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

INTRODUCTION — The last 20 years have seen major advances in the treatment of metastatic colorectal cancer (mCRC). These improvements have been mainly driven by the availability of new active agents against mCRC. The best way to combine and sequence all of these agents is continuing to evolve. Increasingly, enhanced knowledge about tumor biology is driving therapeutic decision-making. Known biologic drugs that are active against mCRC include agents targeting vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), the epidermal growth factor receptor (EGFR), BRAF V600E, human epidermal growth factor receptor 2 (HER2), immunotherapy using immune checkpoint inhibitors, and tropomyosin receptor kinase (TRK) inhibitors. Biomarkers have been defined for patients who are candidates for agents targeting EGFR, HER2, TRK fusions, and for immunotherapy, but are not yet defined for other agents. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Diagnosis' and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

This topic review will address the approach to later lines of systemic therapy after failure of initial systemic chemotherapy for inoperable mCRC. General principles of systemic chemotherapy, selection of the initial therapeutic approach, recommendations for systemic chemotherapy in older adult patients with mCRC, the integration of chemotherapy with surgery for patients with potentially resectable liver metastases, and a compilation of chemotherapy regimens used for mCRC are discussed elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status" and "Treatment protocols for small and large bowel cancer".)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The FDA has approved two gene panel tests (MSK-IMPACT and F1CDx) for analyzing pathogenic changes in solid tumors; these tests can be used on formalin-fixed, paraffin-embedded (FFPE) tissue regardless of the primary organ from which the tumor arose [2-4]. These tests detect variations in the coding regions of over 400 and over 300 genes, respectively, and can 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'.)

While tumor tissue remains the "gold standard" for genetic analysis in cancer patients, circulating tumor DNA (ctDNA) can be detected and quantified in the blood of cancer patients and used for detection of tumor-specific genetic alterations, including RAS mutations [1]. One advantage of "liquid biopsy" is the potential for reducing data turnaround time. However, only a limited number of cases have been studied, and all of the analyses are retrospective. Thus, in our view, additional data are needed before treatment decisions in mCRC can be made based upon ctDNA. A year 2018 joint review by ASCO and the College of American Pathologists (CAP) concluded that the evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and it supports tumor tissue genotyping to confirm results from ctDNA tests [5]. However, the year 2022 ASCO provisional clinical opinion discussed above stated that for patients without tissue-based genomic test results, treatment may be based on actionable alterations identified in ctDNA [1]. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Tissue versus liquid biopsy'.)

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

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

For patients with mCRC, the model of distinct "lines" of chemotherapy (in which regimens containing non-cross-resistant drugs are each used in succession until disease progression) has been largely abandoned in favor of a "continuum of care" approach [6]. This approach emphasizes an individualized treatment strategy that might include phases of "maintenance" or lower intensity chemotherapy interspersed with more aggressive treatment protocols, rechallenging patients who initially responded to first-line treatment with the same agents after a period of alternative treatments [7-10], treatment-free intervals, as well as reutilization of previously administered chemotherapy agents in combination with other active drugs.

An important principle is that exposure to all active drugs during the course of treatment for mCRC, as appropriate, is more important than the specific sequence of drug administration in order to maximize overall survival. The proportion of patients receiving all active agents was correlated strongly with median survival in all large published phase III trials conducted in the 1990s and early 2000s [6,11,12].

OPTIONS FOR TREATMENT AT PROGRESSION

Eligible for molecularly targeted therapy

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

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

●Another option is the combination of nivolumab plus ipilimumab, a monoclonal antibody directed against a different immune checkpoint, cytotoxic T lymphocyte antigen 4 (CTLA-4). Although there are no randomized trials directly comparing dual therapy with monotherapy with either nivolumab or pembrolizumab alone, indirect comparisons from the multicohort phase II CheckMate 142 trial suggest that combined immunotherapy provides improved efficacy over anti-PD-1 monotherapy and has a favorable risk-benefit ratio. Updated analyses with long-term follow-up of the two second-line cohorts reported four-year progression-free survival (PFS) of 52 percent in the combination nivolumab-ipilimumab arm and 36 percent with single-agent nivolumab [13]. The combination has received FDA approval in the United States for patients with MSI-H or dMMR mCRC that has progressed despite other treatments. It is currently not known in which patients with MSI-H mCRC to use combined nivolumab plus ipilimumab, or whether this combination is active in patients who relapse or progress on single-agent checkpoint inhibitor immunotherapy.

