Second- and later-line systemic therapy for metastatic colorectal cancer

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 (OS). Management is also increasingly being driven by tumor biology and gene expression analysis of individual tumors. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Predictive biomarkers'.)

The approach to second and later lines of systemic therapy for advanced unresectable and mCRC are discussed here. General principles of systemic therapy, initial systemic therapy, and other topics related to the management of mCRC are discussed separately.

●(See "General principles of systemic therapy for metastatic colorectal cancer".)

●(See "Initial systemic therapy for metastatic colorectal cancer".)

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

●(See "Management of metastatic colorectal cancer in older adults 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 used 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 deoxyribonucleic acid [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 used, in combination with cetuximab, for the 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 'TMB-H tumors' below.)

●Larotrectinib, entrectinib, and repotrectinib 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.)

●Adagrasib and sotorasib are KRAS G12C inhibitors that are used either alone or in combination with EGFR inhibitors (cetuximab, panitumumab) for KRAS G12C-mutant tumors. (See 'RAS-mutated tumors' 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 "General principles of systemic therapy for metastatic colorectal cancer", 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 TMB 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 "General principles of systemic therapy for metastatic colorectal cancer", 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 "Initial systemic therapy for metastatic colorectal cancer".)

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 "General principles of systemic therapy for metastatic colorectal cancer", 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 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

dMMR/MSI-H tumors

Selection of therapy — Most patients with mismatch repair deficient (dMMR)/high microsatellite instability (MSI-H) mCRC receive initial treatment with immune checkpoint inhibitors (ICIs). Further details on preferred initial agents and the biologic rationale for this approach are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors' and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Biologic principles'.)

Our approach to second-line therapy for dMMR/MSI-H mCRC is as follows:

●For most fit patients with dMMR/MSI-H mCRC who progress on ICIs, we suggest second-line treatment using a fluoropyrimidine-based chemotherapy regimen with or without a biologic agent rather than an alternative ICI-based regimen. This management strategy is extrapolated from data in patients with MMR-proficient (pMMR) mCRC in the initial treatment setting. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair proficient/microsatellite stable tumors'.)

●A small subset of patients may not have received immunotherapy in the initial treatment setting for various reasons. For example, such patients may have declined or lacked access to immunotherapy or may not have been aware of the tumor dMMR status. In the absence of contraindications, such patients may be offered second-line treatment with nivolumab plus ipilimumab due to the high objective response rates and durable responses of this combination. (See 'Nivolumab plus ipilimumab' below.)

Single-agent immunotherapy is an appropriate alternative for those anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab. (See 'Single-agent immunotherapy' below.)

Nivolumab plus ipilimumab — Nivolumab plus ipilimumab is an extremely effective option for the treatment of fit patients (ie, good Eastern Cooperative Oncology Group [ECOG] performance status (table 1) and minimal or well-controlled comorbidities) with relapsed/refractory mCRC with dMMR/MSI-H among who progress on initial systemic therapy and did not previously receive immunotherapy. In indirect comparisons of two different cohorts enrolled in a phase II trial (CheckMate 142), nivolumab plus ipilimumab demonstrated a higher ORR than single-agent nivolumab (65 versus 31 percent) [12,13] with more durable long-term PFS and OS benefit [12]. However, this was not a direct comparison since CheckMate 142 was not a randomized trial, and combination immunotherapy typically causes more toxicity than single-agent immunotherapy. Further randomized trials are necessary to determine the optimal selection of therapy. It is also not known whether the combination of nivolumab plus ipilimumab is active in patients who relapse or progress on single-agent immunotherapy, as data are limited for this approach.

In an open-label, multicohort phase II trial (CheckMate 142) trial, 119 patients were treated with 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) [13,14]. Most patients (76 percent) had received two or more prior systemic therapies. At a median follow-up of 51 months, the ORR was 65 percent, including a complete and partial response rate of 13 and 52 percent, respectively [13]. Median duration of response was not reached. Four-year PFS and OS were 53 and 71 percent, respectively. Results for the cohort of patients in CheckMate 142 who were treated with nivolumab monotherapy are discussed separately. (See 'Nivolumab' below.)

