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Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy

Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy
Literature review current through: Jan 2024.
This topic last updated: Nov 14, 2023.

INTRODUCTION — The treatment of metastatic colorectal cancer (mCRC) is evolving. In addition to chemotherapy, many active agents for mCRC have been developed that are associated with improved overall survival. Management is also increasingly being driven by tumor biology and gene expression analysis of individual tumors. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

The approach to later lines of systemic therapy for inoperable mCRC is discussed here. General principles of systemic chemotherapy, selection of initial systemic therapy, and other topics related to the management of mCRC are discussed separately.

(See "Systemic therapy for metastatic colorectal cancer: General principles".)

(See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

(See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

(See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status".)

AVAILABLE AGENTS AND OVERVIEW OF THE THERAPEUTIC APPROACH — There are multiple different classes of drugs with antitumor activity in mCRC:

Fluoropyrimidines (including fluorouracil [FU], which is usually given intravenously with leucovorin [LV], and the oral agents capecitabine, S-1, and tegafur plus uracil [UFT]).

Irinotecan, which is active as monotherapy as well as in combination with other active agents.

Oxaliplatin, which is only active when partnered with a second cytotoxic agent, most commonly a fluoropyrimidine.

Cetuximab and panitumumab, two monoclonal antibodies (MoAbs) directed against the epidermal growth factor receptor (EGFR), and are only effective for tumors that are RAS/BRAF wild-type. (See 'RAS/BRAF wild-type tumors' below.)

Bevacizumab, a MoAb targeting the vascular endothelial growth factor (VEGF), and ramucirumab, a recombinant MoAb of the immunoglobulin G1 (IgG1) class that binds to the VEGF receptor 2 (VEGFR-2), blocking receptor activation. (See 'Antiangiogenesis therapy' below.)

Intravenous aflibercept, a recombinant fusion protein consisting of VEGF-binding portions from the human VEGF receptor 1 (VEGFR-1) and VEGFR-2 fused to the Fc portion of human IgG1, functions as a decoy receptor that prevents intravascular and extravascular VEGF-A, VEGF-B, and placenta growth factor (PlGF) from binding to their receptors. (See 'Role of aflibercept' below.)

Regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3), as well as other membrane and intracellular kinases. (See 'Regorafenib' below.)

Fruquintinib, a selective small molecule inhibitor of VEGFR 1, 2, and 3 tyrosine kinases. (See 'Fruquintinib' below.)

Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthase and, after modification within tumor cells, is incorporated into DNA, causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. (See 'Trifluridine-tipiracil with or without bevacizumab' below.)

The BRAF inhibitor encorafenib, which is approved, in combination with cetuximab, for treatment of RAS wild-type, BRAF V600E mutant CRC, after prior therapy. (See 'RAS wild-type, BRAF mutated tumors' below.)

Immunotherapy with immune checkpoint inhibitors that target the programmed death receptor 1 (PD-1; ie, nivolumab, pembrolizumab), with or without immune checkpoint inhibitors that target a different checkpoint, cytotoxic T lymphocyte antigen 4 (CTLA-4, ie, ipilimumab), may be beneficial for advanced high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) mCRC. Despite the tumor-agnostic US Food and Drug Administration (FDA) approval for pembrolizumab in patients with a high tumor mutational burden (TMB), benefit in MMR-proficient CRC with high levels of TMB has not yet been established. (See 'MMR-proficient tumors with high tumor mutational burden' below.)

Larotrectinib and entrectinib are tropomyosin receptor kinase (TRK) inhibitors that are approved for treatment of TRK fusion-positive cancers. (See 'TRK fusion-positive tumors' below.)

Human epidermal growth factor receptor 2 (HER2)-overexpressing tumors may respond to treatments targeting HER2, including trastuzumab plus pertuzumab or lapatinib or the antibody-drug conjugate fam-trastuzumab deruxtecan. (See 'RAS wild-type, HER2 overexpressors' below.)

Despite the pace of clinical research, the best way to combine and sequence all of these drugs to optimize treatment is evolving. In general, exposure to all active drugs, as appropriate, is more important than the specific sequence of administration.

Multipanel somatic (tumor) and germline genomic testing — Increasingly, biomarker expression is driving therapeutic decision-making in treatment of advanced cancer. Gene profiling of tumor tissue and germline genomic testing should be undertaken as quickly as possible after diagnosis of mCRC because of the significant treatment implications, both for initial systemic therapy as well as subsequent treatments. However, biomarkers that identify patients who are candidates for most of the approved agents that are active against mCRC are unknown, with several notable exceptions. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

The American Society of Clinical Oncology (ASCO) has issued a provisional clinical opinion that supports somatic and germline genomic testing in metastatic or advanced cancer when there are genomic biomarker-linked therapies approved by regulatory agencies for their cancer [1]. Given the tissue-agnostic approvals for any advanced cancer with a high tumor mutational burden or DNA mismatch repair deficiency (checkpoint inhibitor immunotherapy), or neurotrophic tyrosine receptor kinase (NTRK) fusions (TRK inhibitors), this provides a rationale for testing for all solid tumors, if the individual would be a candidate for these treatments. Testing should also be considered to determine candidacy for targeted therapies approved for other diseases in patients without an approved genomic biomarker-linked therapy; however, off-label/off-study use of such therapies is not recommended when a clinical trial is available, or without evidence of meaningful efficacy in clinical trials. (See 'Options for treatment at progression' below.)

The FDA has approved two gene panel tests (MSK-IMPACT and F1CDx) for analyzing pathogenic changes in solid tumors; these tests can be used on formalin-fixed, paraffin-embedded (FFPE) tissue regardless of the primary organ from which the tumor arose [2-4]. These tests detect pathogenic variations in the coding regions of hundreds of genes. These gene panel tests also provide information about differences between tumor and adjacent noncancerous tissue and about genomic signatures such as MSI, TMB, and the presence of specific mutations/rearrangements for which a molecularly targeted agent may be available, and, in some cases, approved for that patient's individual tumor. Unfortunately, only a minority of patients with mCRC will be found to have truly actionable mutations. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)

The use of circulating tumor DNA (ctDNA) to detect and quantify tumor-specific genetic alterations, including RAS mutations, are discussed separately. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'What is the role of ctDNA?'.)

Approach to initial therapy — Initial chemotherapy for patients with nonoperable disease is generally based upon patient fitness and comorbidity, RAS and BRAF mutation status, the presence of dMMR/MSI-H, the location of the primary tumor, and the intent of therapy. An algorithmic approach to selecting initial therapy based upon these factors is presented in the algorithm (algorithm 1), and specific recommendations, as well as the data supporting this approach are discussed elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

Subsequent treatment and the continuum of care model — The approach to subsequent therapy after the initial regimen is variable and might include retreatment with the original regimen on which there was not already disease resistance (eg, if the patient was transitioned to maintenance chemotherapy following an initial period of combination chemotherapy) or a switch to a different regimen altogether because of disease progression or intolerance to the initial regimen. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

For patients with mCRC, the model of distinct "lines" of chemotherapy (in which regimens containing non-cross-resistant drugs are each used in succession until disease progression) has been largely abandoned in favor of a "continuum of care" approach [5]. This approach emphasizes an individualized treatment strategy that might include phases of "maintenance" or lower intensity chemotherapy interspersed with more aggressive treatment protocols, re-challenging patients who initially responded to first-line treatment with the same agents after a period of alternative treatments [6-9], treatment-free intervals, as well as reutilization of previously administered chemotherapy agents in combination with other active drugs.

An important principle is that exposure to all active drugs during the course of treatment for mCRC, as appropriate, is more important than the specific sequence of drug administration in order to maximize overall survival (OS). The proportion of patients receiving all active agents was correlated strongly with median survival in phase III trials [5,10,11].

OPTIONS FOR TREATMENT AT PROGRESSION

Eligible for molecularly targeted therapy

Microsatellite unstable/deficient mismatch repair tumors — For patients who have high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) tumors who did not receive an immune checkpoint inhibitor for initial first-line therapy, we suggest immune checkpoint inhibitor immunotherapy rather than another form of systemic therapy. Two options are available:

Monotherapy with an immune checkpoint inhibitor that targets the programmed cell death 1 (PD-1) receptor, ie, either nivolumab or pembrolizumab, is one option. In clinical trials, objective response rates (ORRs) with these two PD-1 inhibitors are 30 to 50 percent, and some responses are durable. Both drugs have been approved by the US Food and Drug Administration (FDA) for this indication in the United States, and the choice of one agent over the other is empiric. Patients who experience disease progression on either of these drugs should not be offered the other.

Another option is the combination of nivolumab plus ipilimumab, a monoclonal antibody directed against a different immune checkpoint, cytotoxic T lymphocyte antigen 4 (CTLA-4). Although there are no randomized trials directly comparing dual therapy with monotherapy with either nivolumab or pembrolizumab alone, indirect comparisons from the multicohort phase II CheckMate 142 trial suggest that combined immunotherapy provides improved efficacy over anti-PD-1 monotherapy and has a favorable risk-benefit ratio. Updated analyses with long-term follow-up of the two second-line cohorts reported four-year progression-free survival (PFS) of 52 percent in the combination nivolumab-ipilimumab arm and 36 percent with single-agent nivolumab [12]. The combination has received FDA approval in the United States for patients with MSI-H or dMMR mCRC that has progressed despite other treatments. It is currently not known in which patients with MSI-H mCRC to use combined nivolumab plus ipilimumab, or whether this combination is active in patients who relapse or progress on single-agent checkpoint inhibitor immunotherapy.

Approximately 3.5 to 6.5 percent of stage IV CRCs have dMMR [13-15]. The characteristic genetic signature of dMMR tumors is a high number of DNA replication errors (RER+) and MSI-H. Tumors that lack the mismatch repair (MMR) mechanism harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such MMR defects, and the mutations are also of greater immunogenicity. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Biology of mismatch repair and tumor mutational burden'.)

Cancers with dMMR appear to be uniquely susceptible to inhibition of immune checkpoints, tolerance mechanisms that suppress the body's immune response to self-antigens in order to minimize autoimmune disease, which may also serve to blunt the immune response to tumor antigens in vivo. One well-characterized checkpoint being targeted in several tumor types, including mCRC, is PD-1. PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by programmed death ligand 1 (PD-L1) results in T cell inactivation (figure 1). (See "Principles of cancer immunotherapy".)

Notably, however, only approximately one-half of dMMR tumors respond to immune checkpoint inhibitor immunotherapy, and other predictive biomarkers are under study for their influence of responsiveness [16].

Available data in mCRC

Anti PD-1 monotherapy

In an early phase II study, pembrolizumab, an immunoglobulin G4 (IgG4) monoclonal antagonist antibody to PD-1, was administered intravenously at a dose of 10 mg/kg every 14 days to 11 patients with dMMR mCRC, 21 patients with MMR-proficient (pMMR) mCRC, and 9 patients with noncolorectal dMMR metastatic cancers; all had been heavily pretreated [17].

