib with placebo, showed a significant increase in OS
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      CORRECT Study Group
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      (Table 1). However, 67% of patients treated with regorafenib required dose reduction, and 54% had G3 to 4 toxicity, mainly within the first 2 cycles: hand-foot syndrome (17%), asthenia (10%), diarrhea (37%), hypertension (37%), and rash (30%). Despite toxicity, no significant differences were seen in the QoL. The CONCUR study confirmed the efficacy and safety of regorafenib in an Asian population
      • Li J.
      • Qin S.
      • Xu R.
      • et al.
      CONCUR Investigators
      Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
      (Table 1). This study, unlike the CORRECT study,
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      CORRECT Study Group
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      allowed the inclusion of patients without prior biological treatment; therefore, its main benefit regarding PFS and OS could be related with the difference in the prior exposure to non-targeted agents.
      Given the toxicity seen, alternative dosages have been investigated. The ReDOS study analyzed a weekly dose escalation from 80 to 160 mg/day in the first cycle versus standard dose.
      • Bekaii-Saab T.S.
      • Ou F.-S.
      • Anderson D.M.
      • et al.
      Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC). An ACCRU Network study.
      The percentage of patients who started the third cycle with 160 mg/d was significantly higher in the experimental arm and, in addition, they had longer OS, better QoL, and less G3 to 4 toxicities (high blood pressure, 7% vs. 15% and asthenia, 13% vs. 18%). In the REARRANGE study,
      • Argiles G.
      • Mulet Margalef N.
      • Valladares-Ayerbes M.
      • et al.
      Results of REARRANGE trial: a randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC).
      flexible dosing showed numerical improvement on several parameters that improved tolerance, such as fatigue, hypertension, or hand-foot syndrome, although the study did not meet its primary endpoint of improving regorafenib global tolerability in the reduced- and intermittent-dose groups. The average treatment duration was 3.2 months in the standard group; 3.7 months in the reduced-dose group; and 3.8 months in that with alternating weeks. The median PFS was not different across groups (approximately 2 months). With the future results from the REGOCC study,
      Lower or standard dose regorafenib in treating patients with refractory metastatic colorectal cancer. ClinicalTrials.gov Identifier: NCT02368886.
      we expect to open the door to a dose modification of regorafenib without impact on efficacy.
      We also have observational and real-life studies, such as the REBECCA study
      • Adenis A.
      • de la Fouchardiere C.
      • Paule B.
      • et al.
      Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program.
      that analyzed 654 patients within the French compassionate use program (Table 2) and had results consistent with those of the CORRECT study.
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      CORRECT Study Group
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      A PS > 1, time from diagnosis < 18 months, a regorafenib dose < 160 mg/d, > 3 metastatic sites, and liver metastases were identified as poor prognosis factors for survival. The CONSIGN study
      • Van Cutsem E.
      • Martinelli E.
      • Cascinu S.
      • et al.
      Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study.
      in 2872 patients had a toxicity profile similar to that of the CORRECT study. The subgroup analysis did not show any differences in PFS for patients > 75 years old, but had a slight increase in G3 to 4 toxicity (high blood pressure and fatigue). An exploratory analysis suggested that patients with PS 0 without hepatic involvement and diagnosis > 18 months had better PFS. The CORRELATE study in 1037 patients confirmed a safety profile consistent with the data published. The starting dose for almost one-half of patients was less than 160 mg/day, and PFS and OS were within the range observed in phase III trials.
      • O’Connor J.M.
      • Ducreux M.
      • Petersen L.N.
      • et al.
      Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study.
      Real-life studies reinforce the importance of PS and the selection of patients for the treatment with regorafenib.
      • Schulz H.
      • Janssen J.
      • Strauss U.P.
      • et al.
      Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: final results of the prospective multicentre non-interventional RECORA study.
      In the CORRECT study, a retrospective analysis of circulating tumoral DNA and various genes such as KRAS, PIK3CA, and BRAF was performed without identifying any predictive biomarker of response or survival.
      • Tabernero J.
      • Lenz H.J.
      • Siena S.
      • et al.
      Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial.
      A study analyzing the role of CCL5/CCR5 polymorphisms in the efficacy of regorafenib has been recently published, noting a potential role of these polymorphisms as predictive and prognostic markers of toxicity.
      • Suenaga M.
      • Schirripa M.
      • Cao S.
      • et al.
      Gene polymorphisms in the CCL5/CCR5 pathway as a genetic biomarker for outcome and hand-foot skin reaction in metastatic colorectal cancer patients treated with regorafenib.

       Comparing Trifluridine/Tipiracil and Regorafenib

      A meta-analysis of the main randomized studies with trifluridine/tipiracil and regorafenib was performed in 2018. No differences in efficacy were seen, although regorafenib presented greater toxicity.
      • Abrahao A.B.K.
      • Ko Y.J.
      • Berry S.
      • Chan K.K.W.
      A comparison of regorafenib and TAS-102 for metastatic colorectal cancer: a systematic review and network meta-analysis.
      Currently, we do not have biomarkers or studies that tell us what the optimal sequence of treatment in refractory mCRC is; thus, the choice of treatment will depend on the characteristics and preferences of each patient and the safety profile of the drugs.

      Anti-EGFR Treatment

       De Novo Anti-EGFR Treatment

      Cetuximab was the first anti-EGFR monoclonal antibody to be incorporated into routine clinical practice, showing its efficacy in all treatment lines. Like panitumumab, its development has gone from refractoriness to first line. Several studies support the use of anti-EGFR monoclonal antibodies in monotherapy and in combination with irinotecan for refractory mCRC
      • Jonker D.J.
      • O’Callaghan C.J.
      • Karapetis C.S.
      • et al.
      Cetuximab for the treatment of colorectal cancer.
      • Cunningham D.
      • Humblet Y.
      • Siena S.
      • et al.
      Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.
      • Saltz L.B.
      • Meropol N.J.
      • Loehrer P.J.
      • et al.
      Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.
      • Karapetis C.S.
      • Khambata-Ford S.
      • Jonker D.J.
      • et al.
      K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
      (Table 3). It is worth mentioning the results of the retrospective analysis of patients in the BOND study,
      • Jonker D.J.
      • O’Callaghan C.J.
      • Karapetis C.S.
      • et al.
      Cetuximab for the treatment of colorectal cancer.
      in whom the mutational state of the exon 2 of KRAS was determined.
      • Karapetis C.S.
      • Khambata-Ford S.
      • Jonker D.J.
      • et al.
      K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
      In cases with a mutation in KRAS exon 2 wt treated with cetuximab + best supportive care (BSC) compared with BSC alone, PFS was 3.7 versus 1.9 months (HR, 0.40; 95% CI, 0.30-0.54; P < .001), and OS was 9.5 versus 4.8 months (HR, 0.55; 95% CI, 0.41-0.74; P < .001), respectively.
      Table 3Clinical Trials With Anti-EGFR
      StudyPhaseNDrug RegimenDCRORRPFS, mosOS, mosGrade 3/4 Toxicity
      NCT00079066

      Jonker et al 2007
      • Jonker D.J.
      • O’Callaghan C.J.
      • Karapetis C.S.
      • et al.
      Cetuximab for the treatment of colorectal cancer.
      III287