Approximately 3.5 to 6.5 percent of stage IV CRCs have dMMR [14-16]. The characteristic genetic signature of dMMR tumors is a high number of DNA replication errors (RER+) and MSI-H. Tumors that lack the mismatch repair (MMR) mechanism harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such MMR defects, and the mutations are also of greater immunogenicity. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Biology of mismatch repair and tumor mutational burden'.)

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

Notably, however, only approximately one-half of dMMR tumors respond to immune checkpoint inhibitor immunotherapy, and other predictive biomarkers are under study for their influence of responsiveness [17].

Available data in mCRC

●Anti PD-1 monotherapy

•In an early phase II study, pembrolizumab, an immunoglobulin G4 (IgG4) monoclonal antagonist antibody to PD-1, was administered intravenously at a dose of 10 mg/kg every 14 days to 11 patients with dMMR mCRC, 21 patients with MMR-proficient (pMMR) mCRC, and 9 patients with noncolorectal dMMR metastatic cancers; all had been heavily pretreated [18].

In the latest analysis of an expanded cohort of 54 patients with dMMR or pMMR mCRC, presented at the 2016 meeting of the American Society of Clinical Oncology (ASCO; and still unpublished as of March 2022), patients with dMMR mCRC had a 50 percent ORR and a 89 percent disease control rate (DCR; objective response or stable disease) [19,20]. By contrast, the ORR was 0 percent and DCR was 16 percent in the patients with pMMR mCRC. After a median treatment duration of 5.9 months, no patients in the dMMR group who responded had progressed. Overall survival (OS) and PFS were not reached in the dMMR group versus a median PFS of 2.3 months and an OS of 7.6 months in the pMMR group. Interestingly, patients with germline MMR mutations (Lynch syndrome) were less likely to respond than were those with other forms of MMR deficiency (ORR 27 versus 100 percent) [18].

Largely based upon these data, on May 23, 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of patients with advanced MSI-H or dMMR mCRC that has progressed following conventional chemotherapy [21]. The approval of pembrolizumab also extended to a variety of advanced solid tumors other than CRC that were MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options, thus representing the first such "tissue-agnostic" anticancer drug approval. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Clinical efficacy of anti-PD-1 therapy'.)

High levels of antitumor efficacy for pembrolizumab have now been confirmed in other cohorts and in a multicenter phase II trial of patients with previously treated dMMR mCRC [22,23].

•Benefit for nivolumab, a second anti-PD-1 monoclonal antibody, was shown in a second trial, CheckMate 142, in which patients with refractory dMMR (n = 59) or pMMR (n = 23) mCRC received nivolumab (a fully human anti-PD-L1 monoclonal antibody) with or without ipilimumab, a monoclonal antibody directed against CTLA-4 [24]. In a preliminary report presented at the 2016 annual ASCO meeting that has not been subsequently published, there were no objective responses among those with pMMR tumors and the median PFS was 1.4 months.

In an analysis of the 74 patients with dMMR mCRC treated with nivolumab alone (3 mg/kg every two weeks), at a median follow-up of 12 months, 23 had an objective response (31 percent), and the median duration of response had not been reached. Eight had responses lasting 12 months or longer [25]. Responses were observed regardless of tumor PD-L1 expression level, or BRAF or KRAS mutation status. The most common grade 3 or 4 drug-related adverse events were increased levels of lipase and amylase. In the most recent analysis with long-term follow-up of this cohort, four-year PFS was 36 percent with single-agent nivolumab [26].

Largely based upon these data, in August 2017, the FDA extended the approval of nivolumab to MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan [27].

Patients who experience disease progression on either of these drugs should not be offered the other. However, an important point is that individuals treated with immune checkpoint inhibitors for dMMR/MSI-H mCRC can have pseudoprogression within the first several months of therapy [28], and response criteria specifically geared toward these drugs (eg, immune-modified response evaluation criteria in solid tumors (table 1)) should be used. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

●Combined immunotherapy – Combined immunotherapy targeting two different immune checkpoints was addressed in cohorts from the CheckMate 142 trial that were treated with combined nivolumab plus ipilimumab (four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks, followed by nivolumab alone 3 mg/kg every two weeks) [29]. (See "Principles of cancer immunotherapy", section on 'The "immune synapse"'.)

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

The latest analysis of long-term outcomes from the cohort receiving combined therapy with nivolumab plus ipilimumab (median follow-up 50.9 months) revealed an objective response rate that had risen to 65 percent, with a 13 percent complete response rate, and median duration of response had still not been reached (range 1.4+ to 58+ months) [30]. Four-year PFS and OS rates were 53 and 71 percent, respectively. Four year PFS with nivolumab alone in this trial was 36 percent [26].