In the latest analysis of an expanded cohort of 54 patients with dMMR or pMMR mCRC, presented at the 2016 meeting of the American Society of Clinical Oncology (ASCO; and still unpublished as of March 2022), patients with dMMR mCRC had a 50 percent ORR and a 89 percent disease control rate (DCR; objective response or stable disease) [18,19]. By contrast, the ORR was 0 percent and DCR was 16 percent in the patients with pMMR mCRC. After a median treatment duration of 5.9 months, no patients in the dMMR group who responded had progressed. Overall survival (OS) and PFS were not reached in the dMMR group versus a median PFS of 2.3 months and an OS of 7.6 months in the pMMR group. Interestingly, patients with germline MMR mutations (Lynch syndrome) were less likely to respond than were those with other forms of MMR deficiency (ORR 27 versus 100 percent) [17].

Largely based upon these data, on May 23, 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of patients with advanced MSI-H or dMMR mCRC that has progressed following conventional chemotherapy [20]. The approval of pembrolizumab also extended to a variety of advanced solid tumors other than CRC that were MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options, thus representing the first such "tissue-agnostic" anticancer drug approval. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Clinical efficacy of anti-PD-1 therapy'.)

High levels of antitumor efficacy for pembrolizumab have now been confirmed in other cohorts and in a multicenter phase II trial of patients with previously treated dMMR mCRC [21,22].

Benefit for nivolumab, a second anti-PD-1 monoclonal antibody, was shown in a second trial, CheckMate 142, in which patients with refractory dMMR (n = 59) or pMMR (n = 23) mCRC received nivolumab (a fully human anti-PD-L1 monoclonal antibody) with or without ipilimumab, a monoclonal antibody directed against CTLA-4 [23]. In a preliminary report presented at the 2016 annual ASCO meeting that has not been subsequently published, there were no objective responses among those with pMMR tumors and the median PFS was 1.4 months.

In an analysis of the 74 patients with dMMR mCRC treated with nivolumab alone (3 mg/kg every two weeks), at a median follow-up of 12 months, 23 had an objective response (31 percent), and the median duration of response had not been reached. Eight had responses lasting 12 months or longer [24]. Responses were observed regardless of tumor PD-L1 expression level, or BRAF or KRAS mutation status. The most common grade 3 or 4 drug-related adverse events were increased levels of lipase and amylase. In the most recent analysis with long-term follow-up of this cohort, four-year PFS was 36 percent with single-agent nivolumab [25].

Largely based upon these data, in August 2017, the FDA extended the approval of nivolumab to MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan [26].

Patients who experience disease progression on either of these drugs should not be offered the other. However, an important point is that individuals treated with immune checkpoint inhibitors for dMMR/MSI-H mCRC can have pseudoprogression within the first several months of therapy [27], and response criteria specifically geared toward these drugs (eg, immune-modified response evaluation criteria in solid tumors (table 1)) should be used. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Combined immunotherapy – Combined immunotherapy targeting two different immune checkpoints was addressed in cohorts from the CheckMate 142 trial that were treated with combined nivolumab plus ipilimumab (four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks, followed by nivolumab alone 3 mg/kg every two weeks) [28]. (See "Principles of cancer immunotherapy", section on 'The "immune synapse"'.)

Of the 119 patients in this cohort, 76 percent had received two or more prior systemic therapies. At a median follow-up of 13.4 months, the ORR was 55 percent (51 percent partial, 3 percent complete), and the DCR for 12 weeks or longer was 80 percent. Responses were observed regardless of PD-L1 expression, or BRAF or RAS mutation status. Responses appeared to be durable; at 12 months, 71 percent remained progression free and 85 percent were still alive. Grade 3 or 4 treatment-related adverse events occurred in 32 percent of patients and were manageable. The most common were elevations in aspartate transaminase (AST; 8 percent) or alanine transaminase (ALT; 7 percent). Overall, the most common adverse events of any grade were diarrhea (22 percent, 2 percent severe), fatigue (18 percent, 2 percent severe), pruritus (17 percent, 2 percent severe), and pyrexia (15 percent, none severe).

The latest analysis of long-term outcomes from the cohort receiving combined therapy with nivolumab plus ipilimumab (median follow-up 50.9 months) revealed an objective response rate that had risen to 65 percent, with a 13 percent complete response rate, and median duration of response had still not been reached (range 1.4+ to 58+ months) [29]. Four-year PFS and OS rates were 53 and 71 percent, respectively. Four year PFS with nivolumab alone in this trial was 36 percent [25].

These indirect comparisons suggest that combined immunotherapy using ipilimumab and nivolumab provides improved efficacy over anti-PD-1 monotherapy and has a favorable benefit-risk ratio. Although the final determination of the relative risks and benefits of combined immunotherapy over monotherapy will require large randomized trials (as have been completed in melanoma), the combination of ipilimumab and nivolumab is a reasonable alternative to immune checkpoint inhibitor monotherapy.

Largely based on these data, in July 2018, the FDA approved the combination of nivolumab plus ipilimumab for patients with previously treated MSI-H or dMMR mCRC. It is currently not known in which patients with MSI-H mCRC to use combined nivolumab plus ipilimumab, or whether this combination is active in patients who relapse or progress on single-agent checkpoint inhibitor immunotherapy.

An important point is that MSI-H or dMMR may indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers, including CRC. Given that Lynch syndrome is more prevalent than previously thought, all patients with an MSI-H/dMMR solid tumor should undergo germline genetic assessment for Lynch syndrome, regardless of family history [30]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)

MMR-proficient tumors with high tumor mutational burden — For patients with proficient mismatch repair (pMMR), but high levels of tumor mutational burden (TMB), despite tumor-agnostic FDA approval, a benefit for immune checkpoint inhibitors is not established, and we suggest not pursuing this approach outside of the context of a clinical trial. In our view, use of pembrolizumab in patients with high TMB should be restricted to those with dMMR or whose tumors harbor selected pathogenic variants in polymerase epsilon (POLE) or polymerase delta1 (POLD1) (collectively referred to as pol-d mutations).

Approximately 5 percent of pMMR mCRCs have high TMB levels [31,32], although this has been variably quantified. Although such tumors have lower mutational levels than do those with dMMR, TMB appears to be an independent biomarker of benefit for immune checkpoint inhibitor immunotherapy across a variety of tumor types. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumor mutational burden' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Frequency of high TMB across tumor types'.)

A correlation between high TMB and objective response to pembrolizumab monotherapy was shown in the phase II KEYNOTE-158 study, which included patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor (NET), or small cell lung cancer [33]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

Although none of the patients in this report had mCRC, largely based on this study, in June 2020, the FDA expanded the approval of pembrolizumab to include adult and pediatric patients with unresectable or metastatic solid tumors, including mCRC, that are tissue TMB-high (≥10 mut/Mb) as defined by the approved companion FoundationOne CDx assay, who have progressed following prior therapy and who have no satisfactory alternative treatment options. However, in a subsequent retrospective analysis of 137 patients treated with pembrolizumab, benefit was limited to patients with high TMB and either dMMR or pol-d pathogenic mutations. Median survival following treatment with pembrolizumab in patients with high TMB without dMMR or pol-d mutations was the same as survival in patients with CRC and low TMB [34]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

RAS wild-type, BRAF mutated tumors — For most patients with RAS wild-type but BRAF V600E mutant mCRC that has progressed after initial chemotherapy, we suggest cetuximab plus encorafenib, rather than cetuximab plus irinotecan. Based on results from the BEACON trial, for most patients, doublet therapy (ie, encorafenib plus cetuximab) is preferred over a triplet-therapy regimen targeting BRAF, the epidermal growth factor receptor (EGFR), and MEK. This recommendation is consistent with year 2022 guidelines for treatment of mCRC from ASCO [35]. BRAF mutations are associated with resistance to agents that target EGFR, even in the presence of wild-type RAS. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'BRAF mutations'.)

Resistance to EGFR inhibitors in patients who have mutations in BRAF V600E may be overcome with BRAF inhibitors with or without a MEK inhibitor, in combination with an EGFR inhibitor:

The combination of a BRAF inhibitor and a MEK inhibitor alone, an approach that has been successfully used for BRAF mutant melanoma, has been only moderately successful for mCRC; in one study, 12 percent of patients achieved a partial response with dabrafenib plus trametinib, and 56 percent had stable disease as the best response [36]. Others report higher objective response (30 percent) and overall disease control rates (52 percent) with the combination of cobimetinib plus vemurafenib [37]. However, these rates are much lower than those seen in BRAF-mutated melanoma and non-small cell lung carcinoma. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'BRAF mutations' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Choice of BRAF plus MEK inhibitor therapy'.)

The combination of dabrafenib and trametinib has accelerated approval from the FDA for the treatment of adult and pediatric patients one year of age and older with unresectable or metastatic solid tumors harboring mutations in BRAF V600E (including advanced mCRC) who have progressed following prior treatment and have no satisfactory alternative treatment options [38,39]. However, notably, the two trials that were used to support the accelerated approval, the ROAR and NCI MATCH (subprotocol H) trials, specifically excluded patients with mCRC, and thus, benefits are uncertain [40,41]. There are no data to support or refute the efficacy of dabrafenib plus trametinib in a patient who has progressed on encorafenib plus cetuximab. If there are other available chemotherapy regimens or applicable trials, we favor these approaches over second line dabrafenib plus trametinib given the uncertainty of benefit in mCRC.

Combined inhibition of BRAF and EGFR has also been effective, with responses in 10 to 19 percent in four small trials of vemurafenib plus panitumumab, encorafenib plus cetuximab, dabrafenib plus panitumumab, and vemurafenib plus cetuximab and irinotecan [42-47].

The most influential trial is the phase III BEACON CRC trial, in which patients with RAS wild-type, BRAF V600E mutant mCRC whose disease had progressed after one or two prior regimens were randomly assigned to cetuximab plus the BRAF inhibitor encorafenib, with or without the MEK inhibitor binimetinib, or to irinotecan plus cetuximab alone [45]. In the initial report, median OS was significantly higher for the triplet combination compared with both control regimens (9 versus 5.4 months), as was the ORR.

However, in a later analysis, while median OS remained significantly higher with triplet therapy compared with irinotecan or irinotecan plus LV and short-term infusional FU (FOLFIRI) plus cetuximab (9.3 versus 5.9 months), there was no longer a survival difference between the two targeted regimens [47]. There was still a small (numerical) difference in response rate in favor of the triplet combination (27 versus 20 percent). Both the triplet and the doublet regimens demonstrated improved quality of life compared with standard treatment with an irinotecan/cetuximab combination in an analysis of patient-reported outcomes.

Based on these results, consistent with guidelines from the NCCN [48], for most patients, we suggest doublet therapy with encorafenib plus cetuximab over triplet therapy targeting BRAF, EGFR, and MEK for second-line treatment and beyond of BRAF mutated, RAS wild-type mCRC. The combination of encorafenib and cetuximab is now approved by the FDA for the treatment of adults with mCRC with a BRAF V600E mutation, after prior therapy [49,50].

Of importance, a significant percentage of BRAF V600E mutant CRC (15 to 25 percent [15,51,52]) have dMMR due to a somatic mutation and these patients are strong candidates for checkpoint inhibitor immunotherapy. The presence of a BRAF V600E mutation strongly suggests that a germline Lynch syndrome mutation is not present. (See 'Microsatellite unstable/deficient mismatch repair tumors' above and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genotype phenotype correlation'.)