      285
      Cetuximab

      Placebo
      39.4

      10.9

      P < .0001
      8%

      0%

      P < .001
      HR, 0.68 (95% CI, 0.57-0.80)

      P < .001
      6,1

      4.6

      P = .86
      Rash (11.8)

      Asthenia (33)

      Dyspnoea (16.3)

      Abdominal pain (13.2)
      Cunningham et al, NEJM 2004
      • Cunningham D.
      • Humblet Y.
      • Siena S.
      • et al.
      Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.
      II218

      111
      Cetuximab/irinotecan

      Irinotecan
      55.5%

      32.4%

      P < .0010
      22.9

      10.8

      P = .007
      4.1

      1.5

      P < .001
      8.6

      6.9

      P = .48
      Neutropenia (9.4 vs. 0)

      Asthenia (13.7 vs. 10.4)

      Acne (9.4 vs. 5.2)
      Saltz et al, JCO 2004
      • Saltz L.B.
      • Meropol N.J.
      • Loehrer P.J.
      • et al.
      Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.
      II57Cetuximab45.8%9%NR6.4Allergy (3.5)

      Acne (18)

      Asthenia (9)
      Van Cutsem et al, JCO 2007
      • Van Cutsem E.
      • Peeters M.
      • Siena S.
      • et al.
      Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.
      III231

      232
      Panitumumab

      BSC
      NR10%

      0%
      2

      1.8

      P < .001
      HR, 1 (95% CI, 0.82-1.22)

      P = .8
      Acne (7)

      Cutaneous (2)

      Erythema (5)

      Asthenia (4)
      Kim et al, BJC 2016
      • Kim T.W.
      • Elme A.
      • Kusic Z.
      • et al.
      A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer.
      III189

      188
      Panitumumab

      BSC
      68.8%

      21.8%

      P = NR
      27%

      1.6%

      P < .001
      3.6

      1.7

      P < .001
      10

      7.4

      P = .0135
      Hypomagnesemia (6)

      Rash (6)

      Acne (6)
      NCT01001377

      Price et al, Lancet Oncol 2014
      • Price T.J.
      • Peeters M.
      • Kim T.W.
      • et al.
      Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.
      III499

      500
      Panitumumab

      Cetuximab
      67.5

      69

      P = NS
      13%

      10%

      P = NS
      4.4

      4.1

      P = NS
      10.4

      10.0

      P = NS
      Cutaneous (13% P, 10% C)

      Infusion-related (0.5 P, 2 C)

      Hypomagnesemia (7 P, 3 C)
      Abbreviations: BSC = best supportive care; C = cetuximab; CI = confidence interval; DCR = drug control rate; EGFR = epidermal growth factor receptor; HR = hazard ratio; NR = not reported; NS = non-significant; ORR = objective response rate; OS = overall survival; P = panitumumab; PFS = progression-free survival.
      The activity of panitumumab has been studied in monotherapy in mCRC refractory to oxaliplatin/irinotecan in 3 phase III studies: 2 compared panitumumab + BSC versus BSC alone,
      • Van Cutsem E.
      • Peeters M.
      • Siena S.
      • et al.
      Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.
      ,
      • Kim T.W.
      • Elme A.
      • Kusic Z.
      • et al.
      A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer.
      and the third compared panitumumab versus cetuximab (ASPECCT study).
      • Price T.J.
      • Peeters M.
      • Kim T.W.
      • et al.
      Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.
      In the first study, patients with mCRC and KRAS exon 2 wt presented better PFS and objective response rate (ORR) than those with the mutations (12.3 vs. 7.3 weeks and 17% vs. 0%, respectively).
      • Amado R.G.
      • Wolf M.
      • Peeters M.
      • et al.
      Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
      The second phase III study, more recent and limited to patients with KRAS exon 2 wt mCRC, also showed benefit in OS, the main study objective.
      • Kim T.W.
      • Elme A.
      • Kusic Z.
      • et al.
      A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer.
      To date, differences in terms of efficacy and safety to use one or another antibody have not been documented. The phase III study ASPECCT, with a non-inferiority design, found no significant differences between panitumab and cetuximab in OS (10.2 vs. 9.9 months) or PFS (4.2 vs. 4.4 months). The toxicity profile was consistent with previous studies.
      • Price T.
      • Kim T.W.
      • Li J.
      • et al.
      Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer.
      Therefore, there is robust evidence to recommend that those patients with RAS wt mCRC, showing progression to a standard treatment that does not include anti-EGFR therapy, receive a cetuximab- or panitumumab-based treatment either in monotherapy or in combination with irinotecan.

       Rechallenge With Anti-EGFR

      Rechallenge is at present a strategy with great clinical interest. It consists in the re-administration of a drug or treatment to which the tumor has developed resistance. Rechallenge must be differentiated from reintroduction, defined as the administration of a therapy with which the patient has experienced some benefit and that had been discontinued without progression.
      • Vogel A.
      • Hofheinz R.D.
      • Kubicka S.
      • Arnold D.
      Treatment decisions in metastatic colorectal cancer - beyond first and second line combination therapies.
      ,
      • Arnold D.
      • Prager G.W.
      • Quintela A.
      • et al.
      Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review.
      Different studies try to provide evidence about the potential use of re-administering anti-EGFR agents and thus, various strategies and combinations with chemotherapeutic agents, have been tested.
      • Ciardiello F.
      • Normanno N.
      • Martinelli E.
      • et al.
      Cetuximab beyond progression in RAS wild type (WT) metastatic colorectal cancer (mCRC): the CAPRI-GOIM randomized phase II study of FOLFOX versus FOLFOX plus cetuximab.
      • Feng Q.
      • Wei Y.
      • Ren L.
      • et al.
      Efficacy of continued cetuximab for unresectable metastatic colorectal cancer after disease progression during first-line cetuximab-based chemotherapy: a retrospective cohort study.
      • Fora A.A.
      • McMahon J.A.
      • Wilding G.
      • et al.
      A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS wild-type tumors who progressed after standard dose of cetuximab plus irinotecan.
      • Vladimirova L.Y.
      • Abramova N.A.
      • Kit O.I.
      Treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC): continuation of anti-EGFR therapy while switching chemotherapy regimen.
      • Santini D.
      • Vincenzi B.
      • Addeo R.
      • et al.
      Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance?.
      In a phase II randomized trial, Cremolini et al
      • Cremolini C.
      • Rossini D.
      • Dell’Aquila E.
      • et al.
      Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial.
      evaluated the role of the treatment with cetuximab and irinotecan in a total of 29 patients with RAS and BRAF wt mCRC who had progressed to a first-line irinotecan- and cetuximab-based therapy. The study found a response rate of 21% (95% CI, 10%-40%) and a disease control rate (DCR) of 54% (95% CI, 6%-70%), showing that this rechallenge strategy with may be active in patients with acquired resistance to this therapy. Also, these results indicate the possible role of the liquid biopsy in the selection of candidates for rechallenge. In this sense, dynamic molecular typing of the tumor, as recently published by Parseghian et al,
      • Parseghian C.M.
      • Loree J.M.
      • Morris V.K.
      • et al.
      Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.
      may provide crucial information about clonal selection phenomena that will help to define a significant cutoff point for the mutated allelic fraction of plasma emerging mutations. This would allow identifying better those patients susceptible of maintaining a blockade with anti-EGFR to the progression of a prior treatment with these antibodies or reintroduce it after a biological pressure-free period. However, there are no clinical trials nowadays standardizing the determination of the mutational status of RAS/BRAF in plasma or any criteria for rechallenging with anti-EGFR.
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