The grade 3 or 4 toxicity rate for nivolumab plus ipilimumab was 32 percent, including elevations in aspartate transaminase (AST; 8 percent) or alanine transaminase (ALT; 7 percent), increased lipase (5 percent), anemia, colitis diarrhea, and rash (3 percent each).

Nivolumab, as a single-agent or in combination with ipilimumab, has accelerated approval from the FDA for the treatment of patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan [15].

Single-agent immunotherapy

Pembrolizumab — Pembrolizumab is an option for second-line therapy in patients with dMMR/MSI-H mCRC who progress on initial systemic therapy and did not previously receive immunotherapy.

Based on data from initial clinical studies [16,17], pembrolizumab was evaluated in an open-label phase II trial (KEYNOTE-164) of 124 patients with dMMR/MSI-H mCRC who were previously treated with fluoropyrimidine, oxaliplatin, and/or irinotecan with or without an anti-vascular endothelial growth factor (VEGF)/epidermal growth factor receptor (EGFR) monoclonal antibody targeted therapy [18,19]. In extended follow-up (median of approximately five years), among the 63 patients who had received one or more prior systemic therapies, the overall response rate (ORR) was 35 percent and median duration of response was not reached [19]. Median progression-free survival (PFS) and overall survival (OS) were 4 and 47 months, respectively. Among the 61 patients who had received two or more prior systemic therapies, the ORR was 33 percent. The median duration of response was not reached. Median PFS and OS were 2 and 31 months, respectively. The grade 3 to 4 toxicity rate for pembrolizumab was 13 to 16 percent [18]. In a separate study of older adults with dMMR mCRC, pembrolizumab demonstrated similarly durable responses [20].

Pembrolizumab is approved by the US Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic MSI-H or dMMR CRC as determined by an FDA-approved test. The use of pembrolizumab as initial therapy in dMMR/MSI-H mCRC is discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Pembrolizumab'.)

Nivolumab — Nivolumab is an option for second-line therapy in patients with dMMR/MSI-H mCRC who progress on initial systemic therapy and did not previously receive immunotherapy.

In an open-label multicohort phase II trial (CheckMate 142), nivolumab monotherapy was evaluated in a cohort of 74 patients with recurrent or metastatic dMMR/MSI-H CRC who progressed or were intolerant of at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan [21]. At a median follow-up of 12 months, the ORR for single-agent nivolumab was 31 percent, and the median duration of response was not reached. Eight patients had durable responses lasting 12 months or longer. In preliminary results, four-year PFS and OS for nivolumab monotherapy were 36 and 49 percent, respectively [12]. The grade 3 to 4 toxicity rate for nivolumab was 20 percent [21]. Results for the cohort of patients in CheckMate 142 who were treated with nivolumab plus ipilimumab are discussed separately. (See 'Nivolumab plus ipilimumab' above.)

Nivolumab, as a single-agent or in combination with ipilimumab, has accelerated approval from the FDA for the treatment of patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan [15].

Dostarlimab — Dostarlimab is an option for the treatment of relapsed/refractory mCRC with dMMR/MSI-H who progress on initial systemic therapy and did not previously receive immunotherapy.

Dostarlimab was evaluated in an open-label phase I trial (GARNET) of 347 patients with advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors who had received at least one prior line of therapy [22]. At a median follow-up of approximately 30 months, among the subset of 115 patients with dMMR/MSI-H or POLE-altered mCRC (105 of whom had dMMR/MSI-H mCRC), the ORR was 44 percent. Median duration of response was not reached. Median PFS and OS were eight months and not reached, respectively. The safety profile of dostarlimab was similar to other programmed death receptor 1 (PD-1) inhibitors with a grade ≥3 toxicity rate of 16 percent.

Results of the GARNET trial for the entire study population are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Dostarlimab'.)

Other agents

●Avelumab – Avelumab has also been evaluated in treatment-refractory dMMR/MSI-H CRC [23,24], but the use of this agent remains investigational.