RAS wild-type, HER2 overexpressors — For patients with RAS wild-type, HER2-overexpressing mCRC who progress on fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, we suggest trastuzumab plus tucatinib rather than other trastuzumab-based therapies. Trastuzumab plus tucatinib has a high objective response rate of almost 40 percent (when compared with other HER2-targeted agents evaluated in separate trials), is well-tolerated, and is approved for this population. For patients without access to trastuzumab plus tucatinib, alternative options include trastuzumab plus lapatinib or trastuzumab plus pertuzumab. Further randomized studies are needed to directly compare trastuzumab plus tucatinib with other HER2 targeted agents.

We reserve fam-trastuzumab deruxtecan as a later-line option for patients who previously received trastuzumab-based therapy as well as two or more chemotherapy regimens. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'HER2-positive tumors'.)

Approximately 3 to 5 percent of CRCs have amplification of the HER2 oncogene or overexpress its protein product, HER2.The HER2 oncogene encodes for a transmembrane glycoprotein receptor that functions as an intracellular tyrosine kinase. As with other EGFR receptors, HER2 is critical in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation, and angiogenesis.

HER2 overexpression can be detected in tumor tissue by immunohistochemical staining (IHC) for HER2 protein, in situ hybridization for HER2 gene amplification, or reverse transcription polymerase chain reaction (RT-PCR) for overexpression of HER2 RNA [53,54]. Harmonized recommendations for diagnostic criteria for HER2-amplified mCRC have been proposed [55]. Although circulating tumor DNA (ctDNA) has been used to identify patients for a trial of HER2-directed therapy [56], there is a 10 to 20 percent false-negative rate as compared with tissue analysis [57], and this is not yet a widely accepted approach. Nevertheless, in the absence of tissue, a positive ctDNA result may be used to select patients for HER2-targeted therapy. (See 'Multipanel somatic (tumor) and germline genomic testing' above.)

The following studies have evaluated the benefits of HER2-targeted therapy in RAS wild-type, HER2 positive mCRC:

Trastuzumab plus tucatinib – The combination of trastuzumab plus the selective anti-HER2 tyrosine kinase inhibitor tucatinib was evaluated in an open-label phase II trial (MOUNTAINEER) of 84 patients with HER2-amplified, RAS wild-type mCRC previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and a vascular endothelial growth factor inhibitor [58]. Tucatinib was administered at 300 mg orally twice a day in combination with trastuzumab on day 1 (loading dose of 8 mg/kg for the first cycle, maintenance dose of 6 mg/kg for subsequent cycles) of a 21-day cycle until disease progression or unacceptable toxicity. In a separate treatment arm, 30 patients received single-agent tucatinib arm and were permitted to cross over to combination therapy upon disease progression.

At median follow-up of 16 months, the overall response rate for the combination was 38 percent [58]. Median PFS and OS were 8 and 24 months, respectively. The objective response rate with single-agent tucatinib was minimal (3 percent), and PFS and OS were not reported because of the high cross-over rate.

Grade ≥3 treatment related toxicities for combination therapy included hypertension (7 percent), diarrhea (4 percent), hyperbilirubinemia (6 percent), and increases in AST (6 percent) and ALT (5 percent). Dosing adjustments of tucatinib for hepatoxicity and diarrhea are discussed separately. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Lapatinib, neratinib, and tucatinib' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Lapatinib, pertuzumab, neratinib, and tucatinib'.)

Based on these data, the FDA granted accelerated approval for tucatinib in combination with trastuzumab in adult patients with RAS wild-type, HER-2 positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy [59].

Trastuzumab plus lapatinibTrastuzumab plus lapatinib (a tyrosine kinase inhibitor [TKI] against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2) was evaluated in an open-label phase II trial (HERACLES) of 48 patients with KRAS exon 2 wild-type, HER2-overexpressing mCRC [60]. Of these patients, 27 were treated with intravenous trastuzumab (4 mg/kg loading dose initially followed by 2 mg/kg weekly) plus oral lapatinib (1000 mg daily) until disease progression. At a median follow-up of 94 weeks, objective responses were seen in eight patients (30 percent), including one complete response. Treatment was reasonably well tolerated (grade 3 toxicity rate of 22 percent consisting of fatigue, skin rash, or hyperbilirubinemia; no grade 4 or 5 events).

In a subsequent analysis, a high rate of central nervous system metastases was noted in 6 of 32 patients (19 percent), mirroring the experience with HER2-targeted therapies in HER2-positive breast cancer [61]. (See "Brain metastases in breast cancer", section on 'Risk factors for central nervous system metastases'.)

Trastuzumab plus pertuzumabTrastuzumab plus pertuzumab (a recombinant humanized monoclonal antibody that targets the extracellular HER2 dimerization domain and interferes with downstream HER2 signaling pathways) was evaluated in a phase II basket study (MyPathway) for patients with HER2-overexpressing/amplified tumors other than breast cancer [62,63]. In preliminary results, among the 68 patients with KRAS wild-type and HER2-overexpressing mCRC, objective responses were seen in 21 patients (31 percent) [63].

This combination demonstrated lower response rates in a separate phase II basket trial from the Targeted Agent and Profiling Utilization Registry (TAPUR) [64]. Among 28 heavily pretreated patients with HER2-overexpressing mCRC, objective responses were seen in 7 patients (25 percent), all of which were partial responses and no KRAS or BRAF mutations. The disease control rate was 54 percent.

Fam-trastuzumab deruxtecanFam-trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. We reserve fam-trastuzumab deruxtecan as a later-line off-label option for patients who have previously received trastuzumab-based therapy as well as two or more prior cytotoxic regimens.

For patients with HER2-overexpressing mCRC, we initiate fam-trastuzumab deruxtecan at 5.4 mg/kg intravenously every three weeks, as this dose is equally effective as higher doses and less toxic. In preliminary results of an open-label phase II trial (DESTINY-CRC02), 122 patients with HER-2 overexpressing mCRC were randomly assigned to fam-trastuzumab deruxtecan administered at a dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every three weeks. At median follow-up of ten months, relative to the higher dose (6.4 mg/kg), the lower dose (5.4 mg/kg) demonstrated similar PFS for all patients (median 6 versus 5 months) and objective response rate for those with prior HER2-targeted therapy (41 versus 40 percent). However, the lower dose reduced toxicity (serious adverse event rate 24 versus 31 percent), including rates of drug-related interstitial lung disease (8 versus 13 percent) [65].

The efficacy of fam-trastuzumab deruxtecan was demonstrated in an open-label phase II trial (DESTINY-CRC01). In this study, 86 patients with RAS and BRAF V600E wild-type, HER2-overexpressing mCRC who progressed on two or more prior regimens were treated with fam-trastuzumab deruxtecan at 6.4 mg/kg every three weeks [66,67]. Approximately one-third of the patients had received prior HER2-targeted therapies.

At median follow-up of 14 months, among the subgroup of 53 patients with tumors that were HER2 3+ IHC or 2+ IHC/positive by in situ hybridization (ISH), the ORR was 45 percent, all of which were partial responses [67]. In this subgroup, ORR was similar regardless of whether patients had received prior HER2-targeted therapy or not (44 versus 46 percent). The median duration of response was 7 months. Median PFS and OS were 7 and 16 months respectively. The response rate was highest among those with 3+ IHC disease (57 percent), whereas there were no objective responses among patients with tumors that were either HER2 2+/negative by ISH or 1+ IHC. However, the grade ≥3 toxicity rate for fam-trastuzumab at the 6.4 mg/kg dose was 65 percent, including decreased neutrophil count (22 percent), anemia (14 percent), and thrombocytopenia (9 percent). The rate of treatment-related interstitial lung disease was 9 percent, including three deaths.

RAS mutant, HER2 overexpressors — There are limited data for the management of patients with mCRC whose tumors are RAS mutated and HER2 overexpression. We refer these patients for clinical trials, where available. In addition, these patients should not receive HER2-targeted therapy outside of a clinical trial, as available data suggest low response rates in this population [62,63]. Preliminary results from a randomized clinical trial (DESTINY-CRC02) suggest clinical activity with fam-trastuzumab deruxtecan in patients with RAS-mutant, HER2 overexpressing mCRC, but further data are necessary prior to its routine use in this group [65]. (See 'RAS-mutated tumors' below.)

RAS-mutated tumors — For most patients with RAS-mutated mCRC who progress on fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and VEGF inhibitor therapy and do not have a second actionable genetic alteration, we encourage enrollment in clinical trials, where available (www.clinicaltrials.gov).

For such patients with KRAS G12C mutant mCRC who decline or do not have access to clinical trials, we suggest either sotorasib plus panitumumab or adagrasib plus cetuximab rather than single-agent treatment or other systemic agents. Either of these combinations are appropriate as they have not been directly compared in randomized trials. For patients who are unable to tolerate the combination due to toxicity from the EGFR inhibitor, single-agent sotarasib or adagrasib is a reasonable alternative.

Patients with RAS-mutated mCRC do not benefit from EGFR inhibitors. In particular, patients with mCRC that harbors a KRAS G12C mutation have poor treatment outcomes [68,69]. Treatment-related resistance rapidly develops in these tumors, and studies suggest that the primary resistance mechanism is increased EGFR signaling [70,71]. Further details on mechanisms of disease resistance in RAS-mutated colorectal cancer are discussed separately. (See "Molecular genetics of colorectal cancer", section on 'RAS' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS'.)

Divarasib, sotorasib, and adagrasib are irreversible inhibitors that target KRAS G12C. In patients with KRAS G12C mutant mCRC, these drugs have been evaluated in combination with EGFR inhibitors (to reverse tumor resistance to these inhibitors) and as monotherapy.

Sotorasib plus panitumumab – In patients with treatment-refractory KRAS G12C mutant mCRC, the combination of sotorasib plus panitumumab improved PFS and was well-tolerated in a randomized phase III trial (CodeBreaK 300) [72].

In early phase clinical trials, sotorasib was initially evaluated as a single-agent (CodeBreaK100) [73,74] and in combination with panitumumab (CodeBreaK 101) [75]. These data led to the evaluation of sotorasib plus panitumumab in an open-label phase III trial (CodeBreaK 300) [72]. In this study, 160 patients with mCRC and KRAS G12C mutation who progressed on or were intolerant of fluoropyrimidine, oxaliplatin, and irinotecan were randomly assigned to panitumumab in combination with sotorasib either at a dose of 960 mg daily (53 patients) or 240 mg daily (53 patients), or investigator's choice of trifluridine-tipiracil or regorafenib (54 patients).

At median follow-up of eight months, sotorasib plus panitumumab improved PFS over trifluridine-tipiracil or regorafenib for both sotarasib doses (median PFS 5.6 versus 2.2 months, hazard ratio [HR] 0.49, 95% CI 0.3-0.8 for sotorasib 960 mg plus panitumumab; median PFS 3.9 versus 2.2 months, HR 0.58, 95% CI 0.36-0.93 for sotorasib 240 mg plus panitumumab). Objective responses were highest for sotorasib at 960 mg plus panitumumab (26 percent) compared with sotorasib at 240 mg plus panitumumab (6 percent) and trifluridine-tipiracil or regorafenib (0 percent). OS results are immature.