      Rechallenge With Chemotherapy ± Antiangiogenics

      Therapeutic options for patients treated with irinotecan, oxaliplatin, fluoropyrimidines, anti-angiogenics, and anti-EGFR (RAS wt tumors) are limited, and one possible therapeutic strategy is “rechallenge.” As mentioned above, we define this strategy as the reuse of a treatment in patients who have progressed with this regimen, and not those who discontinued treatment without progression, which is considered reintroduction.
      • Vogel A.
      • Hofheinz R.D.
      • Kubicka S.
      • Arnold D.
      Treatment decisions in metastatic colorectal cancer - beyond first and second line combination therapies.
      ,
      • Arnold D.
      • Prager G.W.
      • Quintela A.
      • et al.
      Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review.
      From a theoretical viewpoint, it is difficult to explain that once the tumor has acquired resistance to a treatment, it will respond again to the same regimen, although there are data indicating a clinical benefit with symptomatic improvement, generally of short duration. The evidence that supports the “rechallenge” is scarce and tends to be based on phase II and retrospective studies.
      • Vogel A.
      • Hofheinz R.D.
      • Kubicka S.
      • Arnold D.
      Treatment decisions in metastatic colorectal cancer - beyond first and second line combination therapies.
      Some of the studies that will be presented in this section consider both rechallenge and reintroduction options.

       Rechallenge With Oxaliplatin

      At present, first-line oxaliplatin-based therapy is the standard treatment of mCRC. However, cumulative sensory neuropathy is a dose-limiting toxicity and often requires therapy to be stopped in patients who are still responding. A pooled analysis of the OPTIMization of OXaliplatin studies (OPTIMOX) shows that the reintroduction of oxaliplatin in sensitive patients after an oxaliplatin-free interval of at least 6 months is a reasonable strategy. Thus, oxaliplatin reintroduction is an important option to be considered in third line.
      • de Gramont A.
      • Buyse M.
      • Abrahantes J.C.
      • et al.
      Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer.
      ,
      • Chibaudel B.
      • Tournigand C.
      • Bonnetain F.
      • et al.
      Platinum-sensitivity in metastatic colorectal cancer: towards a definition.
      Nonetheless, some studies have evaluated the rechallenge strategy. The ORION study assessed the rechallenge with XELOX (capecitabine and oxaliplatin) in patients previously treated with oxaliplatin, reporting a mOS ≥ 9.2 months. Of the 46 patients included, 45.5% had progressed with the first oxaliplatin treatment, whereas the rest had discontinued treatment owing to toxicity or scheduled vacations. The study compared the rechallenge with XELOX biweekly with every 3 weeks without finding differences in efficacy.
      • Matsuda C.
      • Honda M.
      • Tanaka C.
      • et al.
      Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study).
      In another phase II study, 33 patients rechallenged with modified FOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) in the third line reached an ORR of 6%, a PFS of 3.2 months, and an OS of 10 months.
      • Suenaga M.
      • Mizunuma N.
      • Matsusaka S.
      • et al.
      Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study.
      A recent retrospective study in 95 patients rechallenged with oxaliplatin reported a median time to treatment failure (TTF) of 3.7 months and an OS of 12.2 months. In the control arm, in which 29 patients were treated with anti-EGFR and irinotecan, the TTF and OS were 4.8 months and 11.4 months, respectively. The DCR for the rechallenge with oxaliplatin was 47.4% (ORR, 6%).
      • Yang Q.
      • Huang Y.
      • Jiang Z.
      • et al.
      Rechallenge of oxaliplatin-containing regimens in the third- or later-line therapy for patients with heavily treated metastatic colorectal cancer.
      The retrospective study REOX analyzed 83 patients receiving rechallenge with oxaliplatin in ≥ the third line. Bevacizumab and cetuximab were added in 42% and 6%, respectively. DCR was 56%, the median TTF was 6.0 months, and OS was 10.0 months. The response to the first exposure to oxaliplatin was predictive of long-term survival.
      • Costa T.
      • Nunez J.
      • Felismino T.
      • Boente L.
      • Mello C.
      REOX: evaluation of the efficacy of retreatment with an oxaliplatin-containing regimen in metastatic colorectal cancer: a retrospective single-center study.

       Rechallenge With Irinotecan and/or Triple Therapy

      Two real-life studies have evaluated a rechallenge with irinotecan and cetuximab as a third-line treatment or beyond in patients exposed to all available treatments, reporting an OS of 6.0 and 7.3 months, respectively.
      • Gebbia V.
      • Del Prete S.
      • Borsellino N.
      • et al.
      Efficacy and safety of cetuximab/irinotecan in chemotherapy-refractory metastatic colorectal adenocarcinomas: a clinical practice setting, multicenter experience.
      ,
      • Hartmann J.T.
      • Oechsle K.
      • Jager E.
      • et al.
      Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil.
      Triple therapies (FOLFOXIRI [folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan] or FOLFORINOX [folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin]) have been retrospectively studied in 21 patients with an ORR of 38%, DCR of 62%, PFS of 4 months, and OS of 8.6 months. Most cycles required dose adjustment and treatment delays.
      • Fernandes G.D.S.
      • Braghiroli M.I.
      • Artioli M.
      • et al.
      Combination of irinotecan, oxaliplatin and 5-fluorouracil as a rechallenge regimen for heavily pretreated metastatic colorectal cancer patients.

       Rechallenge With Chemotherapy and Bevacizumab

      A real-life study assessing FOLFOXIRI + bevacizumab in 49 patients who had progressed with fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, has reported a PFS of 5.8 months and an OS of 11.9 months.
      • Chaix M.
      • Vincent J.
      • Lorgis V.
      • Ghiringhelli F.
      FOLFIRINOX bevacizumab is a promising therapy for chemorefractory metastatic colorectal cancer.
      A retrospective study of bevacizumab + FOLFOX/FOLFIRI in 46 patients who had received all the available treatments, reported a 22% ORR, a PFS of 8.9 months, and an OS of 13.8 months in third-line therapy.
      • Lièvre A.
      • Samalin E.
      • Mitry E.
      • et al.
      Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study.
      In a series with 31 polytreated patients, the OS was 18.4 months.
      • Geva R.
      • Vecchione L.
      • Tejpar S.
      • Piessevaux H.
      • Van Cutsem E.
      • Prenen H.
      Bevacizumab plus chemotherapy as salvage treatment in chemorefractory patients with metastatic colorectal cancer.
      Another retrospective study in 35 patients treated with chemotherapy + bevacizumab in the third- or fourth-line reported 20% ORR, PFS of 5.98 months, and OS of 14.7 months.
      • Yang Q.
      • Yin C.
      • Liao F.
      • et al.
      Bevacizumab plus chemotherapy as third- or later-line therapy in patients with heavily treated metastatic colorectal cancer.
      In a third-line treatment with bevacizumab + capecitabine, a series of 34 heavily pre-treated patients reported a PFS of 5.4 months and an OS of 12.2 months with good tolerance. However, only 4 patients had previously received bevacizumab.
      • Larsen F.O.
      • Boisen M.K.
      • Fromm A.L.
      • Jensen B.V.
      Capecitabine and bevacizumab in heavily pre-treated patients with advanced colorectal cancer.
      In summary, the rechallenge with previously used drugs may be an alternative for some patients, although no prospective clinical trials support its use.