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

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

An important point is that MSI-H or dMMR may indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers, including CRC. Given that Lynch syndrome is more prevalent than previously thought, all patients with an MSI-H/dMMR solid tumor should undergo germline genetic assessment for Lynch syndrome, regardless of family history [31]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)

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

Approximately 5 percent of pMMR mCRCs have high TMB levels [32,33], although this has been variably quantified. Although such tumors have lower mutational levels than do those with dMMR, TMB appears to be an independent biomarker of benefit for immune checkpoint inhibitor immunotherapy across a variety of tumor types. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumor mutational burden' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Frequency of high TMB across tumor types'.)

A correlation between high TMB and objective response to pembrolizumab monotherapy was shown in the phase II KEYNOTE-158 study, which included patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor (NET), or small cell lung cancer [34]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

Although none of the patients in this report had mCRC, largely based on this study, in June 2020, the FDA expanded the approval of pembrolizumab to include adult and pediatric patients with unresectable or metastatic solid tumors, including mCRC, that are tissue TMB-high (≥10 mut/Mb) as defined by the approved companion FoundationOne CDx assay, who have progressed following prior therapy and who have no satisfactory alternative treatment options. However, in a subsequent retrospective analysis of 137 patients treated with pembrolizumab, benefit was limited to patients with high TMB and either dMMR or pol-d pathogenic mutations. Median survival following treatment with pembrolizumab in patients with high TMB without dMMR or pol-d mutations was the same as survival in patients with CRC and low TMB [35]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

RAS wild-type, BRAF mutated tumors — For most patients with RAS wild-type but BRAF V600E mutant mCRC that has progressed after initial chemotherapy, we suggest cetuximab plus encorafenib, rather than cetuximab plus irinotecan. Based on results from the BEACON trial, for most patients, doublet therapy (ie, encorafenib plus cetuximab) is preferred over a triplet-therapy regimen targeting BRAF, the epidermal growth factor receptor (EGFR), and MEK. This recommendation is consistent with year 2022 guidelines for treatment of mCRC from ASCO [36]. BRAF mutations are associated with resistance to EGFR-targeted agents, even in the presence of wild-type RAS. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'BRAF'.)

Resistance to EGFR-targeted agents 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 [37]. Others report higher objective response (30 percent) and overall disease control rates (52 percent) with the combination of cobimetinib plus vemurafenib [38]. 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'.)

Nevertheless, in June 2022, the combination of dabrafenib and trametinib was granted a tissue-agnostic accelerated approval by the FDA for the treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumors harboring mutations in BRAF V600E (including advanced mCRC) following progression on previous treatment who have no satisfactory alternative treatment options [39]. However, notably, the two trials that were used to support the accelerated approval, the ROAR and NCI MATCH (subprotocol H) trials, specifically excluded patients with mCRC, and thus, benefits are uncertain [40,41]. There are no data to support or refute the efficacy of dabrafenib plus trametinib in a patient who has progressed on encorafenib plus cetuximab. If there are other available chemotherapy regimens or applicable trials, we favor these approaches over second line dabrafenib plus trametinib given the uncertainty of benefit in mCRC.

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

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

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

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

Of importance, a significant percentage of BRAF V600E mutant CRC (15 to 25 percent [16,51,52]) have dMMR due to a somatic mutation and these patients are strong candidates for checkpoint inhibitor immunotherapy. The presence of a BRAF V600E mutation strongly suggests that a germline Lynch syndrome mutation is not present. (See 'Microsatellite unstable/deficient mismatch repair tumors' above and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genotype phenotype correlation'.)

HER2 overexpressors — We suggest human epidermal growth factor receptor 2 (HER2)-targeted therapy for HER2-overexpressing mCRC after failure of conventional chemotherapy. Available options include trastuzumab plus lapatinib, trastuzumab plus pertuzumab, tucatinib plus trastuzumab, or, for individuals who previously received trastuzumab for HER2-positive mCRC who have progressed on two or more prior cytotoxic regimens, fam-trastuzumab deruxtecan. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'HER2-targeted agents'.)

Approximately 3 to 5 percent of CRCs have amplification of the HER2 oncogene or overexpress its protein product, HER2. Accumulating data provide proof-of-principle support for the potential benefit from HER2-targeted therapies (eg, trastuzumab plus pertuzumab or lapatinib, fam-trastuzumab deruxtecan) in these patients.

The HER2 oncogene encodes for a transmembrane glycoprotein receptor that functions as an intracellular tyrosine kinase. As with other EGFR receptors, HER2 is critical in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation, and angiogenesis.