Grade ≥3 toxicity rates were lower for panitumumab plus sotorasib at 960 mg (36 percent) or 240 mg (30 percent) versus trifluridine-tipiricil or regorafenib (43 percent). The most frequent grade ≥3 toxicities for panitumumab plus either sotorasib at 960 mg or 240 mg included diarrhea (4 and 6 percent), nausea (2 and 4 percent), hypomagnesemia (6 and 8 percent), rash (6 and 2 percent), dermatitis acneiform (11 and 4 percent), and skin-related toxic effect (4 and 2 percent).

Adagrasib plus cetuximabAdagrasib plus cetuximab is another option for treatment-refractory RAS mutant mCRC with high objective response rates and durable disease control.

In a nonrandomized multicohort phase I/II trial (KRYSTAL-1), 76 patients with previously treated mCRC harboring a KRAS G12C mutation were treated with either adagrasib alone or in combination with cetuximab [76].

At median follow-up of 18 months, among the 32 patients treated with adagrasib plus cetuximab, the ORR for adagrasib plus cetuximab was 46 percent and the disease control rate was 100 percent. The median duration of response was 7.6 months, and median PFS was 6.9 months.

At median follow-up of 20 months, among the 44 patients who received adagrasib monotherapy, the objective response rate (ORR) was 23 percent and the disease control rate was 86 percent. The median duration of response was 4.3 months, and median PFS was 5.6 months.

Divarasib – The use of divarasib remains investigational in mCRC. Divarasib was evaluated in a phase I trial of 137 patients with advanced or metastatic treatment-refractory solid tumors with a KRAS G12C mutation [77]. Among the subgroup of 55 patients with mCRC, the confirmed response rate was 29 percent, and median PFS was 6 months. Divarasib was also well tolerated among patients with mCRC (grade ≥3 toxicity rate of 7 percent).

RET fusion-positive tumors — Selpercatinib is an option for refractory mCRC with a rearranged during transfection (RET) gene fusion and disease progression on or following prior systemic treatment. Efficacy in 45 patients with a variety of solid tumors containing a RET fusion gene was addressed on the Libretto-001 basket trial [78]. In the entire cohort, the objective response rate was 44 percent and median duration of response was 24.5 months; two of the ten patients with advanced colon cancer had a partial response (20 percent) and the median duration of response was 9.4 months. The most common grade ≥3 treatment-emergent adverse effects were hypertension and transaminase elevation.

In September 2022, the FDA granted a tissue-agnostic, accelerated approval of selpercatinib for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion and disease progression on or following prior systemic treatment who have no satisfactory alternative treatment options. Unfortunately, only 0.2 to 1.2 percent of advanced CRCs harbor a RET fusion [79-81].

TRK fusion-positive tumors — For patients who have tropomyosin receptor kinase (TRK) fusion-positive mCRC, we suggest a TRK inhibitor (larotrectinib or entrectinib) rather than another form of therapy for treatment at progression after the initial regimen.

Genomic translocations in one of several neurotrophic tyrosine kinase receptor (NTRK) genes that lead to the constitutive activation of a TRK are found in approximately 0.5 to 1 percent of mCRCs, and they appear to identify a subset of patients with poor prognosis. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Prevalence'.)

More importantly, finding one of these fusion genes/oncoproteins in the tumor identifies a subset of patients who might benefit from a TRK inhibitor. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)

Two such drugs, larotrectinib and entrectinib, are approved in the United States for use in adults and children with TRK fusion-positive solid tumors for which there are no other effective treatments. Larotrectinib is also approved by the European Medicines Agency (EMA). Entrectinib has also been approved in Japan for treatment of 10 tumor types with a NTRK gene fusion, including CRC.

Although sequencing trials are not available in mCRC or any other cancer type, it is reasonable to consider a TRK inhibitor early in the course of chemotherapy treatment (such as after progression on the initial line of chemotherapy) in patients with fusion-positive advanced cancers, given the very high response rates and durable disease control. This subject, as well as a general discussion of side effects from TRK inhibitors, is presented in detail elsewhere. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Timing of therapy for patients with advanced disease' and "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Side effects'.)

Not eligible for or progressing during targeted therapy

The cytotoxic chemotherapy backbone — For fit patients who were initially treated with an oxaliplatin-containing chemotherapy doublet (ie, oxaliplatin plus leucovorin [LV] and short-term infusional fluorouracil [FU; FOLFOX] or oxaliplatin plus capecitabine [CAPOX/XELOX]), we switch to FOLFIRI or irinotecan alone at the time of disease progression. For patients initially treated with FOLFIRI, we switch to an oxaliplatin-based regimen at the time of progression.

The optimal sequence of oxaliplatin and irinotecan-containing chemotherapy for mCRC remains unresolved, and may differ between patients based on tumor-related heterogeneity and pharmacogenetic issues. As noted above, exposure to all active agents is probably more important than the specific sequence of administration [10,82]. Nevertheless, most American oncologists initiate chemotherapy for mCRC with FOLFOX or CAPOX/XELOX, using irinotecan alone [83] or irinotecan-based regimens such as FOLFIRI as second-line therapy after the failure of FOLFOX.

The available data suggest similar survival outcomes and efficacy regardless of the specific order of administration:

Irinotecan after oxaliplatin failure – Although limited, the most mature data from three series suggest response rates between 4 and 20 percent, and PFS of 2.5 to 7.1 months, respectively, for patients receiving a FOLFIRI-like regimen after progression on FOLFOX [84-86].

Single-agent irinotecan is also an option. Available data suggest small differences in efficacy between second-line FOLFIRI and irinotecan. In the small phase II DaVINCI trial [87] performed in Australia and New Zealand, response rates were similar for single-agent irinotecan (350 mg/m2 every 21 days) and FOLFIRI (11 percent in both arms), with small but not statistically significant improvements in PFS (6.2 versus 4 months) and OS (15.4 versus 11.2 months) favoring FOLFIRI, while overall quality of life favored irinotecan. In the meta-analysis accompanying the DaVINCI trial, there were no significant differences in response rate, PFS, or OS between single-agent irinotecan and FOLFIRI. However, severe diarrhea and alopecia were more common with single-agent irinotecan at 350 mg/m2. Given what appears to be similar outcomes in second-line following oxaliplatin-5FU combinations, patients should be informed of the differences in toxicity and infusion requirements of these regimens. Notably, the starting dose of single agent irinotecan for older patients and those with performance status ≥2 is 300 mg/m2, though clinicians could consider starting with lower doses, and dose escalation as tolerated given the risk of neutropenia and severe enteritis.

S-1 is an oral fluoropyrimidine that includes ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of dihydropyrimidine dehydrogenase [DPD]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in some countries outside of the United States. Where S-1 is available, irinotecan plus S-1 represents a reasonable alternative to FOLFIRI for second-line treatment after failure of first-line FOLFOX [88].

The contribution of bevacizumab and cetuximab to the efficacy of second-line irinotecan-based chemotherapy is discussed below. (See 'Antiangiogenesis therapy' below and 'RAS/BRAF wild-type tumors' below.)

Oxaliplatin after irinotecan failure – The benefit of oxaliplatin-based therapy in patients failing an initial irinotecan-based regimen has been addressed in four multicenter trials:

In an early crossover phase III trial, both sequences of FOLFOX followed by FOLFIRI, or FOLFIRI followed by FOLFOX were directly compared, and both sequences achieved a prolonged survival and similar efficacy, although the toxicity profiles differed (grade 3 or 4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, but grade 3 or 4 neutropenia and neurosensory toxicity were more frequent with FOLFOX) [84]. The response rate with FOLFOX6 in patients failing initial FOLFIRI was 15 percent, and the PFS was 4.2 months.

The largest trial, conducted in the United States and Canada, randomly allocated 812 irinotecan-refractory patients to one of three different treatment groups [89,90]:

-Oxaliplatin alone (85 mg/m2 every two weeks)

-The de Gramont FU/LV regimen (LV 200 mg/m2 over two hours, followed by FU [bolus 400 mg/m2 and a 22-hour infusion of 600 mg/m2 per day], days 1 and 2 every two weeks)

-The combination (FOLFOX4) (table 2)

The ORR with FOLFOX4 was significantly higher than with either oxaliplatin alone or FU/LV (10 versus 1 percent with the other regimens, respectively) [90]. Median time to progress (TTP) was also significantly longer with FOLFOX4 as compared with FU/LV (4.2 versus 2.1 months), and more patients had symptomatic benefit (28 versus 15 percent). The higher frequency of grade 3 or 4 toxicity with FOLFOX4 (ie, diarrhea, nausea, vomiting, neutropenia) did not translate into a higher rate of treatment discontinuation or mortality [89,90].

Second-line FOLFOX4 was directly compared with CAPOX (oxaliplatin 130 mg/m2 over 30 minutes on day 1 every three weeks plus capecitabine 1000 mg/m2 orally twice daily on days 1 to 14) in a phase III trial of 627 patients failing initial FU/irinotecan [91]. Results with XELOX were not inferior to FOLFOX4 in terms of response rates, TTP, or median OS (12.5 and 11.9 months for FOLFOX and XELOX). Toxicity profiles were also comparable, with the exception of fewer grade 3 or 4 neutropenia (5 versus 35 percent), and more grade 3 or 4 diarrhea (19 versus 5 percent) and hand-foot syndrome (4 versus <1 percent) with XELOX.

In the United States, oxaliplatin is approved in combination with infusional FU/LV for patients who recur or progress during or within six months of completion of first-line irinotecan-based therapy. Capecitabine/oxaliplatin could be considered in patients who desire to avoid a central venous line ambulatory infusion pump, although increasingly oxaliplatin is being administered through a central line because of pain with peripheral vein administration. The contribution of bevacizumab to the efficacy of oxaliplatin/fluoropyrimidine regimens is discussed below.

Patients initially treated with FOLFOXIRI — The best chemotherapy backbone regimen for individuals who are treated initially with a three drug regimen (eg, oxaliplatin plus irinotecan, LV plus short-term FU [FOLFOXIRI], (table 3)) is not established. For patients who are RAS and BRAF wild-type and have not received an EGFR inhibitor, and who discontinued FOLFOXIRI for reasons other than disease progression, options include an EGFR inhibitor, FOLFIRI, FOLFOX, or reintroduction of FOLFOXIRI [92]. If an antiangiogenic agent was not used first-line, then bevacizumab plus either FOLFOX or FOLFIRI are additional options.

For patients who are RAS/BRAF wild-type and who discontinued FOLFIRINOX because of disease progression, options include an EGFR inhibitor (either cetuximab or panitumumab) alone or with irinotecan.

For patients previously treated with FOLFIRINOX who have received an anti-VEGF agent, and (if RAS and BRAF wild-type) an EGFR inhibitor, and who require additional therapy, options include single-agent trifluridine-tipiracil with or without bevacizumab, regorafenib, or fruquintinib. (See 'Subsequent therapy' below.)

Patients not eligible for intensive therapy — The best way to treat patients with a borderline performance status or extensive comorbidity who initially received fluoropyrimidine monotherapy is not clear, and several options may be considered.