      Immunotherapy

       Biomarkers

      MSI-H mCRC represents ∼5% of patients with mCRC
      • Venderbosch S.
      • Nagtegaal I.D.
      • Maughan T.S.
      • et al.
      Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.
      and is considered a highly immunogenic tumor with very high tumor mutation burden (TMB) as compared with microsatellite stability (MSS) mCRC. Although the complexity of TMB is high and its accessibility limited, it is one of the best-known characteristics of the CRC subtypes.
      Cancer Genome Atlas Network
      Comprehensive molecular characterization of human colon and rectal cancer.
      It can be measured and has been largely explored as a biomarker for immunotherapy. Programmed death-ligand 1 (PD-L1) expression in tumor microenvironment has also been largely investigated as a biomarker. These and other biomarkers are under intensive research with too many controversies around (heterogeneous expression of PD-L1, assay interpretation, lack of standardization platforms, etc) but have demonstrated some success in identifying patients most likely to benefit from immune checkpoint inhibitors. It is likely we will see hereafter and according to published results in the MSI-H population with mCRC treated in these non-randomized phase II studies, PD-L1 expression does not seem to be a good biomarker as a companion diagnostic as it is in the case of other tumors.
      • Garon E.B.
      • Rizvi N.A.
      • Hui R.
      • et al.
      KEYNOTE-001 Investigators
      Pembrolizumab for the treatment of non-small-cell lung cancer.

       Pretreated MSI-H mCRC

      Checkmate 142 is a multiple cohort phase II study in heavily pre-treated patients with MSI-H mCRC. In one cohort, nivolumab monotherapy at 3 mg/kg every 2 weeks was administered to 74 patients.
      • Overman M.J.
      • McDermott R.
      • Leach J.L.
      • 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.
      ,
      • Overman M.J.
      • Bergamo F.
      • McDermott R.S.
      • et al.
      Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): long-term survival according to prior line of treatment from CheckMate-142.
      In another cohort, 119 patients were treated with the combination of nivolumab, at the same dose, plus ipilimumab at 1 mg/kg every 3 weeks × 4 doses and then nivolumab monotherapy at the same doses.
      • Overman M.J.
      • Lonardi S.
      • Wong K.Y.M.
      • et al.
      Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): long-term follow-up.
      Both cohorts were heavily pretreated with at least 2 previous lines (30% and 36%, respectively) or even 3 or more (54% and 40%, respectively). This heavily pre-treated population with MSI-H mCRC is very similar to the patients with mCRC treated in the phase III trials with trifluridine/tipiracil
      • Mayer R.J.
      • Van Cutsem E.
      • Falcone A.
      • et al.
      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      ,
      • Xu J.
      • Kim T.W.
      • Shen L.
      • et al.
      Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study.
      and regorafenib.
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      CORRECT Study Group
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      ,
      • Li J.
      • Qin S.
      • Xu R.
      • et al.
      CONCUR Investigators
      Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Another relevant aspect is the distribution of patients based on their PD-L1 expression, where only 28% and 23% of the patients included in each cohort had a PD-L1 expression ≥ 1%.
      The primary endpoint in both studies was the investigator-assessed ORR by Response Evaluation Criteria in Solid Tumors (RECIST), v1.1, which was higher in the combination cohort (58%). More relevant, ORR was independent of PD-L1 expression, which is not what we see in other tumors treated with these agents. The median PFS (mPFS) and OS were not reached in the combination study: PFS and OS at 24 months were 60% and 74%, respectively, which seems very high and with G3 to 4 treatment-related adverse events in 31% of patients. To highlight these results, and although they are indirect comparisons, they look much better than those obtained in a similar heavily pretreated population that received trifluridine/tipiracil or regorafenib.
      Pembrolizumab (anti PD-1) has also been studied in MSI-H pretreated patients with mCRC. A phase II trial evaluated 41 patients with progressive metastatic carcinoma, including colorectal, with and without mismatch-repair deficiency (cohorts A and B, respectively), and non-colorectal mismatch-deficient (cohort C). Focusing on patients with mCRC, the objectives of mPFS and OS were not reached in cohort A, whereas in cohort B, both endpoints were 2.2 and 5.0 months respectively. TMB revealed a mean of 1782 somatic mutations per tumor in MSI-H tumors, as compared with 73 in MSS tumors, and was associated with prolonged PFS (P < .02).
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      The phase II open-label study (KEYNOTE-164) has evaluated pembrolizumab in 61 previously treated patients mCRC with MSI-H/deficient mismatch repair. At a median follow-up of 31.3 months (range, 0.2-35.6 months), pembrolizumab provided an ORR of 33%, a median OS of 31.4 months, and a median PFS of 2.3 months, which seems to be very similar to the results obtained with other immune checkpoint inhibitors in this population.
      • Le D.T.
      • Durham J.N.
      • Smith K.N.
      • et al.
      Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
      ,
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      ,
      • Le D.T.
      • Kim T.W.
      • Van Cutsem E.
      • et al.
      Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164.

       Pretreated MSS mCRC

      Contrary to what happens in MSI-H mCRC, patients with MSS mCRC do not seem to respond to checkpoint inhibitors. The phase III study IMblaze370
      • Eng C.
      • Kim T.W.
      • Bendell J.
      • et al.
      Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.
      compared atezolizumab (anti PD-L1) versus atezolizumab plus cobimetinib (MEK1/2 inhibitor) versus regorafenib in 365 heavily pretreated patients with mCRC, 92% of them MSS. Atezolizumab in monotherapy or combined with cobimetinib was not superior to regorafenib. The mOS was 7.1, 8.9, and 8.5 months, respectively, and 12-month OS was 27%, 38%, and 36.6%, respectively; figures clearly lower than those seen in the MSI-H cohorts but similar to those seen in the population treated with trifluridine/tipiracil or regorafenib (Table 2). A recent randomized (2:1) phase II trial compared durvalumab (anti PD-L1) combined with tremelimumab (anti CTLA-4) versus BSC in 180 refractory patients with MSS mCRC.
      • Chen E.X.
      • Jonker D.J.
      • Kennecke H.F.
      • et al.
      CCTG CO.26 trial: A phase II randomized study of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with advanced refractory colorectal carcinoma (rCRC).
      The primary endpoint mOS was 6.6 versus 4.1 months (HR, 0.72; P = .07), and mPFS was 1.8 versus 1.9 months. Sixty-four percent of patients experienced G ≥ 3 treatment-related adverse events.
      In conclusion, today and despite the absence of positive phase III trials, nivolumab or pembrolizumab in monotherapy or a combination of nivolumab plus ipilimumab is probably the best alternative in pretreated patients with MSI-H mCRC. The results of an open-label, phase Ib trial (REGONIVO, EPOC1603) has been recently communicated. This study enrolled 50 patients with advanced gastric (n = 25) or colorectal (n = 25) cancer and a median of 3 prior treatment lines. They were treated with regorafenib plus nivolumab in a dose-finding phase, and an objective tumor response was observed in 7 patients with MSS CRC and 1 patient with MSI-H CRC.
      • Hara H.
      • Fukuoka S.
      • Takahashi N.
      • et al.
      Regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer: an open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).
      Other ongoing trials in both populations (MSI-H and MSS) in earlier lines and combined with many other agents will better define the best strategy, particularly in the MSS population.