TMB-H tumors — Patients with mCRC and high tumor mutational burden (TMB-H) who have progressed on all available systemic therapies and have not received prior immunotherapy may be treated with immune checkpoint inhibitors, such as pembrolizumab. In a phase II trial (KEYNOTE-158) of over 1000 patients with previously treated, advanced unresectable or metastatic solid tumors of various histologies, pembrolizumab was associated with higher objective response rates among those with TMB-H tumors (≥10 mutations per megabase) relative to those with TMB-low tumors [25]. However, this trial did not include any patients with mCRC. Further details on this trial are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Pembrolizumab'.)

Among patients with pMMR mCRC, the frequency of TMB-H levels is approximately 5 percent [26,27]. TMB-H tumors can also be either dMMR/MSI-H or pMMR/microsatellite stable (MSS), which also influences the approach to second- and later-line therapy. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Biologic principles'.)

For patients with TMB-H mCRC, other concurrent molecular alterations may influence the approach to second- and later-line therapy.

●TMB-H and dMMR/MSI-H tumors – For patients with TMB-H and dMMR/MSI-H mCRC who progress on initial systemic therapy, the approach to second-line therapy is discussed separately. (See 'dMMR/MSI-H tumors' above.)

●TMB-H, pMMR/MSS, and POLE or POLD1-negative tumors – Although there is debate, we do not routinely offer immunotherapy as second- or later-line therapy to patients with mCRC that express high levels of TMB-H, are MSS/pMMR, and lack a functional polymerase epsilon (POLE) or polymerase delta1 (POLD1) mutation. Studies suggest that the efficacy of pembrolizumab is limited in this specific population despite this agent having a tissue-agnostic approval from the FDA for patients with unresectable or metastatic solid tumors that are TMB-H, have progressed following prior treatment, and who have no satisfactory alternative treatment option [15]. As examples:

•In a phase II basket study (TAPUR), the ORR for pembrolizumab was limited in the patients with TMB-H mCRC (11 percent, 3 of 28 patients), most of whom had pMMR/MSS disease [28]. A partial response was seen in one patient with mCRC that was both TMB-H and had a POLE mutation.

•In a retrospective analysis, pembrolizumab was evaluated in 137 patients with advanced CRC [29]. An OS benefit for pembrolizumab was limited to patients with TMB-H tumors (≥10 mutations per megabase) and either dMMR or POLE or POLD1 pathogenic variants [29]. In patients with TMB-H mCRC who were pMMR and lacked a POLE or POLD1 mutation, OS was similar to that of patients with TMB-low mCRC (<10 mutations per megabase).

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 [30]. BRAF mutations are associated with resistance to agents that target EGFR, even in the presence of wild-type RAS. (See "General principles of systemic therapy for metastatic colorectal cancer", 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 [31]. Others report higher objective response (30 percent) and overall disease control rates (52 percent) with the combination of cobimetinib plus vemurafenib [32]. 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 [15]. 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 [33,34]. 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 [35-40].

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 [38]. 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 [40]. 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 [41], 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 approved by the FDA for the treatment of adults with mCRC with a BRAF V600E mutation, after prior therapy [15].

Of importance, a significant percentage of BRAF V600E mutant CRC (15 to 25 percent [42-44]) 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 'dMMR/MSI-H tumors' above and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genotype phenotype correlation'.)

RAS wild-type, HER2 overexpressors

Selection of therapy — For patients with RAS wild-type, human epidermal growth factor receptor 2 (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 "General principles of systemic therapy for metastatic colorectal cancer", 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 [45,46]. Harmonized recommendations for diagnostic criteria for HER2-amplified mCRC have been proposed [47]. Although circulating tumor DNA (ctDNA), which is DNA that is released from tumor cells into the bloodstream, has been used to identify patients for a trial of HER2-directed therapy [48], there are differences seen in HER2 expression in a subset of patients, likely due to a number of factors including tumor heterogeneity and the timing of when the two tests (the ctDNA as compared with tissue analysis) are performed [49]. Evaluating HER2 expression via tissue analysis remains the standard of care, although this is an area of active study that continues to evolve. 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 [50]. 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 ORR for the combination was 38 percent [50]. 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 "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Lapatinib, neratinib, and tucatinib' and "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", 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 mCRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy [15].

Trastuzumab plus lapatinib — Trastuzumab 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 [51]. 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 [52]. (See "Brain metastases in breast cancer", section on 'Risk factors for central nervous system metastases'.)