Capecitabine plus bevacizumab – ORRs with second-line capecitabine monotherapy are quite low in patients with FU-refractory disease [93,94]. As such, capecitabine alone is an inappropriate treatment strategy for patients with progressive mCRC on initial intravenous FU-based regimens. However, capecitabine plus bevacizumab might be an option, if it was not used for initial therapy, and there are no contraindications to the use of bevacizumab. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)

Irinotecan monotherapy – Another option is irinotecan monotherapy. As a single agent, irinotecan has demonstrated clinical benefit after FU failure in patients with mCRC [95-98]. As an example, in a trial of 279 patients with FU-refractory disease who were randomly assigned to best supportive care with or without irinotecan, the irinotecan group had superior one-year survival (36 versus 14 percent) and quality of life [96].

Different administration schedules for irinotecan (weekly, every two weeks, or every three weeks) appear to result in similar therapeutic outcomes, although in one report, the every-three-week schedule was associated with significantly less grade 3 diarrhea (36 versus 19 percent) than a weekly regimen [99]. Diarrhea is the dose-limiting side effect of irinotecan and may be severe; early use of loperamide decreases its severity and is essential to prevent treatment-related mortality. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

RaltitrexedRaltitrexed (Tomudex), a folate analog, is a pure thymidylate synthase inhibitor [100]. It is not more active than FU and is not approved in the United States [101-103]. In at least one randomized trial that assigned 905 patients with mCRC to raltitrexed, infusional FU, or bolus plus short-term infusional FU/LV (the de Gramont regimen), raltitrexed was associated with the greatest toxicity and worst health-related quality of life [101].

However, raltitrexed, which is not available in the United States, may be a useful substitute for FU in patients with DPD deficiency (which markedly increases FU toxicity) or possibly as a component of second-line therapy in patients failing irinotecan or oxaliplatin [104-107]. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

Antiangiogenesis therapy

Patients initially treated with bevacizumab — For patients treated with a first-line bevacizumab-containing chemotherapy regimen, we suggest continuation of an antiangiogenic agent at the time of progression. For most patients, we suggest bevacizumab rather than aflibercept beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy backbone, particularly if an EGFR inhibitor is not indicated (eg, those with a RAS or BRAF mutation), as long as drug therapy is well tolerated. However, if bevacizumab is used as a component of the second-line chemotherapy regimen for patients with RAS wild-type disease, it should not be administered concurrently with an EGFR-targeting monoclonal antibody (MoAb). (See 'Dual antibody therapy' below.)

Continuation of bevacizumab — In view of the increasing use of bevacizumab in first-line regimens, an important clinical issue is whether it should be continued in patients who switch to an alternative regimen after cancer progression on first-line bevacizumab-containing therapy. An association between survival and exposure to bevacizumab beyond first progression was suggested in an analysis of the observational BRiTE registry of 1953 patients who progressed after receiving a first-line bevacizumab-containing regimen [108], in a preliminary report from the ARIES observational cohort study [109], and from a retrospective analysis of 573 patients treated with and without second-line bevacizumab from community-based United States Oncology practices [110].

This issue was directly studied in two trials:

In the European TML (ML18147) study, 820 patients with unresectable mCRC progressing within three months of receiving first-line chemotherapy with bevacizumab were randomly assigned to fluoropyrimidine-based chemotherapy with or without bevacizumab (2.5 mg/kg/week) [111]. Continuation of bevacizumab with the second-line chemotherapy regimen was associated with a significant improvement in PFS (median 5.7 versus 4.1 months) and OS (median 11.2 versus 9.8 months), and bevacizumab-related adverse events were not increased compared with historical data of first-line bevacizumab treatment. Although significantly more patients achieved disease control in the bevacizumab group (68 versus 54 percent), ORRs in both arms were low (5.4 versus 3.9 percent for bevacizumab and no bevacizumab, respectively). Based upon these results, in January 2013, the FDA approved bevacizumab for use in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for treatment of patients with mCRC whose disease had progressed on a first-line bevacizumab-containing regimen.

Benefit was also suggested in a second trial, the BEBYP trial, which randomly assigned 185 patients undergoing first-line fluoropyrimidine-plus bevacizumab chemotherapy to second-line FOLFOX or FOLFIRI with or without bevacizumab [112]. Accrual to the trial was prematurely stopped when the results of the TML trial became known. Median PFS was significantly improved by continuation of bevacizumab with the second-line regimen (median 6.8 versus 5 months), although the differences in ORRs to the second-line regimen (17 versus 21 percent), and DCRs overall (58 versus 70 percent) were not statistically significant.

A different question, whether to switch to cetuximab or continue with second-line bevacizumab in patients with RAS wild-type tumors progressing on first-line bevacizumab, was addressed in the phase II PRODIGE 18 trial [113]. Continuation with bevacizumab was associated with a numerically higher, but not statistically significant, median PFS (7.1 versus 5.6 months) and OS (15.8 versus 10.4 months) compared with cetuximab plus chemotherapy. These results favor continuation of bevacizumab with an alternative chemotherapy backbone in patients who progress with first-line bevacizumab plus chemotherapy.

Role of aflibercept — Intravenous aflibercept (VEGF Trap, Zaltrap) is a recombinant fusion protein, consisting of vascular endothelial growth factor (VEGF) binding portions from key domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1. It acts as a soluble "decoy" receptor that binds to human VEGF-A, VEGF-B, and placental growth factor (PIGF), thereby inhibiting the binding of these ligands and activation of their respective receptors. In cell-free systems, this molecule binds with higher affinity to VEGF-A than does bevacizumab [114].

Aflibercept is approved in the United States for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen. Approval was based on the placebo-controlled VELOUR trial, in which 1226 patients with oxaliplatin-refractory mCRC were randomly assigned to aflibercept (4 mg/kg intravenously) or placebo, plus FOLFIRI, every two weeks until progression [115]. Median OS was significantly longer in patients treated with aflibercept (13.5 versus 12.1 months) as was median PFS (6.9 versus 4.7 months). Benefit and safety were similar regardless of prior bevacizumab exposure [116].

While the side effect profile of aflibercept plus FOLFIRI in the VELOUR trial was consistent with other agents targeting VEGF (bleeding, hypertension, proteinuria, wound infection, arterial thromboembolic events), rates of diarrhea, mucositis, complicated neutropenia, infection, and fatigue associated with aflibercept in this trial were higher than usually seen with bevacizumab, as were rates of treatment discontinuation for toxicity or refusal (30 versus 12 percent). (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

There are no randomized trials directly comparing second-line bevacizumab and aflibercept in patients who progressed on first-line bevacizumab. Data are available from a multicenter retrospective analysis of 681 patients treated with second-line aflibercept (n = 326) or bevacizumab (n = 355) after progressing on first-line bevacizumab; 81 percent had RAS-mutated tumors [117], and it was concluded that after adjusting for age, performance status, PFS of first-line therapy, primary tumor location, metastasis location, and RAS/BRAF status, the use of bevacizumab was associated with longer PFS and OS (HR 0.71, 95% CI 0.59-0.86), as well as better tolerability.

As with bevacizumab, because of the risk of impaired wound healing, at least 28 days (and preferably six to eight weeks) should elapse between major surgery and administration of aflibercept, except in emergency situations. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Delayed wound healing'.)

Ramucirumab — Ramucirumab is a recombinant MoAb of the IgG1 class that binds to the VEGFR-2, blocking receptor activation. The efficacy of ramucirumab for second-line treatment of mCRC was addressed in the double blind phase III RAISE trial in which 1072 patients with progressing after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomly assigned to FOLFIRI with ramucirumab (8 mg/kg intravenously every two weeks) or placebo until disease progression, unacceptable toxicity, or death [118]. Median survival was modestly but significantly greater with ramucirumab (13.3 versus 11.7 months), as was median PFS (5.7 versus 4.5 months). ORRs were comparable in the two arms. Grade 3 or worse side effects that were more prominent with ramucirumab included neutropenia (38 versus 23 percent), hypertension (11 versus 3 percent), and fatigue (12 versus 8 percent).

Based on these results, ramucirumab was approved in April 2015 for use in combination with FOLFIRI for the treatment of mCRC in patients whose disease has progressed on a first-line bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing regimen. However, given this modest degree of benefit, the expense of this agent [119], and the competing data indicating benefit from continuation of second-line bevacizumab in this same setting, we do not consider ramucirumab the agent of choice if continued VEGF inhibition beyond first-line progression is considered.

RAS/BRAF wild-type tumors — Cetuximab and panitumumab, therapeutic MoAbs that target the EGFR, both have well-documented and comparable single-agent activity in patients with previously treated mCRC that lacks mutations in RAS and BRAF V600E [120-122]. Regimens that combine an EGFR inhibitor with irinotecan alone or a chemotherapy doublet are also efficacious, with the exception of regimens that contain oxaliplatin with a non-infusional fluoropyrimidine (ie, CAPOX/XELOX). (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

No prior initial therapy with cetuximab/panitumumab — Cetuximab (or panitumumab) is useful in combination with irinotecan for patients with RAS and BRAF wild-type tumors that are refractory to irinotecan and as a single agent for those who are intolerant of irinotecan-based chemotherapy. If rapid tumor growth is observed after first-line FOLFOX plus bevacizumab-based therapy, the addition of cetuximab (or panitumumab) to irinotecan-based therapy is a reasonable option to elicit higher anti-tumor activity, particularly because the biology of the disease in these patients might not allow for a step-wise, sequential therapeutic approach. By contrast, in a case of a rather indolent, slowly progressive tumor, sequential use of agents (irinotecan first, followed by irinotecan plus cetuximab [or panitumumab]) might be preferable.

Another alternative is to continue bevacizumab with the second-line cytotoxic chemotherapy backbone. Emerging data support the view that EGFR inhibitors do not appear to be useful for right-sided tumors in the setting of first-line therapy. However, whether these results can be extrapolated to later lines of therapy is not clear; there are few data addressing this issue [123] and no consensus. The authors and editors associated with this topic review would not withhold EGFR inhibitors for second-line treatment for right sided RAS/BRAF wild-type tumors. However, other clinicians would favor the use of continued bevacizumab over an EGFR inhibitor for right-sided tumors after failure of an initial bevacizumab-containing regimen. (See 'Initial therapy with bevacizumab' below and 'Patients initially treated with bevacizumab' above.)

Efficacy of monotherapy

Cetuximab, a mouse/human chimeric MoAb, binds to the EGFR of both tumor and normal cells, competitively inhibiting ligand binding, and inducing receptor dimerization and internalization. It is unclear whether these actions represent the mechanism of antitumor action. Cetuximab is useful in combination with irinotecan for patients with wild-type RAS tumors who are refractory to irinotecan and as a single agent for those who are intolerant of irinotecan-based chemotherapy. The approved dosing regimen is weekly, although at least some data support the safety and efficacy of every-other-week dosing. (See 'Are cetuximab and panitumumab interchangeable?' below.)

Cetuximab monotherapy was compared with best supportive care (BSC) in a randomized trial of 572 patients who had failed or were intolerant of all recommended therapies [120]. Median OS was significantly better with cetuximab (6.1 versus 4.6 months), as were measures of health-related quality of life, including physical function and global health scores. In a subsequent reanalysis, the benefits of cetuximab were restricted to patients whose tumors lacked a KRAS mutation [124,125].