      Promising Molecular Anti-targeted Therapies

       Anti-BRAF Agents

      Mutations in the BRAF gene are present in nearly 10% of patients with CRC. It is associated with poor prognosis, with a median mOS of 12 months. BRAF V600E represents approximately the 96% of all BRAF mutations.
      • Caputo F.
      • Santini C.
      • Bardasi C.
      • et al.
      BRAF-mutated colorectal cancer: clinical and molecular insights.
      Anti-BRAF agents are potent and selective oral inhibitors of serine-threonine kinase BRAF containing the activating mutation V600E (BRAFV600E). In mCRC, several clinical trials have been conducted using first-generation inhibitors (vemurafenib 960 mg/12h and dabrafenib 150 mg/12h) and one using a second-generation inhibitor (encorafenib 450 mg/day).
      Unlike the good results obtained in melanoma, the efficacy of BRAF inhibitors (BRAFi) in monotherapy for mCRC is disappointing, with a 0% to 5% ORR.
      • Kopetz S.
      • Desai J.
      • Chan E.
      • et al.
      Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer.
      ,
      • Gomez-Roca C.A.
      • Delord J.
      • Robert C.
      • et al.
      Encorafenib (LGx818), an oral BRAF inhibitor, in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC): results of dose expansion in an open-label, phase 1 study.
      Preclinical studies have described the development of mechanisms of resistance to BRAF blockade, with a quick reactivation of the EGFR-mediated MAPK pathway. Therefore, drug combination strategies have been designed to simultaneously block several effectors of this pathway. The results of these trials are dissimilar, obtaining a modest benefit from the 2-drug combinations
      • Hyman D.M.
      • Puzanov I.
      • Subbiah V.
      • et al.
      Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.
      • Yaeger R.
      • Cercek A.
      • O’Reilly E.M.
      • et al.
      Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.
      • Corcoran R.B.
      • Andre T.
      • Atreya C.E.
      • et al.
      Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer.
      • van Geel R.
      • Tabernero J.
      • Elez E.
      • et al.
      A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer.
      • Tabernero J.
      • Geel R.V.
      • Guren T.K.
      • et al.
      Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC).
      but a more promising benefit from 3-drug combinations.
      • Corcoran R.B.
      • Andre T.
      • Atreya C.E.
      • et al.
      Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer.
      ,
      • van Geel R.
      • Tabernero J.
      • Elez E.
      • et al.
      A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer.
      ,
      • Corcoran R.B.
      • Atreya C.E.
      • Falchook G.S.
      • et al.
      Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer.
      • Kopetz S.
      • McDonough S.L.
      • Morris V.K.
      • et al.
      Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406).
      • Van Cutsem E.
      • Atreya C.
      • André T.
      • et al.
      Updated results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).
      • Hong D.S.
      • Morris V.K.
      • El Osta B.
      • et al.
      Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation.
      Thirty percent of patients with BRAF mutation have MSI.
      • Sveen A.
      • Kopetz S.
      • Lothe R.A.
      Biomarker-guided therapy for colorectal cancer: strength in complexity.
      In the KEYNOTE-164 study, 15% (n = 9) of the population was BRAF-mutated V600 E obtaining an ORR of 55%. On the other hand, in the Checkmate 142 study, 24% (n = 29) of the population presented this mutation with an ORR of 55%. The analyses of these studies indicate that immunotherapy benefits this population subgroup regardless of the BRAF stage.
      The BEACON study is a randomized phase III trial comparing the standard treatment (FOLFIRI/irinotecan ± cetuximab) versus a dual-therapy (encorafenib + cetuximab) versus triple therapy (encorafenib + binimetinib + cetuximab) (NCT02928224) in second-line therapy. The results in the 29 patients enrolled in the safety lead-in phase using the triple therapy were promising, with an ORR of 48% (10% complete responses), DCR of 93%, PFS of 8.0 months, and OS of 15.3 months.
      • Van Cutsem E.
      • Huijberts S.
      • Grothey A.
      • et al.
      Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E-mutant metastatic colorectal cancer: safety lead-in results from the phase III BEACON colorectal cancer study.
      The final results of this study, with 655 patients included, show that the triple combination (encorafenib + binimetinib + cetuximab) increased OS compared with control (9 months vs. 5.4 months; HR, 052; 95% CI, 0.39-0.70; P < .001), as well as TR 26% versus 2% for triplet and control, respectively. On the other hand, the dual combination showed an increase in OS compared with the control arm (8.4 months; HR, 0.60; 95% CI, 0.45-0.79; P = .001). Although this is a 2-line study, 35% of patients were treated in third or subsequent lines, which means that the treatment represent a possibility in this subgroup.
      • Kopetz S.
      • Grothey A.
      • Yaeger R.
      • et al.
      Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer.

       Anti-HER2 Drugs

      Several HER2 inhibitors have been tested in mCRC: 2 recombinant humanized monoclonal antibodies directed against various extracellular epitopes of the HER2 receptor: trastuzumab (ligand-independent inhibition) and pertuzumab (ligand-dependent inhibition), both administered intravenously, and an oral inhibitor of the intracellular domains of tyrosine kinase (ErbB1) EGFR and HER2 (ErbB2) receptors, lapatinib.
      As it happens with BRAFi, in preclinical studies, HER2 inhibitors have not shown efficacy in monotherapy but in combination. These findings served as the basis for the design of HERACLES, a phase II study with 3 cohorts. In cohort A (trastuzumab intravenously [IV] loading dose 4 mg/kg followed by 2 mg/kg/weekly + lapatinib 1000 mg/day orally continuous, in 21-day cycles), in 27 patients with mCRC KRAS exon 2 wt and HER2 amplification (immunohistochemistry: 3+ or 2+ plus fluorescence in situ hybridization +) resistant to standard therapies (including anti-EGFR). The results were: ORR of 30% (95% CI, 14%-50%), DCR of 74%, and a median duration of response of 38 weeks, with a good toxicity profile (22% of G3 toxicity).
      • Sartore-Bianchi A.
      • Trusolino L.
      • Martino C.
      • et al.
      Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
      A subsequent phase IIa study including various refractory solid tumors with different molecular alterations (“Mypathway basket trial”) reproduced these good results. In the cohort of 37 patients with mCRC with HER2 amplification, treatment with trastuzumab (loading dose 8 mg/kg followed by 6 mg/kg every 3 weeks) + pertuzumab (loading dose 840 mg followed by 420 mg every 3 weeks) obtained an ORR of 38% (95% CI, 23%-55%), with a median duration of response of 11 months.
      • Hainsworth J.D.
      • Meric-Bernstam F.
      • Swanton C.
      • et al.
      Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study.