Trastuzumab plus pertuzumab — Trastuzumab plus pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular HER2 dimerization domain and interferes with downstream HER2 signaling pathways. Data for trastuzumab plus pertuzumab are as follows:

●In a randomized phase II trial of 54 patients with metastatic RAS and BRAF wild-type HER2-positive mCRC who progressed on one or two lines of prior systemic therapy, trastuzumab plus pertuzumab demonstrated similar PFS relative to cetuximab plus irinotecan (median PFS five versus four months) [53]. OS was higher with trastuzumab plus pertuzumab relative to chemotherapy (two-year OS 67 and 57 months), but the difference was not statistically significant. ORRs were 35 versus 28 percent, respectively.

●Trastuzumab plus pertuzumab was evaluated in a phase II basket study (MyPathway) for patients with HER2-overexpressing/amplified tumors other than breast cancer [54,55]. Among the 69 patients with KRAS wild-type and HER2-overexpressing mCRC, objective responses were seen in 22 patients (32 percent) [55]. This combination demonstrated a slightly lower response rate in a separate phase II basket trial from the Targeted Agent and Profiling Utilization Registry (TAPUR) [56]. 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 deruxtecan — Fam-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 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 [57,58]. In 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 [57]. At a median follow-up of 10 months, relative to the higher dose (6.4 mg/kg), the lower dose (5.4 mg/kg) demonstrated similar PFS for all patients (median 5.8 versus 5.5 months) and objective response rate for those with prior HER2-targeted therapy (41 versus 40 percent). However, the lower dose had a more favorable toxicity profile (grade ≥3 toxicity rate 41 versus 49 percent), including a lower rate of drug-related interstitial lung disease (8 versus 13 percent). (See "Overview of the management of adults with interstitial lung disease".)

The efficacy of fam-trastuzumab deruxtecan in pretreated HER2-positive mCRC has been demonstrated in multiple phase II studies, including DESTINY-PanTumor01 [59], DESTINY-CRC02 [60], DESTINY-CRC01 [61,62], and HERALD [58]. As examples:

●In an open-label phase II trial (DESTINY-CRC01), 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 [61,62]. Approximately one-third of the patients had received prior HER2-targeted therapies. At a 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 [62]. 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.

●Similar results with fam-trastuzumab (administered at 5.4 mg/kg intravenously every three weeks) were seen in another single-arm phase II basket trial (HERALD) of 62 patients with metastatic treatment-refractory tumors of various histologies identified as HER2-positive using cell-free DNA (cfDNA). [58]. This study did not require immunohistochemistry to confirm HER2 expression on tumor tissue samples. In the entire study population, the ORR for fam-trastuzumab deruxtecan was 56 percent. Among the 10 patients with mCRC, objective responses were seen in five patients (50 percent). Of note, cfDNA, which is DNA circulating in the bloodstream that is obtained from both normal and cancer cells, is different from ctDNA, which is DNA circulating in the bloodstream that is only obtained from cancer cells. Further studies are necessary prior to the routine use of cfDNA, to detect HER2-positive tumors in mCRC. Guidance on other methods to identify tumoral HER2-expression, including ctDNA, is provided separately. (See 'Selection of therapy' above.)

Fam-trastuzumab deruxtecan has accelerated approval from the FDA for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options [15].

RAS mutant, HER2 overexpressors — There are limited data for the management of patients with mCRC whose tumors are RAS mutated and human epidermal growth factor receptor 2 (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 [54,63]. 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 [60]. (See 'RAS-mutated tumors' below.)

RAS-mutated tumors

Selection of therapy — 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 sotorasib 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 [64,65]. Treatment-related resistance rapidly develops in these tumors, and studies suggest that the primary resistance mechanism is increased EGFR signaling [66,67]. Further details on mechanisms of disease resistance in RAS-mutated CRC are discussed separately. (See "Molecular genetics of colorectal cancer", section on 'RAS' and "General principles of systemic therapy for metastatic colorectal cancer", 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) [68].

In early phase clinical trials, sotorasib was initially evaluated as a single-agent (CodeBreaK100) [69,70] and in combination with panitumumab (CodeBreaK 101) [71]. These data led to the evaluation of sotorasib plus panitumumab in an open-label phase III trial (CodeBreaK 300) [68]. 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 sotorasib 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-tipiracil 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).