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

The potential for benefit from HER2-targeted therapy in mCRC is illustrated by the following data:

●The efficacy of dual targeted therapy with trastuzumab (a monoclonal antibody that binds the extracellular domain of HER2) plus lapatinib (a tyrosine kinase inhibitor [TKI] against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2) in patients with KRAS exon 2 wild-type, HER2-overexpressing mCRC was evaluated in the proof-of-concept multicenter open-label phase II trial (HERACLES) [58]. Only 48 of the 914 patients with KRAS wild-type tumors (5 percent) were HER2-positive, and 27 were eligible to participate. All received intravenous trastuzumab (4 mg/kg loading dose initially followed by 2 mg/kg weekly) plus oral lapatinib (1000 mg daily) until progression. At a median follow-up of 94 weeks, there were 8 objective responders (30 percent), 1 complete, and 12 others (44 percent) had stable disease. Treatment was reasonably well tolerated, with grade 3 toxicity in only six patients (22 percent; consisting of fatigue, skin rash, or hyperbilirubinemia) and no grade 4 or 5 events.

In a later analysis, a high rate of central nervous system metastases was noted (6 of 32), mirroring the experience with HER2-targeted therapies in HER2-positive breast cancer [59]. (See "Brain metastases in breast cancer", section on 'Risk factors for central nervous system metastases'.)

●The MyPathway study (NCT02091141) evaluated the combination of trastuzumab plus pertuzumab (a recombinant humanized monoclonal antibody that targets the extracellular HER2 dimerization domain and interferes with downstream HER2 signaling pathways) for patients with HER2-overexpressing/amplified tumors other than breast cancer [60,61]. In the latest analysis, among the 84 HER2-overexpressing mCRCs, there were 22 objective antitumor responses (26 percent), but 21 of which were in patients with KRAS wild-type tumors [61].

Somewhat less impressive results for this combination were presented at the 2020 ASCO Gastrointestinal Cancers Symposium from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [62]. Among 28 heavily pretreated patients with HER2-overexpressing mCRC, there were four partial responses and 10 patients with stable disease for 16 weeks or longer (objective response rate [ORR] 14 percent, DCR 50 percent).

●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; it is approved for HER2-overexpressing gastric and esophagogastric junction adenocarcinomas after failure of first-line trastuzumab. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'HER2-positive disease and continued targeting of HER2 after progression'.)

Benefit for HER2+ mCRC was suggested in the phase II open-label DESTINY-CRC01 trial, which enrolled 78 patients with HER2-overexpressing mCRC that had progressed on two or more prior regimens (approximately 30 percent had received prior HER2-targeted therapies) [63]. In the latest analysis, presented at the 2021 ASCO annual meeting [64], at a median follow-up of 62.4 weeks the cohort with HER2 3+ IHC or 2+ IHC but positive by in situ hybridization (ISH+) disease (n = 53) had an ORR of 45 percent, including one complete and 23 partial responses; the total DCR was 83 percent. The median duration of response was 7 months, and median PFS was 6.9 months. Responses were seen regardless of prior HER2-targeted therapy. The response rate was highest among those with 3+ IHC disease (57 percent), and there was only one objective response among the 13 patients with HER2 2+ IHC disease, and none in the cohort with HER2 1+ or ISH- disease.

However, it is important to note that serious adverse reactions grade 3 or worse occurred in 61 percent of patients; the most common hematologic and gastrointestinal. There were eight patients with treatment-emergent interstitial lung disease (incidence approximately 9 percent), three of which were fatal.

●The phase II Mountaineer study evaluated the combination of trastuzumab plus the selective anti-HER2 tyrosine kinase inhibitor tucatinib in 84 patients with HER2 amplified, RAS wild-type, chemotherapy-refractory mCRC; a separate single agent tucatinib arm enrolled 30 patients who were permitted to cross over to combination therapy at progression [65]. In a preliminary report presented at the 2022 European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer, the overall response rate in the combination arm was 38 percent, with a median PFS of 8.2 months and median OS of 24.1 months. The objective response rate with single-agent tucatinib was only 3.3 percent, and PFS and OS were not reported because of the high cross-over rate.

RAS mutated tumors — Patients with a RAS mutation do not benefit from treatments targeting the epidermal growth factor receptor. The best way to manage patients with the specific RAS G12C mutation is unclear. For most, we encourage participation in a clinical trial testing new strategies.