Panitumumab is a fully human MoAb specific for the extracellular domain of EGFR. The benefit of panitumumab monotherapy was initially shown in a multicenter trial in which 463 patients refractory to FU, irinotecan, and oxaliplatin were randomly assigned to BSC with or without panitumumab (6 mg/kg every two weeks) [121]. The ORR with panitumumab was 10 percent, and 27 percent had stable disease; the corresponding rates with BSC alone were 0 and 10 percent. Patients receiving panitumumab were significantly more likely to be alive and progression free at eight weeks (49 versus 30 percent). The lack of a survival difference was likely due to panitumumab use after crossover in the BSC group [126]. In a later reanalysis, efficacy was limited to patients whose tumors were wild type for KRAS exon 2 (partial response and stable disease in 17 and 34 percent, respectively, versus 0 and 12 percent with mutated KRAS) [127].

Combined therapy – Combined therapy with a cytotoxic chemotherapy backbone increases ORRs and TTP compared with monotherapy, but treatment-related toxicity is worse.

Two randomized trials have explored the activity of cetuximab or panitumumab in combination with second-line FOLFIRI after failure of initial FOLFOX; neither included bevacizumab as a component of the first-line regimen in all patients.

In the large EPIC (Erbitux Plus Irinotecan in Colorectal cancer) trial, in which 1300 patients with EGFR-expressing, but not RAS-selected, mCRC who had failed initial FOLFOX therapy were randomly assigned to single-agent irinotecan with or without cetuximab, the addition of cetuximab quadrupled the response rate (16 versus 4 percent), significantly prolonged PFS (4 versus 2.6 months), and despite the higher frequency of side effects, was associated with better quality of life [128].

Similarly, the BOND trial compared irinotecan (350 mg/m2 every three weeks, 180 mg/m2 every two weeks, or 125 mg/m2 weekly for four of every six weeks) plus weekly cetuximab versus cetuximab alone in 329 patients with irinotecan-refractory mCRC [129]. Combined therapy was associated with a significantly better response rate (23 versus 11 percent) and TTP (4.1 versus 1.5 months) but only a trend towards better median survival (8.6 versus 6.9 months).

A randomized trial of panitumumab plus FOLFIRI versus FOLFIRI alone after failure of initial FU-containing chemotherapy (two-thirds prior oxaliplatin, 20 percent prior bevacizumab) also showed that, in the KRAS wild-type group (n = 597), the addition of panitumumab was associated with a significant improvement in response rate (35 versus 10 percent) and median PFS (5.9 versus 3.9 months) [130] but no statistically significant difference in OS.

These results confirm that the addition of cetuximab or panitumumab to an irinotecan-based chemotherapy regimen after failure of initial FU-containing chemotherapy is associated with greater treatment activity than is monotherapy. Although the combination of panitumumab and irinotecan is not approved by the FDA for the treatment of RAS and BRAF wild-type mCRC, we offer this combination in this population since it is safe and effective. This approach is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and the ESMO [48,131]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)

Initial therapy with bevacizumab — A separate question, given the demonstrated benefit of second-line bevacizumab in patients progressing on an initial bevacizumab-containing regimen, is whether it is preferable to continue second-line bevacizumab or switch to a regimen containing an EGFR inhibitor. (See 'Patients initially treated with bevacizumab' above.)

The benefit of adding bevacizumab or cetuximab to the cytotoxic chemotherapy backbone in RAS wild-type tumors that have progressed after first-line bevacizumab was directly addressed in the PRODIGE 18 trial [113]. Continuation with bevacizumab was associated with a numerically higher but not statistically significant median PFS and OS advantage compared with cetuximab plus chemotherapy. In our view, there is insufficient evidence to draw any conclusions from these data, and either bevacizumab or an EGFR inhibitor is acceptable in this setting, although use of an EGFR inhibitor for right sided tumors in the second-line setting is controversial. (See 'No prior initial therapy with cetuximab/panitumumab' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

Are cetuximab and panitumumab interchangeable? — Cetuximab and panitumumab appear to have comparable efficacy when used for single agents for salvage therapy in patients with chemotherapy-refractory mCRC [120,121,132-134], and when used for first-line or second-line therapy of mCRC in conjunction with an irinotecan-based chemotherapy regimen.

Both MoAbs target the same antigen (EGFR), and preclinical data suggest a similar mode of action (interference with ligand binding, downregulation of signaling activity, internalization of receptors) [135]. From a pharmacologic standpoint, the main difference between both agents lies in their IgG backbones: cetuximab is a chimeric mouse/human MoAb, while panitumumab is a completely human MoAb. As a result, the incidence of hypersensitivity reactions with panitumumab is lower, and this eliminates the need for routine premedication before therapy. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

The difference in the original on-label dosing schedules (every two weeks for panitumumab, weekly for cetuximab) were based more on how the respective trials leading to approval by the FDA were designed than on true pharmacokinetic, pharmacodynamic, or pharmacogenomic differences. The two drugs have similar half-lives (approximately seven days) and pharmacokinetics [136], and results from a nonrandomized phase II trial [137] and a multicenter retrospective analysis [138] suggest that cetuximab at a dose of 500 mg/m2 every two weeks results in similar plasma concentrations and single-agent activity as does weekly dosing. In April, the United States Prescribing Information for cetuximab was modified to allow for every two week dosing as an alternative to weekly dosing, for cetuximab when used as monotherapy, or in combination with irinotecan (table 4), or in combination with irinotecan plus LV and short-term FU (FOLFIRI, (table 5)) [139].

In clinical practice, there is no therapeutic preference for using cetuximab versus panitumumab either as monotherapy, or in combination with chemotherapy. However, the lower rate of infusion reactions with panitumumab favors the use of this agent in regions with a high rate of cetuximab-related infusion reactions (eg, middle southeastern region of the United States, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee). We consider that the addition of panitumumab to an irinotecan or oxaliplatin-containing chemotherapy regimen in patients with RAS and BRAF wild-type tumors is appropriate, an approach that is also allowed in consensus-based guidelines from the NCCN and ESMO [48,131]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)

Patients receiving either drug should undergo periodic monitoring of serum electrolytes, including magnesium and potassium. (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'Anti-EGFR monoclonal antibodies'.)

Prior initial therapy with cetuximab or panitumumab — For patients with RAS and BRAF wild-type mCRC who progress on initial treatment with chemotherapy plus an EGFR inhibitor (ie, cetuximab or panitumumab) and have no other actionable molecular alterations, our approach to second-line therapy is as follows:

For patients who previously received FOLFOX plus an EGFR inhibitor, we suggest FOLFIRI plus bevacizumab or irinotecan plus bevacizumab rather than other systemic agents.

For patients who previously received FOLFIRI plus an EGFR inhibitor, we suggest FOLFOX plus bevacizumab or CAPOX plus bevacizumab rather than other systemic agents.

For those who are not candidates for bevacizumab, chemotherapy alone is an acceptable alternative. Contraindications to bevacizumab are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Contraindications'.)

This approach to second-line therapy exposes the tumor to agents not previously received. It is also extrapolated from the initial management of mCRC, where the addition of bevacizumab to chemotherapy confers an OS advantage and is a treatment option for patients with either right- or left-sided primary tumors. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Efficacy and toxicity of bevacizumab and biosimilars' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

In contrast, randomized trials have established PFS but not OS benefit for EGFR inhibitor re-challenge in second-line therapy for RAS wild-type mCRC [140]. Re-challenging with regimens that include an EGFR inhibitor may be reserved for third or later lines of therapy. (See 'Re-challenge with previously used classes of agents' below.)

Studies have evaluated EGFR inhibitor challenge in RAS wild-type metastatic CRC. The rationale for this approach is that resistant RAS and EGFR ectoderm clones, which can develop during initial treatment with these agents [141], decay over time once the EGFR inhibitor is discontinued for approximately four months or longer [142]. This results in reemergence of tumor sensitivity to EGFR blockade [143,144].

Re-challenge with cetuximab was evaluated in a randomized phase II trial of 153 patients with mCRC initially treated with FOLFIRI plus cetuximab. At median follow-up of 35 months, the combination of FOLFOX plus cetuximab failed to improve PFS over FOLFOX alone in the entire study population [140]. Among the subset of patients with RAS, BRAF, and PIK3CA wild-type disease, the addition of cetuximab to FOLFOX improved PFS (median 6.9 versus 5.3 months, HR 0.56, 95% CI 0.33-0.94), but not OS (median 24 versus 20 months, HR 0.57, 95% CI 0.32-1.02).

Clinical trials are evaluating the use of circulating tumor DNA (ctDNA) to identify patients who benefit from EGFR inhibitor re-challenge [145-150], but this approach remains investigational.

Treatments not used

What is the role of panitumumab after progression on cetuximab? — A separate questions is whether resistance to cetuximab also predicts resistance to panitumumab. The majority of patients who have been evaluated in a trial setting do not achieve durable benefit from the use of panitumumab in patients who progress on cetuximab, and vice versa. In our view, this approach should only be undertaken in the context of a clinical trial aimed at better defining this question. This approach is consistent with consensus-based guidelines from the NCCN and ESMO [48,131].

Whether panitumumab is active in patients whose cancer has progressed on cetuximab therapy (and vice versa) is unclear. The similar mode of action would seem to support the existence of cross resistance, but there are few data that inform this issue. Two clinical trials of panitumumab in patients progressing on a cetuximab-containing regimen have come to different conclusions:

In the first, 26 patients with KRAS wild-type mCRC received panitumumab after progressing on cetuximab plus irinotecan [151]. A partial response was achieved in three (12 percent), and seven additional patients (27 percent) had stable disease.

On the other hand, in a second trial of 20 patients with KRAS wild-type mCRC who had progressed on cetuximab, no patient responded, although 45 percent had stable disease (no progression for at least two cycles) [152]. The authors concluded that panitumumab was of minimal benefit in cetuximab-refractory disease.

A possible explanation for these discrepant results has been provided by studies examining the mutational landscape of cetuximab-refractory tumors:

In one study, investigators used a cetuximab-sensitive human CRC cell line to develop a resistant version by prolonged in vitro exposure to cetuximab [153]. The cetuximab-resistant cells contained a secondary EGFR mutation in the extracellular domain of the receptor that impaired binding of cetuximab but not other EGFR ligands, including panitumumab. This specific mutation was identified in 2 of 10 tumors from people with cetuximab resistance, one of whom received panitumumab and had an objective response.

In another report of tissue samples derived from 37 patients with CRC who became refractory to cetuximab, a complex pattern of mutations was observed, converging on two main patterns of resistance: activating mutations affecting EGFR downstream signaling and mutations in the EGFR ectodomain that disrupt antibody receptor binding, a subset of which prevented binding to cetuximab but not panitumumab [154].

Thus, while there may be a small subset of patients with cetuximab-refractory RAS wild-type tumors who will respond to panitumumab, the best way to identify this subset is unclear. Further details are discussed separately. (See 'Prior initial therapy with cetuximab or panitumumab' above.)

Dual antibody therapy — Based upon the available data, a chemotherapy regimen containing both bevacizumab and an anti-EGFR MoAb cannot be considered a standard approach for treatment of RAS/BRAF wild-type mCRC for second-line therapy or beyond outside of a clinical trial.