Based on these data, the FDA approved sotorasib, in combination with panitumumab, for the treatment of adult patients with KRAS G12C-mutated mCRC, as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based therapy [15]. Panitumumab is not indicated for the treatment of RAS-mutant mCRC unless used in combination with sotorasib for KRAS G12C-mutated mCRC, or for patients with mCRC for whom the RAS mutation status is unknown.

Adagrasib plus cetuximab — Adagrasib 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), 94 patients with previously treated mCRC harboring a KRAS G12C mutation were treated with adagrasib in combination with cetuximab, and 42 patients were treated with adagrasib monotherapy [72,73].

●Adagrasib plus cetuximab – At median follow-up of 12 months, the ORR for adagrasib plus cetuximab was 34 percent. Median PFS and OS were 7 and 16 months, respectively [73]. The grade 3 to 4 toxicity rate for the combination was 28 percent, including nausea (2 percent), headache (3 percent), hypomagnesemia, dermatitis acneiform, and rash (2 percent each), and fatigue and diarrhea (1 percent each).

●Adagrasib monotherapy – At median follow-up of 16 months, the ORR for adagrasib monotherapy was 21 percent [73]. Median PFS and OS were 4 and 12 months, respectively. The grade 3 to 4 toxicity rate for adagrasib monotherapy was 31 percent, including nausea (7 percent), diarrhea and fatigue (5 percent each), and vomiting (2 percent).

Adagrasib in combination with cetuximab has accelerated approval from the FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or mCRC who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based therapy [15]. Further randomized trials are necessary to confirm these findings.

Other agents

●Divarasib – The use of divarasib, a covalent KRAS G12C inhibitor, alone or in combination with an EGFR inhibitor 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 [74]. 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). In another phase I trial of 29 patients with advanced recurrent or metastatic KRAS G12C-positive mCRC treated with divarasib plus cetuximab, the ORR was 63 percent and the median PFS was eight months [75].

●Onvansertib – The use of onvansertib, a polo-like kinase 1 (PLK1) inhibitor in combination with chemotherapy remains investigational in mCRC. In an open-label, single-arm phase II trial, 53 patients with KRAS-mutant mCRC who previously received fluorouracil and oxaliplatin with or without bevacizumab were treated with onvansertib plus FOLFIRI and bevacizumab. ORR for this combination was 26 percent [76]. Relative to those previously treated with bevacizumab, patients who were naïve to bevacizumab demonstrated higher ORR (77 versus 10 percent) and longer PFS with this combination (15 versus 7 months), suggesting that prior bevacizumab exposure may contribute to onvansertib resistance.

RET fusion-positive tumors

Selpercatinib — 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 [77]. In the entire cohort, the objective response rate was 44 percent and median duration of response was 24.5 months; two of the 10 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.

Selpercatinib has a tissue-agnostic, accelerated approval from the FDA in 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 [78-80].

TRK fusion-positive tumors

Selection of therapy — For patients with a tropomyosin receptor kinase (TRK) fusion-positive mCRC who progress on initial systemic therapy, we suggest second-line treatment with a TRK inhibitor rather than other systemic agents due to the high response rates and durable disease control seen with these agents. Options include larotrectinib, entrectinib, or repotrectinib. (See 'Larotrectinib and entrectinib' below and 'Repotrectinib' below.)

For patients who progress on either larotrectinib or entrectinib, we prefer to resume standard systemic therapy. (See 'Not eligible for or progressing during targeted therapy' below.)

Repotrectinib is also an option that is effective in patients with prior TRK inhibitor therapy, including those with acquired TRK resistance mutations, but data are limited for this approach. (See 'Repotrectinib' below.)

Neurotrophic tyrosine kinase receptor (NTRK) gene fusions occur at a low frequency in patients with mCRC (0.5 to 1 percent). For the rare patient with NTRK gene fusion-positive mCRC, TRK inhibitors provide durable treatment responses. The prevalence of NTRK gene fusions in mCRC and other solid tumors is discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Prevalence'.)