Mutations in the RAS oncogene are present in nearly 50 percent of mCRCs, and these are dominated by mutations in KRAS codon 12; all RAS mutations are associated with lack of efficacy of agents targeting the EGFR, although whether this is true for the G12D variant is debated. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'RAS mutations'.)

The G12C variant (a glycine-to-cysteine amino acid substitution at codon 12) is present in only 3 percent of cases [66], but this represents an important subset since these patients have a poor treatment outcome with currently available agents [67,68], and irreversible inhibitors of G12C have been developed that may reverse refractoriness to anti-EGFR agents.

Sotorasib is the first targeted agent with efficacy and regulatory approval for advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RAS mutations'.)

Unfortunately, the benefit of sotorasib for KRAS G12C mutated mCRC is uncertain:

●The original phase I trial of sotorasib in advanced solid tumors with a KRAS G12C mutation included 42 patients with mCRC; overall 3 of 42 patients responded, 7.1 percent) and the disease control rate was 67 percent [69]. Among the 25 patients who received 960 mg daily (the approved dose for NSCLC0, there were three responses (12 percent) and the overall disease control rate was 80 percent.

●The subsequent phase II CodeBreak100 study of 62 patients with previously treated mCRC and a KRAS G12C mutation confirmed a low overall objective response rate with only 6 patients (9.7 percent) obtaining a partial response [70].

Treatment-related resistance rapidly develops, especially in mCRC [71], and preclinical models suggest that increased EGFR signaling is the primary resistance mechanism, providing a rationale for combining selective KRAS G12C inhibitors with anti-EGFR therapy [72]. At least two trials are exploring this strategy, one with sotorasib, and one with a related agent, adagrasib:

●The phase II CodeBreak101 study of sotorasib plus panitumumab is ongoing [73].

●The KRYSTAL-1 trial is a nonrandomized multicohort phase I/II study of adagrasib with (n = 32) or without (n = 44) cetuximab in patients with previously treated mCRC with a KRAS G12C mutation [74]. In a preliminary report. The objective response rate with adagrasib monotherapy was 19 percent and the disease control rate was 86 percent, median duration of response was 4.3 months, and median PFS 5.6 months. The corresponding values for combined therapy were objective response rate 46 percent, disease control rate 100 percent, median duration of response 7.6 months, and median PFS 6.9 months.

The combination of adagrasib plus cetuximab is being compared with conventional cytotoxic chemotherapy for second-line therapy of KRAS G12C mutated mCRC in the phase III KRYSTAL-10 trial.

RET fusion-positive tumors — Selpercatinib is an option for refractory mCRC with a rearranged during transfection (RET) gene fusion and disease progression on or following prior systemic treatment. Efficacy in 45 patients with a variety of solid tumors containing a RET fusion gene was addressed on the Libretto-001 basket trial [75]. In the entire cohort, the objective response rate was 44 percent and median duration of response was 24.5 months; two of the ten patients with advanced colon cancer had a partial response (20 percent) and the median duration of response was 9.4 months. The most common grade ≥3 treatment-emergent adverse effects were hypertension and transaminase elevation.

In September 2022, the US FDA granted a tissue-agnostic, accelerated approval of selpercatinib for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion and disease progression on or following prior systemic treatment who have no satisfactory alternative treatment options. Unfortunately, only 0.2 to 1.2 percent of advanced CRCs harbor a RET fusion [76-78].

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

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

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

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

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

Not eligible for or progressing during targeted therapy

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

The optimal sequence of oxaliplatin and irinotecan-containing chemotherapy for mCRC remains unresolved, and may differ between patients based on tumor-related heterogeneity and pharmacogenetic issues. As noted above, exposure to all active agents is probably more important than the specific sequence of administration [11,79]. Nevertheless, most American oncologists initiate chemotherapy for mCRC with FOLFOX or CAPOX/XELOX, using irinotecan alone [80] 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 [81-83].

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 [84] 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 [85].

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 [81]. 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 [86,87]:

-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) [87]. 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 [86,87].

•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 [88]. Results with XELOX were not inferior to FOLFOX4 in terms of response rates, TTP, or median OS (12.5 and 11.9 months for FOLFOX and XELOX). Toxicity profiles were also comparable, with the exception of fewer grade 3 or 4 neutropenia (5 versus 35 percent), and more grade 3 or 4 diarrhea (19 versus 5 percent) and hand-foot syndrome (4 versus <1 percent) with XELOX.