       Anti-ALK Drugs, Fusions

      The incidence of genetic fusions (ALK, ROS1, and NTRK1/2/3) in mCRC is between 0.2% and 2.4%. Currently, few data on the role of these molecular alterations in mCRC are available. Apart from the publication of some clinical cases treated successfully with these kinase inhibitors (ceritinib, ALK or entrectinib, ALK, ROS1, and TrkA-B-C-), the combined results from 2 phase I clinical trials (ALKA-372-001 and STARTRK-1) with entrectinib (600 mg/day) have been reported
      • Drilon A.
      • Siena S.
      • Ou S.I.
      • et al.
      Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
      as well as 3 phase I/II clinical trials with larotrectinib (TrkA-B-C inhibitor, 100 mg/12 hours)
      • Drilon A.
      • Laetsch T.W.
      • Kummar S.
      • et al.
      Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.
      in solid tumors (including patients with refractory CRC: 15% with gastrointestinal tumors and 7% with mCRC), with promising results (long-term responses) that need to be confirmed.

       Fruquintinib

      It represents a new generation of tyrosine kinase inhibitors (TKIs) that blocks VEGFR 1-3 with higher power and high selectivity. After the promising results of a phase Ib/II trial
      • Xu R.H.
      • Li J.
      • Bai Y.
      • et al.
      Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study.
      with fruquintinib at a dose of 5 mg/day for 21 days in a 28-day cycle, the results of FRESCO, a randomised (2:1) double-blind phase III placebo-controlled study including 416 Chinese patients with refractory mCRC (≥ 2 previous treatment lines, although only 30% and 14% of patients in both arms had received prior treatment with anti-VEGF and anti-EGFR, respectively) were published.
      • Li J.
      • Qin S.
      • Xu R.H.
      • et al.
      Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial.
      The study has been positive regarding all efficacy parameters: OS (main objective): 9.3 versus 6.6 months (HR, 0.65; 95% CI, 0.51-0.83; P < .001); PFS: 3.7 versus 1.8 months (HR, 0.26; 95% CI, 0.21-0.34; P < .001); ORR (4.7% vs. 0%; P = .01); and DCR (62.2% vs. 12.3%; P < .001). G3 to 4 adverse events were more frequent in the fruquintinib arm (61.2% vs.19.7%). Its efficacy in Western patients treated with all available drugs is still to be determined.

      Drugs With Poor Results or Insufficient Evidence

      Some drugs, with some preclinical anti-tumor activity or in phase I to II studies, have not managed to increase survival in phase III clinical trials in refractory mCRC. Here below are the most relevant.
      Nindetanib is a triple angiokinase inhibitor of VEGFR 1-3, PDGF-alpha/beta, and FGFR 1-3, administered orally. In the phase III study, LUME-Colon1, comparing nindetanib versus placebo, PFS and OS were not clinically significant, and no improvement in the QoL was seen.
      • Van Cutsem E.
      • Yoshino T.
      • Lenz H.J.
      • et al.
      Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.
      Napabucasin is a STAT3 inhibitor and a gene transcription factor, overexpressed in CRC and necessary to keep its stem cells. A phase III study compared napabucasin versus placebo without showing any benefits in DCR, PFS, or OS.
      • Jonker D.J.
      • Nott L.
      • Yoshino T.
      • et al.
      Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial.
      Dalotuzumab is a monoclonal antibody against insulin-like growth factor receptor. The phase III study compared dalotuzumab (10 mg/kg weekly), dalotuzumab (7.5 mg/kg twice weekly), or placebo combined with cetuximab and irinotecan. The study was prematurely terminated with PFS and OS not significant, but elevated, suggesting that patients did not have strictly refractory mCRC.
      • Sclafani F.
      • Kim T.Y.
      • Cunningham D.
      • et al.
      A randomized phase II/III study of dalotuzumab in combination with cetuximab and irinotecan in chemorefractory, KRAS wild-type, metastatic colorectal cancer.
      Brivanib is a VEGFR 2-3 and FGFR-1-3 TKI. The phase III study, CO.20, compared cetuximab associated with brivanib or placebo. Although the brivanib arm obtained better results in terms of PFS (P < .001) and ORR, there were no differences in the OS, the main objective of the study.
      • Siu L.L.
      • Shapiro J.D.
      • Jonker D.J.
      • et al.
      Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial.
      Xilonix (MABp1) is an antibody that inhibits interleukin-1-alpha, which has been investigated in 2 phase III studies comparing MABp1 versus placebo. In the first study, weight gain and clinical improvement was significant with MABp1 (33% vs. 19%; P = .0045), and the OS was 11.5 months and 4.2 months depending on whether or not patients met the aim of weight gain (P < .0001).
      • Hickish T.
      • Andre T.
      • Wyrwicz L.
      • et al.
      MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study.
      A second phase III study of Xilonix versus placebo (NCTO1767857), which started in 2013 and was completed in 2017, has not yet reported its results.
      A phase III study of xilonix in patients with advanced colorectal cancer (XCITE). Clinicaltrials.gov Identifier: NCT01767857.
      Mitomycin-C (MMC) is an alkylating agent widely used in gastrointestinal tumors before the arrival of biological agents. A pooled analysis of several phase II studies and case series (n = 681) of MMC combined with fluoropyrimidine reported an ORR of 7%, DCR of 39%, PFS of 2.8 months, and OS of 7.5 months. Although the authors conclude that MMC combined with fluoropyrimidine is a valid option when standard treatments fail, the efficacy of this combination has not been tested in any phase III study, and currently, there is not enough evidence to recommend its use on a routine basis.