Larotrectinib and entrectinib — In phase I/II trials, among patients with NTRK-fusion positive mCRC, larotrectinib and entrectinib demonstrated high ORRs (50 and 20 percent, respectively) that were durable (median duration of response of 4 and 18 months, respectively), regardless of prior therapy [81-83]. Further details on the efficacy of these agents are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor activity'.)

Larotrectinib and entrectinib are both approved by the FDA for the treatment of patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, who are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy [15].

Repotrectinib — Repotrectinib was evaluated in a single-arm, open-label, multicohort phase I/II trial (TRIDENT-1) of 98 patients with NTRK fusion-positive tumors of various histologies. In preliminary results, among 40 patients with TRK inhibitor naïve disease, the ORR for repotrectinib was 58 percent, and the median duration of response was not reached [15]. Among the 48 patients who previously received a TRK inhibitor, the ORR was 50 percent, and the median duration of response was 10 months. Among the 25 patients with prior TRK inhibitor therapy who also had a TRK resistance mutation, the ORR was 60 percent. Among the three patients with CRC, one demonstrated a partial response and two demonstrated stable disease; the median duration of response was 18 months.

Repotrectinib has accelerated approval from the FDA for the treatment of patients with solid tumors that have a NTRK gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy [15]. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor activity'.)

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 [10,84]. Nevertheless, most American oncologists initiate chemotherapy for mCRC with FOLFOX or CAPOX/XELOX, using irinotecan alone [85] 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 [86-88].

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 [89] 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 [90].

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) [86]. 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 [91,92]:

-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) [92]. 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 [91,92].

•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 [93]. 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, except for 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 [94]. 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 [95,96]. 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 "Initial systemic therapy for metastatic colorectal cancer", 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 [97-100]. 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 [98].

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 [101]. 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 "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation".)

●Raltitrexed – Raltitrexed (Tomudex), a folate analog, is a pure thymidylate synthase inhibitor [102]. It is not more active than FU and is not approved in the United States [103-105]. 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 [103].

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 [106-109]. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation".)

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 VEGF and EGFR inhibitors' 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 [110], in a preliminary report from the ARIES observational cohort study [111], and from a retrospective analysis of 573 patients treated with and without second-line bevacizumab from community-based United States Oncology practices [112].

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) [113]. 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 [114]. 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 [115]. 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. However, 20 percent of patients had right-sided tumors, which complicates interpretation of these results given the lower anticipated effect of cetuximab in patients with right-sided CRC. Although the results favor continuation of bevacizumab with an alternative chemotherapy backbone in patients who progress with first-line bevacizumab plus chemotherapy, definitive conclusions cannot be drawn from this study.

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 [116].

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 [117]. 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 [118].

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 [119], 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 [120]. 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 [121], 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 [122-124]. 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 "General principles of systemic therapy for metastatic colorectal cancer", 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 [125] 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 [122]. 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 [126,127].

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) [123]. 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 [128]. 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) [129].

●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 [130].

•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 [131]. 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) [132] 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 [41,133]. (See "Initial systemic therapy for metastatic colorectal cancer", 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 [115]. 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 "Initial systemic therapy for metastatic colorectal cancer", 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 [122,123,134-136], 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) [137]. 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 monoclonal antibodies 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 [138], and results from a nonrandomized phase II trial [139] and a multicenter retrospective analysis [140] 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)) [15].

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 [41,133]. (See "Infusion-related reactions to monoclonal antibodies for cancer therapy", section on 'Cetuximab' and "Initial systemic therapy for metastatic colorectal cancer", 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 "Initial systemic therapy for metastatic colorectal cancer", 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 "Initial systemic therapy for metastatic colorectal cancer", section on 'Efficacy and toxicity of bevacizumab and biosimilars' and "Initial systemic therapy for metastatic colorectal cancer", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

By contrast, randomized trials have established PFS but not OS benefit for EGFR inhibitor re-challenge in second-line therapy for RAS wild-type mCRC [141]. 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 [142], decay over time once the EGFR inhibitor is discontinued for approximately four months or longer [143]. This results in reemergence of tumor sensitivity to EGFR blockade [144,145].

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 [141]. 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 [146-151], but this approach remains investigational.