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

Patients initially treated with FOLFOXIRI — The best chemotherapy backbone regimen for individuals who are treated initially with a three drug regimen (eg, oxaliplatin plus irinotecan, LV plus short-term FU [FOLFOXIRI], (table 3)) is not established. For patients who are RAS and BRAF wild-type and have not received an anti-EGFR agent, and who discontinued FOLFOXIRI for reasons other than disease progression, options include an anti-EGFR agent plus irinotecan, FOLFIRI, FOLFOX, or reintroduction of FOLFOXIRI [89]. 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 anti-EGFR therapy (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 anti-EGFR agent, and who require additional therapy, options include single-agent regorafenib, trifluridine-tipiracil, or, where available, fruquintinib. If regorafenib is chosen, we suggest initiating therapy 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. If trifluridine-tipiracil is chosen, it is reasonable to add bevacizumab to the regimen, as long as there are no contraindications to use of bevacizumab and reimbursement is not an issue. (See 'Patients with refractory disease' 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 [90,91]. As such, capecitabine alone is an inappropriate treatment strategy for patients with progressive mCRC on initial intravenous FU-based regimens. However, capecitabine plus bevacizumab might be an option, if it was not used for initial therapy, and there are no contraindications to the use of bevacizumab. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)

●Irinotecan monotherapy – Another option is irinotecan monotherapy. As a single agent, irinotecan has demonstrated clinical benefit after FU failure in patients with mCRC [92-95]. 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 [93].

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 [96]. Diarrhea is the dose-limiting side effect of irinotecan and may be severe; early use of loperamide decreases its severity and is essential to prevent treatment-related mortality. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

●Raltitrexed – Raltitrexed (Tomudex), a folate analog, is a pure thymidylate synthase inhibitor [97]. It is not more active than FU and is not approved in the United States [98-100]. 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 [98].

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 [101-104]. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

Antiangiogenesis therapy

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

Continuation of bevacizumab — In view of the increasing use of bevacizumab in first-line regimens, an important clinical issue is whether it should be continued in patients who switch to an alternative regimen after cancer progression on first-line bevacizumab-containing therapy. An association between survival and exposure to bevacizumab beyond first progression was suggested in an analysis of the observational BRiTE registry of 1953 patients who progressed after receiving a first-line bevacizumab-containing regimen [105], in a preliminary report from the ARIES observational cohort study [106], and from a retrospective analysis of 573 patients treated with and without second-line bevacizumab from community-based United States Oncology practices [107].

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) [108]. 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 [109]. 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 [110]. Continuation with bevacizumab was associated with a numerically higher, but not statistically significant, median PFS (7.1 versus 5.6 months, p = 0.06) and OS (15.8 versus 10.4 months, p = 0.08) compared with cetuximab plus chemotherapy. These results favor continuation of bevacizumab with an alternative chemotherapy backbone in patients who progress with first-line bevacizumab plus chemotherapy.

Role of aflibercept — Intravenous aflibercept (VEGF Trap, Zaltrap) is a recombinant fusion protein, consisting of vascular endothelial growth factor (VEGF) binding portions from key domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1. It acts as a soluble "decoy" receptor that binds to human VEGF-A, VEGF-B, and placental growth factor (PIGF), thereby inhibiting the binding of these ligands and activation of their respective receptors. In cell-free systems, this molecule binds with higher affinity to VEGF-A than does bevacizumab [111].

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 [112]. 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 [113].

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 "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".)

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 [114], 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 "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", 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 [115]. 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 [116], 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 [117-119]. Regimens that combine an anti-EGFR agent with irinotecan alone or a chemotherapy doublet are also efficacious, with the exception of regimens that contain oxaliplatin with a non-infusional fluoropyrimidine (ie, CAPOX/XELOX). (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

Patients not initially treated 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 anti-EGFR antibodies 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 [120] and no consensus. The authors and editors associated with this topic review would not withhold anti-EGFR therapies for second-line treatment for right sided RAS/BRAF wild-type tumors. However, other clinicians would favor the use of continued bevacizumab over an anti-EGFR antibody for right-sided tumors after failure of an initial bevacizumab-containing regimen. (See 'Patients initially treated 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 [117]. 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 [121,122].

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) [118]. 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 [123]. 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) [124].

●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 [125].