The results of the phase II BOND-2 trial, which compared a combination of cetuximab/bevacizumab with (CBI) or without (CB) irinotecan as last-line therapy in patients with chemorefractory mCRC generated interest in dual-antibody combinations [155]. BOND-2 reported unprecedented outcome results for patients previously treated with FU, irinotecan, and (in 85 to 90 percent of cases) oxaliplatin with regard to response rate (20 versus 37 for CB and CBI, respectively), TTP (4.9 versus 7.3 months), and OS (11.4 versus 14.5 months). The toxicity profile was also tolerable.

However:

BOND-2 was a small randomized phase II trial of 83 patients treated in a few highly specialized cancer centers, thus limiting the extrapolation of the findings to the unselected patient population treated by community oncologists. The unexpectedly long median OS in both treatment arms underscores the highly select nature of the patient population enrolled to the study.

Patients who were considered candidates for the trial had already received (and apparently tolerated) several lines of therapy and still maintained a good enough performance status (0 to 1) (table 6) to be enrolled in the trial. This again underscores the fact that the patients enrolled on BOND-2 were highly selected and clearly not representative of the typical patient population with refractory mCRC.

This issue might in part explain the unexpected results of both the PACCE and the CAIRO2 trials, both of which suggested a possible detrimental impact of concurrent use dual antibodies targeting VEGF and the EGFR in the setting of first-line therapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Dual antibody therapy'.)

Patients on BOND-2 were all bevacizumab-naive so that the data cannot necessarily be used to justify therapy with dual antibodies in patients who have already received bevacizumab as part of their prior palliative medical therapy. This approach was being studied for second-line therapy in SWOG S0600; however, the protocol was terminated prematurely due to insufficient accrual.

The benefit of combining cetuximab and ramucirumab was addressed in the E7208 trial, in which 102 patients with RAS wild-type mCRC progressing after a fluoropyrimidine-, oxaliplatin-, and bevacizumab-containing regimen were randomly assigned to irinotecan plus cetuximab with ramucirumab (ICR) or without ramucirumab (IC) [156]. The ICR regimen was modified after the initial 35 patients were enrolled because of excessive toxicity. In a preliminary report presented at the 2018 annual American Society of Clinical Oncology (ASCO) meeting, patients assigned to ICR had similar median PFS (5.8 versus 5.7 months), and combination treatment was also more toxic (myelosuppression, hypertension, mucositis). Subset analysis suggested that patients who progressed while not receiving oxaliplatin and those with a longer time since last treatment might have preferentially benefited from dual therapy, but this is hypothesis generating at most.

SUBSEQUENT THERAPY — For patients who have been exposed to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) agent, and (if RAS and BRAF wild-type) an epidermal growth factor receptor (EGFR) inhibitor, options include trifluridine-tipiracil with or without bevacizumab, regorafenib, or fruquintinib.

Trifluridine-tipiracil with or without bevacizumab — Trifluridine-tipiracil plus bevacizumab is an option for patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and an EGFR inhibitor (if RAS wild-type). Trifluridine-tipiracil monotherapy may be offered to patients who are unable to tolerate or have contraindications to bevacizumab.

Trifluridine-tipiracil (TAS-102) is an oral cytotoxic agent that consists the nucleoside analog trifluridine (trifluorothymidine, a cytotoxic antimetabolite that, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well [157].

Trifluridine-tipiracil is administered twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle, and bevacizumab is administered at 5 mg/kg on days 1 and 15 of a 28-day cycle. Other studies suggest that an every-two-weeks schedule of administration of trifluridine-tipiracil (twice daily on days 1 to 5 of a 14-day cycle) with bevacizumab (5 mg/kg on day 1 of a 14-day cycle) is associated with less toxicity, especially neutropenia [158] This schedule is a reasonable alternative for patients who have difficulty tolerating the standard dosing of this combination.

Trifluridine-tipiracil plus bevacizumab – Based on initial data from a phase II trial [159], an open-label phase III trial (SUNLIGHT) was conducted to evaluate the addition of bevacizumab to trifluridine-tipiracil in 492 patients with mCRC who progressed on one to two lines of systemic therapy [160]. Most patients had received prior therapy with bevacizumab (72 percent) and had RAS-mutated tumors (70 percent). Patients were randomly assigned to either trifluridine-tipiracil plus bevacizumab or trifluridine-tipiracil alone. At median follow-up of 14 months, the addition of trifluridine-tipiracil to bevacizumab improved OS (median OS 11 versus 8 months, one-year OS 43 versus 30 percent, HR 0.61, 95% CI 0.49-0.77) and PFS (median PFS 6 versus 2 months, one-year PFS HR 0.44, 95% CI 0.36-0.54) [160]. OS and PFS benefit were seen across all prespecified subgroups, including patients previously treated with bevacizumab. Objective response rates were also higher with the combination (6 versus 1 percent). Grade ≥3 toxicity rates were similar between the treatment arms (72 versus 70 percent). The combination had higher rates of grade 3 to 4 hypertension (6 versus 1 percent) and neutropenia (43 versus 32 percent), but not febrile neutropenia (one patient for the combination versus six patients for trifluridine-tipiracil monotherapy).

Based on these data, the US Food and Drug Administration (FDA) approved trifluridine-tipiracil in combination with bevacizumab for the treatment of adult patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy [161].

Trifluridine-tipiracil monotherapy – An OS benefit of trifluridine-tipiracil as a single-agent in refractory mCRC was initially suggested in a randomized placebo-controlled phase II trial of 172 Japanese patients with refractory mCRC [162].

This clinical benefit was subsequently confirmed in two subsequent placebo-controlled phase III trials (the RECOURSE and TERRA trials) [163,164]. In the RECOURSE trial, 800 patients with mCRC refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and EGFR inhibitors (if KRAS wild-type) were randomly assigned to trifluridine-tipiracil or placebo [163]. When compared with placebo, trifluridine-tipiracil improved OS (median 7 versus 5 months, HR 0.68, 95% CI 0.58-0.81), irrespective of prior regorafenib use. In a separate analysis, among patients with a KRAS G12C mutated tumors, trifluridine-tipiracil did not improve OS over placebo; these data suggest less clinical benefit for this agent in this population [165]. Although trifluridine-tipiracil also improved the disease control rate (44 versus 16 percent), only eight patients had an objective response (versus one patient in the placebo arm).

The most frequently observed toxicities were gastrointestinal and hematologic. The rate of serious adverse events were similar for trifluridine-tipiracil versus placebo (30 versus 34 percent), and there was one treatment-related death with trifluridine-tipiracil. Importantly, gastrointestinal toxicities with trifluridine-tipiracil were almost all grade 1 and 2 with few grade ≥3 events recorded. That is a relevant quality-of-life benefit for patients with longstanding treatment-refractory disease who often experience gastrointestinal distress from their disease.

Largely based upon these results, the FDA approved trifluridine-tipiracil as a single agent for the treatment of adult patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy [161]. Trifluridine-tipiracil is also approved in Japan for treatment of refractory mCRC.

Regorafenib — Regorafenib is an option for patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, anti-EGFR inhibitor (if RAS wild-type), and molecularly targeted therapy, if appropriate. Regorafenib may also be offered to those who progress on trifluridine-tipiracil with or without bevacizumab.

We suggest initiating regorafenib with 80 mg per day rather than 160 mg (the approved dose), escalating the dose weekly in the absence of toxicity, and ending at 160 mg daily for 21 days of each 28-day cycle.

Regorafenib is an orally active inhibitor of angiogenic (including the VEGF receptors [VEGFRs] 1 to 3), stromal, and oncogenic receptor tyrosine kinases. It is structurally similar to sorafenib and targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways.

Activity in refractory mCRC was initially shown in the CORRECT trial, in which 760 patients who had progressed after multiple standard therapies were randomly assigned to best supportive care plus regorafenib (160 mg orally once daily for three of every four weeks) or placebo [166]. Patients assigned to regorafenib had a modest though statistically significant improvement in median overall survival (OS; 6.4 versus 5 months, hazard ratio [HR] 0.77, 95% CI 0.64-0.94), and the difference in progression-free survival (PFS), while very small, was statistically significant (HR 0.49, median 1.9 versus 1.7 months). While the disease control rate (DCR) was higher with regorafenib (41 versus 15 percent), only five patients (1 percent) experienced a partial response. The group receiving regorafenib had more grade 3 or 4 hand-foot skin reaction (17 versus 0.4 percent), fatigue (10 versus 5 percent), hypertension (7 versus 1 percent), diarrhea (7 versus 1 percent), and skin rash (6 versus 0 percent). Fatal hepatic failure occurred in 1.6 percent of patients treated with regorafenib versus 0.4 percent in the placebo group. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Largely based on this study, in 2012, regorafenib received approval from the FDA for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and, if KRAS wild-type, an EGFR inhibitor. It was approved by the European Medicines Agency (EMA) in 2013.

Benefit for regorafenib monotherapy was confirmed in the multicenter CONCUR trial, in which 204 Asian patients with mCRC who progressed after standard therapies were randomly assigned to regorafenib (160 mg daily for 21 of every 28 days) or placebo [167]. Regorafenib was associated with a significantly longer median PFS (3.2 versus 1.7 months) and OS (8.8 versus 6.3 months). As was seen in the CORRECT trial, the DCR was significantly higher with regorafenib (51 versus 7 percent), although only six patients (4 percent) achieved a partial response (versus none in the placebo group).

The initial approved dose of regorafenib (160 mg daily for 21 days of every 28-day cycle) may be too high for many patients. In the phase II ReDOS trial, a weekly dose escalating strategy (starting with 80 mg daily, escalating weekly in the absence of treatment-related toxicity to a target of 160 mg daily) allowed more patients to initiate the third cycle of therapy compared with starting at 160 mg per day (43 versus 26 percent) [168]. Median OS also trended better in the dose escalation cohort (9.8 versus 6 months), and toxicity was more favorable.

Fruquintinib — Fruquintinib is an option for patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor such as bevacizumab; and an EGFR inhibitor (for RAS wild-type tumors). Fruquintinib may also be offered to those who progress on trifluridine-tipiracil with or without bevacizumab. In phase III trials of treatment-refractory mCRC, fruquintinib, a selective small molecule inhibitor of VEGFR 1, 2, and 3 tyrosine kinases, improved OS and PFS over placebo [169,170].

In an international, double-blind, placebo controlled phase III trial (FRESCO-2), 691 patients with heavily pretreated mCRC were randomly assigned 2:1 to receive either fruquintinib (5 mg orally once daily on days 1 through 21 of a 28-day cycle) or placebo until disease progression or intolerable toxicity [170]. Patients had previously received chemotherapy (fluoropyrimidine, oxaliplatin, or irinotecan); a VEGF inhibitor; targeted agents for tumors with actionable molecular alterations (an EGFR inhibitor if RAS wild-type; immunotherapy if mismatch repair deficient [dMMR] or microsatellite instability-high (MSI-H); or a BRAF inhibitor if BRAF V600E-mutant); and had progressed on or were intolerant of trifluridine-tipiracil, regorafenib, or both.