      Interventional Techniques: Chemoembolization and Radioembolization

      Hepatic artery infusion (HAI), transarterial chemoembolisation (TACE), and radioembolization (selective internal radiation therapy [SIRT]) are among the local treatments for predominantly hepatic metastases not susceptible of surgery or radio-frequency treatments.
      HAI of chemotherapy could be useful patients in advanced line, especially with oxaliplatin. A randomized phase II study (HEARTO) included patients with unresectable mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy for wt KRAS tumors. Patients were randomized to HAI raltitrexed (3 mg/m2 over 1 hours) followed by oxaliplatin (130 mg/m2 over 2 hours) every 3 weeks versus standard of care in a 2:1 ratio. The study was prematurely terminated, owing to insufficient accrual, with 27 patients; mPFS was significantly longer in the HAI group versus standard of care (6.7 and 2.2 months, respectively), although no differences were seen in mOS. In spite of the low recruitment, the study provides evidence for the benefit and safety of HAI with raltitrexed and oxaliplatin in liver-only chemoresistant mCRC.
      • Ghiringhelli F.
      • Vincent J.
      • Bengrine L.
      • et al.
      Hepatic arterial chemotherapy with raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure (HEARTO): a randomized phase-II study.
      A phase I/II trial has evaluated HAI of oxaliplatin combined with intravenous 5-fluorouracil (5-FU) and l-leucovorin in patients with CRC with unresectable liver metastases and systemic chemotherapy failure. In phase I, none of the 6 enrolled patients exhibited dose-limiting toxicity, and the recommended dose for oxaliplatin by HAI was estimated as 100 mg/m2. In phase II, 7 additional patients were included. The 6-month survival rate was 53.3%, less than the expected 80%, and the OS was 6.9 months. This combination therapy was feasible and safe, but the expected efficacy was not achieved.
      • Sato Y.
      • Inaba Y.
      • Ura T.
      • et al.
      Outcomes of a phase I/II trial of hepatic arterial infusion of oxaliplatin combined with intravenous 5-fluorouracil and l-leucovorin in patients with unresectable liver metastases from colorectal cancer after systemic chemotherapy failure.
      There are several studies with TACE in refractory patients. A first multicenter study in 55 patients, some with extrahepatic disease, assessed the embolization with irinotecan according to the “drug-elluting beds” system (DEBIRI), achieving ORR of 66% and 75% at 6 and 12 months, respectively, with PFS of 11 months and OS of 19 months.
      • Martin R.C.
      • Joshi J.
      • Robbins K.
      • et al.
      Hepatic intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver metastases refractory to systemic chemotherapy: results of multi-institutional study.
      After that, a phase III randomised clinical trial in 74 patients poly-treated in ≥ third-line without extrahepatic involvement showed greater OS with DEBIRI versus FOLFIRI (22 vs. 15 months; P = .03).
      • Fiorentini G.
      • Aliberti C.
      • Tilli M.
      • et al.
      Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study.
      SIRT in hepatic artery with yttrium-90 showed, in a phase III study in 46 patients with chemotherapy-refractory mCRC and exclusively liver disease, a better PFS with the combination of 5-FU + SIRT versus 5-FU alone (4.5 vs. 2.1 months: HR, 0.51; 95% CI, 0.28-0.94; P = .03).
      • Hendlisz A.
      • Van den Eynde M.
      • Peeters M.
      • et al.
      Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy.
      At the same time, its benefits have been confirmed in retrospective case reviews.
      • Kennedy A.
      • Cohn M.
      • Coldwell D.M.
      • et al.
      Updated survival outcomes and analysis of long-term survivors from the MORE study on safety and efficacy of radioembolization in patients with unresectable colorectal cancer liver metastases.
      Likewise, promising results with other radiopharmaceuticals such as radioactive holmium (166Ho-microspheres) have also been reported.
      • Prince J.F.
      • van den Bosch M.A.A.J.
      • Nijsen J.F.W.
      • et al.
      Efficacy of radioembolization with (166)Ho-microspheres in salvage patients with liver metastases: a phase 2 study.
      National Comprehensive Cancer Network guidelines recommend the use of locoregional therapy for hepatic metastases in non-resectable mCRC refractory to chemotherapy with the objective of increasing local control and survival. They conclude that HAI, TACE, and SIRT show similar efficacy,
      NCCN Guidelines: in Oncology (NCCN Guidelines®) Colon Cancer. PA: National Comprehensive Cancer Network; 2019. v3.
      based on the results of the meta-analysis.
      • Zacharias A.J.
      • Jayakrishnan T.T.
      • Rajeev R.
      • et al.
      Comparative effectiveness of hepatic artery based therapies for unresectable colorectal liver metastases: a meta-analysis.

      Recommendations and Conclusions

      The survival of patients with mCRC has increased prominently in recent years, reaching a median of 25 to 30 months. This increase in survival is owing to the sum of several strategies: the continuum of care, multidisciplinary care, resection of metastatic disease, local ablative therapies in oligometastatic disease, the selection of drugs based on biomarker expression, oral drugs approved for refractory mCRC, rechallenge with drugs previously used, the administration of drugs targeted against new molecular targets (compassionate use), and the inclusion in clinical trials.
      Currently, many patients who have progressed with previous lines of regimens containing oxaliplatin, irinotecan, fluoropyrimidines, anti-angiogenic, and anti-EGFR (RAS wt) maintain a good performance status and are candidates for ≥ third-line treatments.
      In this situation of refractoriness, there are several alternatives. One is to sequentially administer the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in PFS and OS with a different toxicity profile. Derived from the fact that the evidence of these drugs comes from randomized studies, we are faced with a level of evidence “I” and in turn an “A” degree of recommendation (I, A), although there is not enough evidence to establish the optimal sequence of these 2 drugs.
      Another option is to administer cetuximab or panitumumab in patients with RAS wt if they have not previously received it (I, A), which is increasingly rare because they are usually indicated in first- or second-line therapy.
      A third alternative is to reuse drugs already administered and discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-EGFR [if RAS wt]), such as oxaliplatin reintroduction, which is an important option to be considered in third line, mainly after an oxaliplatin-free interval of 6 months.
      High-quality evidence is limited, but this strategy is often used in routine clinical practice especially in patients with good PS in the absence of alternative therapies.
      Further from the BEACON results in the 35% of patients treated in third or subsequent lines, the use of double or triple chemotherapy seems advisable in this subgroup of patients.
      Another option is to use specific treatments for very selected populations such as trastuzumab + lapatinib in mCRC HER2+, immunotherapy in MSI+, or intrahepatic therapies in limited disease or primarily located in the liver, and if the results of the phase III study BEACON are positive, a therapy based on BRAF inhibitors + anti-EGFR in BRAF-mutated tumors.
      The main recommendation is to include patients in clinical trials. Studies evaluating the synergy of inhibition between BRAF and EGFR in BRAF-mutated tumors, and studies assessing the resistance to EGFR inhibitors are ongoing. In general, ongoing phase III studies in refractory mCRC are scarce, because most studies are phase II or I to II with drugs with new mechanisms of action such as vasculature disruptor agents, autophagy modulators, STAT3 inhibitors, immune check point inhibitors, CCR5 inhibitors, etc. (Table 4). It is noteworthy that many of these studies are already selecting patients by the molecular profile of the CRC and many are MSS. From the ongoing studies, those offering the possibility of a quick move to daily practice, such as the combination of irinotecan + regorafenib (phase III study NEXT-REGIRI) or trifluridine/tipiracil + ramucirumab (randomised phase II study RAMTAS), are of special interest if the results are positive.
      Table 4Clinical Trials in Refractory mCRC: Recruiting, Active but Not Recruiting, or Not Recruiting Yet
      StudyPhaseNDrugsMolecular ProfileObjectivesStatusGeographical Area
      NCT02390947III543Famitinib vs. placeboOSUnknownChina
      NCT02332499III450Anlotinib vs. placeboOSCompletedChina
      NCT03829462

      NEXT-REGIRI
      III78Regorafenib + irinotecan vs. regorafenibOSRecruitingFrance
      NCT03522649III668Napabucasin + FOLFIRI vs. napabucasinOSRecruitingChina
      NCT02870582III510Donafenib vs. placeboOSActiveChina
      NCT04322539

      FRESCO-2
      III522Fruquitinib or placeboOSActive, not yet recruitingUS
      NCT03520946

      RAMTAS
      II rand144Ramucirumab + FTD/TPI

      FTD/TPI
      OSRecruitingGermany
      NCT03647839

      MODULATE
      II rand90Nivolumab + BNC105

      Nivolumab + BBI-608
      MSSORR (iRECIST)RecruitingAustralia
      NCT03475004II rand40Pembrolizumab + binimetinib + bevacizumab vs. binimetinib + bevacizumabORRRecruitingUS
      NCT02316340II rand78Vorinostat + hidroxicloroquina vs. regorafenibPFSActive, not recruitingUS
      NCT02870920II rand179Durvalumab + tremelimumab + BSC vs