•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 [126]. 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) [127] 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 United States Prescribing Information for panitumumab does not include use of panitumumab in combination with irinotecan, we disagree with this viewpoint and consider that the addition of panitumumab to a non-bevacizumab-containing irinotecan-based chemotherapy regimen in patients with RAS and BRAF wild-type mCRC is safe and effective. This approach is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and the ESMO [48,128]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)

Patients initially treated 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 anti-EGFR agent. (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 [110]. 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 anti-EGFR agent is acceptable in this setting, although use of an anti-EGFR agent for right sided tumors in the second-line setting is controversial. (See 'Patients not initially treated with cetuximab/panitumumab' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Anti-EGFR agent 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 [117,118,129-131], 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) [132]. From a pharmacologic standpoint, the main difference between both agents lies in their IgG backbones: cetuximab is a chimeric mouse/human MoAb, while panitumumab is a completely human MoAb. As a result, the incidence of hypersensitivity reactions with panitumumab is lower, and this eliminates the need for routine premedication before therapy. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

The difference in the original on-label dosing schedules (every two weeks for panitumumab, weekly for cetuximab) were based more on how the respective trials leading to approval by the FDA were designed than on true pharmacokinetic, pharmacodynamic, or pharmacogenomic differences. The two drugs have similar half-lives (approximately seven days) and pharmacokinetics [133], and results from a nonrandomized phase II trial [134] and a multicenter retrospective analysis [135] 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)) [136].

In clinical practice, there is no therapeutic preference for using cetuximab versus panitumumab either as monotherapy, or in combination with chemotherapy. However, the lower rate of infusion reactions with panitumumab favors the use of this agent in regions with a high rate of cetuximab-related infusion reactions (eg, middle southeastern region of the United States, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee). We consider that the addition of panitumumab to an irinotecan or oxaliplatin-containing chemotherapy regimen in patients with RAS and BRAF wild-type tumors is appropriate, an approach that is also allowed in consensus-based guidelines from the NCCN and ESMO [48,128]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)

Patients receiving either drug should undergo periodic monitoring of serum electrolytes, including magnesium and potassium. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies", section on 'Anti-EGFR monoclonal antibodies'.)

Patients initially treated with cetuximab or panitumumab — For patients with RAS and BRAF wild-type tumors initially treated with cetuximab or panitumumab plus either FOLFOX or FOLFIRI, we would add bevacizumab to second-line treatment with the alternative chemotherapy doublet (or XELOX, if initially treated with FOLFIRI), as long as the patient is a reasonable candidate for bevacizumab. Treatment with cytotoxic chemotherapy alone is another option.

Rechallenge with an anti-EGFR agent — For most patients, we prefer cytotoxic chemotherapy alone or a switch to a bevacizumab-containing regimen after failure of an initial regimen that includes an anti-EGFR agent rather than continuation of an anti-EGFR agent at progression.

There are scant data supporting benefit for rechallenge with an EGFR agent during a later line of therapy after progression on an initial anti-EGFR agent. A single phase II trial randomly assigned 153 patients with RAS wild-type mCRC initially treated with FOLFIRI plus cetuximab to FOLFOX with or without cetuximab [137]. There was a statistically significant improvement in PFS when the analysis was restricted to RAS wild-type patients (median 6.9 versus 5.3 months), but the difference in OS was not statistically significant (median 23.7 versus 19.8 months).

One reason for acquired resistance to EGFR-targeted therapies is that mutant RAS and EGFR ectoderm clones emerge in blood during EGFR blockade, and at least some data suggest that without the selective pressure of EGFR inhibition, these resistant clones can decay over time (median half-life of approximately four months in one report [138]). with reemergence of sensitivity to EGFR blockade [139,140].

Paired tissue and circulating tumor DNA (ctDNA) sequencing has revealed several genes with increased mutation frequency after anti-EGFR therapy [141], although few of the data are in patients who received an anti-EGFR agent for first-line treatment [142] The benefit of rechallenge with an anti-EGFR agent in molecularly selected patients with mCRC, all of which have stratified outcomes according to persisting wild-type versus mutated RAS ctDNA, has been addressed in at least three studies:

●A single arm phase II study addressed the benefit of rechallenge with cetuximab plus irinotecan in 28 patients with RAS/BRAF wild-type mCRC that had previously achieved at least a partial response with the same regimen [143]. There were six partial responses and nine disease stabilizations, and patents with persistent RAS wild-type ctDNA prior to treatment had a significantly longer PFS than did those with detectable RAS mutations (4 versus 1.9 months).

●A similar result was noted in the phase II CHRONOS trial, in which 36 individuals who retained RAS, BRAF, and EGFR ectoderm wild-type status in ctDNA at molecular screening after initially being treated with an EGFR agent, and progressing after the last anti-EGFR-free regimen all received panitumumab monotherapy [144]. In a preliminary report presented at the 2021 annual ASCO meeting, there were eight partial responses (ORR 30 percent), but the median PFS was only four months; some had durable periods of stable disease >4 months.