Treatments not used

Switching EGFR inhibitors — For patients with KRAS/BRAF wild-type mCRC who progress on regimens that contain cetuximab, we do not offer second- or later-line therapy with regimens that contain panitumumab, and vice-versa, as data suggest that this approach offers minimal clinical benefit [152,153].

Dual VEGF and EGFR inhibitors — For patients with RAS/BRAF wild-type mCRC, we do not offer second- or later-line treatment with dual antibody therapy (simultaneously targeting both the vascular endothelial growth factor [VEGF] and epidermal growth factor receptor [EGFR] pathways) in combination with chemotherapy. A randomized phase II trial (BOND-2) in patients with treatment-refractory mCRC initially suggested that adding bevacizumab to cetuximab plus irinotecan improved OS and was well-tolerated [154]. However, in a subsequent randomized phase II trial of patients with treatment-refractory mCRC, the addition of ramucirumab to cetuximab plus irinotecan did not confer an OS benefit and was more toxic [155]. This approach is also not used as initial therapy in mCRC. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Dual antibody therapy'.)

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 [156].

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 [157] 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 [158], 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 [159]. 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 overall survival (OS; median OS 11 versus 8 months, one-year OS 43 versus 30 percent, HR 0.61, 95% CI 0.49-0.77) and progression-free survival (PFS; median PFS 6 versus 2 months, one-year PFS HR 0.44, 95% CI 0.36-0.54) [159]. 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 biologic therapy, and if RAS wild-type, an anti-EGFR therapy [15].

●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 [160].

This clinical benefit was subsequently confirmed in two subsequent placebo-controlled phase III trials (the RECOURSE and TERRA trials) [161,162]. 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 [161]. 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 [163]. 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 biologic therapy, and, if RAS wild-type, an anti-EGFR therapy [15]. 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 [164]. 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 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 [165]. 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) [166]. 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 [167,168].

●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 [168]. 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 a 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). Relative to placebo, fruquintinib delayed time to deterioration of performance status and did not worsen health-related quality of life [169].

●Similar OS benefits were seen for fruquintinib in a separate randomized, double-blind, placebo-controlled phase III trial conducted in China (FRESCO) [167]. 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 [15]. 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 [170,171].

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 [172]. 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 [173,174].

●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 [146]. 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) [175]. (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 of metastatic 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 5^th to 6^th 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 10^th to 12^th 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: Treatment of metastatic colorectal 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 – Most patients with mismatch repair deficient (dMMR)/high microsatellite instability (MSI-H) mCRC receive initial treatment with immune checkpoint inhibitors (ICIs). Further details are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors'.)

•For most fit patients (ie, good Eastern Cooperative Oncology Group [ECOG] performance status (table 1) and minimal or well-controlled comorbidities) who progress on ICIs, we suggest second-line treatment using a fluoropyrimidine-based chemotherapy regimen with or without a biologic agent rather than an alternative ICI-based regimen (Grade 2C). This management strategy is extrapolated from data on MMR-proficient (pMMR) mCRC in the initial treatment setting. (See 'dMMR/MSI-H tumors' above and "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair proficient/microsatellite stable tumors'.)

•A small subset of patients may not have received immunotherapy in the initial treatment setting for various reasons. In the absence of contraindications, such patients may be offered second-line treatment with nivolumab plus ipilimumab. Single-agent immunotherapy (eg, pembrolizumab, nivolumab, or dostarlimab) is appropriate for those anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab. (See 'Nivolumab plus ipilimumab' above and 'Single-agent immunotherapy' above.)

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

•For those who progress on either larotrectinib or entrectinib, we resume standard systemic therapy as next-line therapy. (See 'Not eligible for or progressing during targeted therapy' above.)

Repotrectinib is also an option which is effective in patients with prior TRK inhibitor therapy, including those with acquired TRK resistance mutations, but data are limited for this approach. (See 'Repotrectinib' above.)

●RAS wild-type, HER2-overexpressing tumors – For patients with RAS wild-type, human epidermal growth factor receptor 2 (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 sotorasib 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 6) 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 7A-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 8) or FOLFIRI (table 9) or FOLFOXIRI (table 10) 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 VEGF and EGFR inhibitors' 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.