At median follow-up of 11 months, relative to placebo, fruquintinib improved PFS (median 3.7 versus 1.8 months, HR 0.32, 95% 0.27-0.39), OS (median 7.4 versus 4.8 months, HR 0.66, 95% CI 0.55-0.80), and the disease control rate (56 versus 16 percent). Fruquintinib also conferred an OS benefit across clinically relevant subgroups including RAS status, prior VEGF or EGFR inhibitors, prior trifluridine-tipiracil and/or regorafenib, and the presence or absence of liver metastases. The grade ≥3 toxicity rate was higher for fruquintinib than placebo (63 versus 50 percent). Common grade ≥3 toxicities for fruquintinib included hypertension (14 percent), asthenia (8 percent), and hand-foot syndrome (6 percent).

Similar OS benefits were seen for fruquintinib in a separate randomized, double-blind, placebo-controlled phase III trial conducted in China (FRESCO) [169]. In this study, 416 patients with treatment-refractory mCRC were randomly assigned to either fruquintinib or placebo until disease progression or intolerable toxicity. Patients had disease progression after two or more lines of therapy that did not include a VEGFR inhibitor (such as regorafenib), but could include a VEGF inhibitor (such as bevacizumab or aflibercept). At median follow-up of 13 months, fruquintinib improved OS (median 9.3 versus 6.6 months, HR 0.65, 95% CI 0.51-0.83), and PFS (median 3.7 versus 1.8 months, HR 0.26, 95% CI 0.21-0.34). Grade ≥3 toxicity was higher for fruquintinib compared with placebo (61 versus 19 percent).

Fruquintinib is approved by the FDA for adult patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, a VEGF inhibitor, and, if RAS wild-type and medically appropriate, an EGFR inhibitor [171]. Fruquintinib is also approved in China by the National Medical Products Administration (NMPA) for patients with mCRC who have progressed on at least two prior systemic therapies include fluoropyrimidine, oxaliplatin, and irinotecan, with or without prior use of VEGF or EGFR inhibitors [172,173].

Re-challenge with previously used classes of agents — For patients with mCRC who progress on all available systemic agents, we offer enrollment in clinical trials, where available. Patients must have adequate performance status and a tumor-directed therapeutic approach must still warranted and desired, after a realistic discussion with the patient and/or family about the risks and benefits.

For patients who are ineligible for or do not have access to clinical trials, one option is re-challenging with a regimen initially used in the treatment sequence, especially if the regimen was discontinued because of toxicity and not disease progression [174]. During the lengthy phase of sequential therapy, tumors may retain or regain sensitivity to previously used drugs. (See 'Subsequent treatment and the continuum of care model' above.)

Examples of systemic agents that could be reused include:

FOLFOX or CAPOX. Of note, caution is warranted during oxaliplatin re-challenge. The risk of oxaliplatin infusion reaction is higher in patients with prior exposure, and tend to occur earlier (eg, cycles 2 to 3) in the treatment course [175,176].

For RAS wild-type disease, regimens that include an EGFR inhibitor such as cetuximab or panitumumab. (See 'Prior initial therapy with cetuximab or panitumumab' above.)

In a randomized phase II trial (VELO), re-challenge with panitumumab, an EGFR inhibitor, was investigated as third-line therapy in 62 patients with RAS wild-type tumors. All patients were initially treated with chemotherapy plus an EGFR inhibitor and did not receive an EGFR inhibitor for at least four months during second-line therapy [145]. The addition of panitumumab to trifluridine-tipiracil improved PFS (median 4 versus 2.5 months, HR 0.48, 95% CI 0.28-0.82) but not OS (13 versus 12 months, HR 0.96, 95% CI 0.54-1.71) [177]. (See 'Trifluridine-tipiracil with or without bevacizumab' above.)

LOCAL THERAPIES FOR METASTATIC DISEASE — Some patients may have metastatic disease limited to (or predominantly progressing within) one organ system, such as the liver, lungs, ovaries, or adrenal glands. For such patients, alternatives to systemic therapy include local treatment strategies, such as limited surgical resection, stereotactic body radiation therapy (SBRT), or ablative therapies. Further details are discussed separately.

(See "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer".)

(See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Colorectal cancer'.)

(See "Hepatic resection for colorectal cancer liver metastasis".)

(See "Nonsurgical local treatment strategies for colorectal cancer liver metastases".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Colon and rectal cancer (The Basics)")

Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General principles

Molecular testing – The approach to later lines of systemic therapy in mCRC is based on molecular testing and prior therapy. Regimens listed for patients with no molecular marker can be used for subsequent therapy in those with an identified molecular marker. (See 'Multipanel somatic (tumor) and germline genomic testing' above.)

Selecting therapy – At disease progression, select patients may be candidates for retreatment with the original regimen (eg, those on maintenance chemotherapy) or a switch to a different regimen (eg, those with disease progression on or intolerance to therapy). (See 'Subsequent treatment and the continuum of care model' above.)

dMMR/MSI-H tumors – For patients whose tumors have high levels of microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) not previously exposed to an immune checkpoint inhibitor, we suggest immune checkpoint inhibitor immunotherapy rather than other systemic therapy (Grade 2C). Options include pembrolizumab (table 7), nivolumab (table 8), or the combination of nivolumab plus ipilimumab. (See 'Microsatellite unstable/deficient mismatch repair tumors' above.)

TRK fusions – For patients who have tropomyosin receptor kinase (TRK) fusion-positive mCRC progressing after initial therapy, we suggest a TRK inhibitor (larotrectinib or entrectinib) rather than other therapy (Grade 2C). (See 'TRK fusion-positive tumors' above.)

RAS wild-type, HER2-overexpressing tumors – For patients with RAS wild-type, HER2-overexpressing mCRC who progress on fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, we suggest trastuzumab plus tucatinib rather than other trastuzumab-based therapies (Grade 2C). For patients without access to trastuzumab plus tucatinib, alternative options include trastuzumab plus lapatinib or trastuzumab plus pertuzumab. (See 'RAS wild-type, HER2 overexpressors' above.)

We reserve fam-trastuzumab deruxtecan as a later-line option for patients who previously received trastuzumab-based therapy as well as two or more chemotherapy regimens.

RAS wild-type, BRAF-mutated tumors – For most patients with RAS wild-type but BRAF V600E mutant mCRC, we suggest cetuximab plus encorafenib, rather than cetuximab plus irinotecan (Grade 2B) or a triplet regimen targeting BRAF, the epidermal growth factor receptor (EGFR), and MEK (Grade 2C). (See 'RAS wild-type, BRAF mutated tumors' above.)

RAS-mutated tumors, without another actionable target – For patients with RAS-mutated mCRC who progress on fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and VEGF inhibitor therapy and who do not have a second actionable genetic alteration, we encourage enrollment in clinical trials, where available.

For such patients with KRAS G12C mutant mCRC who decline or do not have access to clinical trials, we suggest either sotorasib plus panitumumab or adagrasib plus cetuximab rather than single-agent treatment or other systemic agents (Grade 2C). For patients who are unable to tolerate the combination due to toxicity from the EGFR inhibitor, single-agent sotarasib or adagrasib is a reasonable alternative. (See 'RAS-mutated tumors' above.)

No molecular marker (RAS/BRAF wild-type) or progression on targeted therapy

Prior doublet oxaliplatin-based chemotherapy – For fit patients initially treated with an oxaliplatin-containing chemotherapy doublet (ie, FOLFOX or CAPOX/XELOX), we switch to FOLFIRI (table 9) or irinotecan alone at the time of disease progression. For patients initially treated with FOLFIRI, we switch to an oxaliplatin-based regimen. (See 'The cytotoxic chemotherapy backbone' above.)

Prior FOLFOXIRI – For patients previously treated with FOLFOXIRI, choice depends on the reason for discontinuation and prior exposure to EGFR inhibitors and antiangiogenic agents.

-For patients who discontinued FOLFOXIRI because of disease progression, options include an EGFR inhibitor (either cetuximab or panitumumab) alone (table 10A-B) or in combination with irinotecan (table 4).

-For patients who discontinued FOLFOXIRI for reasons other than disease progression and have not received an EGFR inhibitor, options include an EGFR inhibitor plus irinotecan, FOLFIRI, or FOLFOX, or reintroduction of FOLFOXIRI (table 3). If an antiangiogenic agent was not used first-line, then bevacizumab plus either FOLFOX (table 11) or FOLFIRI (table 12) or FOLFOXIRI (table 13) are additional options.

Addition of antiangiogenic or EGFR inhibitor – Second-line fluoropyrimidine-based chemotherapy may be combined with antiangiogenic agents or EGFR inhibitors, but not both. (See 'Dual antibody therapy' above.)

Prior bevacizumab – For patients initially treated with bevacizumab plus cytotoxic chemotherapy, we suggest the continuation of an antiangiogenic agent in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen, as tolerated (Grade 2B). For most patients we suggest bevacizumab rather than aflibercept (Grade 2C). (See 'Patients initially treated with bevacizumab' above.)

No prior cetuximab or panitumumab – Cetuximab or panitumumab may be used for second-line therapy if neither was administered first-line, although use of these agents for second-line therapy of right sided tumors is controversial. (See 'No prior initial therapy with cetuximab/panitumumab' above.)

-If rapid tumor growth was observed following bevacizumab plus FOLFOX, the combination of cetuximab (or panitumumab) plus irinotecan-based therapy is a reasonable alternative to monotherapy with either agent, as the disease tempo might not allow for a stepwise, sequential approach. For an indolent, slowly progressive tumor, sequential use of agents (irinotecan first, followed by irinotecan plus cetuximab [or panitumumab]) might be preferable.

Prior cetuximab or panitumumab – For patients with RAS and BRAF wild-type mCRC who progress on initial therapy with chemotherapy plus an EGFR inhibitor (ie, cetuximab or panitumumab) and have no other actionable molecular alterations, our approach to second-line therapy is as follows:

-For those who previously received FOLFOX plus an EGFR inhibitor, we suggest FOLFIRI plus bevacizumab or irinotecan plus bevacizumab rather than other systemic agents (Grade 2C). (See 'Prior initial therapy with cetuximab or panitumumab' above.)

-For those who previously received FOLFIRI plus an EGFR inhibitor, we suggest FOLFOX plus bevacizumab or CAPOX plus bevacizumab rather than other systemic agents (Grade 2C).

-For those who are not candidates for bevacizumab, chemotherapy alone is an acceptable alternative.

Patients unable to tolerate intensive therapy – For patients not able to tolerate intensive therapy, treatment with sequential single chemotherapy agents, single targeted agents, or the combination of capecitabine plus bevacizumab are all reasonable approaches. Supportive care alone is also an option. (See 'Patients not eligible for intensive therapy' above.)

Subsequent therapy – For patients who have been exposed to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and (if RAS and BRAF wild-type) an EGFR inhibitor, options include trifluridine-tipiracil with or without bevacizumab, regorafenib, or fruquintinib. (See 'Subsequent therapy' above.)

Re-challenge with previously used classes of agents – For patients with mCRC who progress on all available systemic agents, we offer enrollment in clinical trials, where available. For patients who are ineligible for or do not have access to clinical trials, one option is re-challenging with a regimen initially used in the treatment sequence. Options include FOLFOX, CAPOX, or regimens that include an EGFR inhibitor (cetuximab or panitumumab) for those with RAS wild-type disease. (See 'Re-challenge with previously used classes of agents' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Axel Grothey, MD, who contributed to earlier versions of this topic review.

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Topic 129349 Version 38.0

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