      BSC
      OSActive, not recruitingCanada
      NCT03800602II28Nivolumab + metforminaMSSORR (RECIST)RecruitingUS
      NCT03542877II44CabozantinibPFSActive, not recruitingUS
      NCT03087071II84Panitumumab + trametinib in cetuximab-refractory mCRCEGFR mt

      KRAS mt or NRAS mt or BRAF mt in DNAcl
      ORRRecruitingUS
      NCT03843749II30Pirotinib + trastuzumabHER2+ORRRecruitingChina
      NCT03190616II54ApatinibPFSCompletedChina
      NCT01930864II41Irinotecan + metforminNo PD 12wRecruitingBrazil
      NCT02723578II50Pemetrexed + erlotinibORR and PFSCompletedKorea
      NCT03405272II110AcMo anti-EGFR recombinante (SCT200)RAS y BRAF wtORRUnknownChina
      NCT03843853II50Pemetrexed + S-1 + bevacizumabPFSNot recruiting yetChina
      NCT03711058I-II54Nivolumab + copanlisib (TKI PI3Kinasa)Cohort MSSMTD

      ORR
      RecruitingUS
      NCT03436563I-II59M7824CMS4 o MSI+ORRRecruitingUS
      NCT03332498I-II42Pembrolizumab + ibrutinibMTD

      DCR
      Active, not recruitingUS
      NCT03206073I-II35Durvalumab + pexal-vac oncolytic vírus

      Durvalumab + tremelimumab

      Durvalumab + tremelimumab + pexa-vac
      ToleranceRecruitingUS
      NCT03531632I-II52MGD007 + MGA012MTDActive, not recruitingUS
      NCT02393755I-II39Nintedanib + capecitabinaMTD

      PFS 18 w
      Active, not recruitingUS
      NCT03258398I-II56eFT508 + avelumabMSSMTDCompletedUS
      NCT03576963I-II45Nivolumab + guadecitabineMSSMTD

      ORR
      RecruitingUS
      NCT03144804II32LamivudineTP53 mutant/deletedORRRecruitingUS
      NCT03668431II25Dabrafenib + trametinib + PDR001BRAF V600E mutantORRRecruitingUS
      NCT04166435II30Temozolomide + olaparibMGMT promoter hipermetilatedORRRecruitingUS
      NCT03981146II36NivolumabStrong class II expression MSSDCBRecruitingUK
      NCT03086538II29Pemetrexed + erlotinibEGFR overexpressedORRRecruitingKorea
      NCT03832621II100Nivolumab + ipilimumab + temozolomideMGMT silenced8-month PFS rateRecruitingItaly
      NCT03457896II35Neratinib + cetuximab or trastuzumabHER2 amplifiedPFSRecruitingUS
      NCT03909724II60Sunitinib malate or TAS102PFSRecruitingNetherlands
      NCT03946917I/II38JS001 and regorafenibMSSMTD, DLT, ORRRecruitingChina
      NCT04166383II27VB-111 and nivolumabSafety and BORActive, not yet recruitingUS
      NCT03657641I/II75Pembrolizumab and regorafenibDLT, PFS, OSRecruitingUS
      NCT04067986II62Camrelizumab and apatinibORRRecruitingChina
      NCT03403634II12Celecoxib, interferon alfa-2b, rintatolimodChange in TILsRecruitingUS
      NCT04322539

      FRESCO-2
      III522Fruquitinib or placeboOSActive, not yet recruitingUS
      NCT03983993

      NIPAVect
      II26Niraparib and panitumumabRAS wtCBRRecruitingUS
      NCT04119830IIa25Pembrolizumab and rintatolimodMSSORRActive, not yet recruitingUS
      NCT04096417II24PemigatinibFGFR alterationsORRActive, not yet recruitingUS
      NCT03981614II112Binimetinib and palbociclib or TAS 102KRAS/NRAS mtPFSRecruitingUS
      NCT03087071II84Panitumumab with or without trametinibKRAS/NRAS/BRAF V600E mt

      EGFR ectodomain mutation
      ORRRecruitingUS
      NCT03992456II120Panitumumab or TAS 102 or regorafenibKRAS/NRAS/BRAF V600E wtOSActive, not yet recruitingUS
      NCT03043313

      MOUNTAINEER
      II110Tucatinib plus trastuzumabHER2 overexpression or amplificationORRRecruitingUS
      NCT03791398

      BrUOG379
      Ib/II34ONC201 + nivolumabMTD, PFSRecruitingUS
      NCT03592641II15SavonitinibMET amplifiedORRRecruitingUS
      NCT03446157II57Palbociclib and cetuximabKRAS/NRAS/BRAF V600E wtDCRRecruitingUS
      NCT04044430I/II38Encorafenib, binimetinib, and nivolumabBRAF V600EmtORRRecruitingUS
      NCT03524820II60Cetuximab or cetuximab/chemotherapy rechallengeKRAS/NRAS/BRAF V600E wtORRRecruitingIsrael
      NCT03712943I28Regorafenib + nivolumabMSSMTDRecruitingUS
      NCT03274804I20Pembrolizumab + maraviroc
      Maraviroc CCR 5 (chemokine receptor 5) inhibitor.
      MSSTolerabilityCompletedGermany
      NCT03626922Ib33Pembrolizumab + pemetrexed ± oxaliplatinMSSMTDNot recruiting yetUS
      Clinicaltrials.gov consulted 06-04-2020.
      Abbreviations: BOR = best overall response; BSC = best supportive care; CBR = clinical benefit rate; cfDNA = circulating free DNA; DCG = durable clinical benefit; DCR = drug control rate; DLT = dose-limiting toxicity; EGFR = epidermal growth factor receptor; FGFR = fibroblast growth factor receptor; FTD/TPI = Trifluridine/tipiracil; FOLFIRI = folinic acid, 5-fluorouracil, and irinotecan; HER2 = human epidermal growth factor receptor 2; mCRC = metastatic colorectal cancer; MSI+ = microsatellite instability; MSS = microsatellite stability; mt = mutated; MTD = maximum tolerated dose; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; rand = randomized; RECIST = Response Evaluation Criteria in Solid Tumors; TILs = tumor-infiltrating lymphocytes; TKI = tyrosine kinase inhibitor; US = United States; W = weeks; wt = wild type.
      a Maraviroc CCR 5 (chemokine receptor 5) inhibitor.

      Disclosure

      A. Fernández-Montes has received honoraria from Sanofi, Roche, Lilly, Celgene, Amgen, and Servier. B. García Paredes has received honoraria for advisory activities from Sanofi and Amgen; honoraria (lecture fees) from Roche, Servier, Merck, Sanofi, Ipsen, and Amgen; and travels from Roche, Sanofi, and Servier. M. J. Safont has received honoraria from Merck, Roche, AMGEN, Servier, and Bayer; and travels from Roche, Merck, and AMGEN. E. Aranda has received honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche, and Sanofi. The remaining authors have stated that they have no conflicts of interest.

      Acknowledgments

      The authors wish to thank Springer Healthcare (Ana Ma Palma and Eliana Mesa for medical translation and proofreading, respectively) for their help in the preparation of the manuscript. Medical writing assistance was funded by Servier . This work was supported by the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), Madrid, Spain.

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