●Others have shown benefit from rechallenge with cetuximab plus an immune checkpoint inhibitor (the anti-PD-L1 monoclonal antibody avelumab) in single arm phase II trial of 77 pretreated patients with RAS wild-type mCRC who had an initial response to first-line chemotherapy with an EGFR agent, but then failed second-line therapy due to acquired resistance [145]. Patients with RAS wild-type ctDNA had better outcomes (median OS 17.3 versus 10.4 months, PFS 4.1 versus 3 months) compared with those who had mutated ctDNA.

Taken together, these data suggest that genotyping tumor DNA in the blood might be beneficial to direct therapy for recurrent disease, although further study is needed to address whether better disease control might be achieved with combined chemotherapy or immunotherapy plus an anti-EGFR agent.

While molecular selection of patients for rechallenge with an anti-EGFR agent may eventually become a cost-effective approach to treatment selection, this is not yet a standard approach. A major problem is insurance coverage for serial ctDNA testing.

Panitumumab after failure of cetuximab — A separate questions is whether resistance to cetuximab also predicts resistance to panitumumab. The majority of patients who have been evaluated in a trial setting do not achieve durable benefit from the use of panitumumab in patients who progress on cetuximab, and vice versa. In our view, this approach should only be undertaken in the context of a clinical trial aimed at better defining this question. This approach is consistent with consensus-based guidelines from the NCCN and ESMO [48,128].

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

●In the first, 26 patients with KRAS wild-type mCRC received panitumumab after progressing on cetuximab plus irinotecan [146]. A partial response was achieved in three (12 percent), and seven additional patients (27 percent) had stable disease.

●On the other hand, in a second trial of 20 patients with KRAS wild-type mCRC who had progressed on cetuximab, no patient responded, although 45 percent had stable disease (no progression for at least two cycles) [147]. The authors concluded that panitumumab was of minimal benefit in cetuximab-refractory disease.

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

●In one study, investigators used a cetuximab-sensitive human CRC cell line to develop a resistant version by prolonged in vitro exposure to cetuximab [148]. The cetuximab-resistant cells contained a secondary EGFR mutation in the extracellular domain of the receptor that impaired binding of cetuximab but not other EGFR ligands, including panitumumab. This specific mutation was identified in 2 of 10 tumors from people with cetuximab resistance, one of whom received panitumumab and had an objective response.

●In another report of tissue samples derived from 37 patients with CRC who became refractory to cetuximab, a complex pattern of mutations was observed, converging on two main patterns of resistance: activating mutations affecting EGFR downstream signaling and mutations in the EGFR ectodomain that disrupt antibody receptor binding, a subset of which prevented binding to cetuximab but not panitumumab [149].

Thus, while there may be a small subset of patients with cetuximab-refractory RAS wild-type tumors who will respond to panitumumab, the best way to identify this subset is unclear. Testing for specific mutations in the EGFR that might confer cetuximab resistance but panitumumab sensitivity is currently only available in research laboratories. Notably, as discussed above, rechallenge with cetuximab and irinotecan or panitumumab can benefit some patients with acquired resistance to first-line anti-EGFR agent, particularly if they continue to lack RAS mutations at the time of rechallenge. (See 'Rechallenge with an anti-EGFR agent' above.)

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

The results of the phase II BOND-2 trial, which compared a combination of cetuximab/bevacizumab with (CBI) or without (CB) irinotecan as last-line therapy in patients with chemorefractory mCRC generated interest in dual-antibody combinations [150]. BOND-2 reported unprecedented outcome results for patients previously treated with FU, irinotecan, and (in 85 to 90 percent of cases) oxaliplatin with regard to response rate (20 versus 37 for CB and CBI, respectively), TTP (4.9 versus 7.3 months), and OS (11.4 versus 14.5 months). The toxicity profile was also tolerable.

However:

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

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

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

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

The benefit of combining cetuximab and ramucirumab was addressed in the E7208 trial, in which 102 patients with RAS wild-type mCRC progressing after a fluoropyrimidine-, oxaliplatin-, and bevacizumab-containing regimen were randomly assigned to irinotecan plus cetuximab with ramucirumab (ICR) or without ramucirumab (IC) [151]. The ICR regimen was modified after the initial 35 patients were enrolled because of excessive toxicity. In a preliminary report presented at the 2018 annual American Society of Clinical Oncology (ASCO) meeting, patients assigned to ICR had similar median PFS (5.8 versus 5.7 months), and combination treatment was also more toxic (myelosuppression, hypertension, mucositis). Subset analysis suggested that patients who progressed while not receiving oxaliplatin and those with a longer time since last treatment might have preferentially benefited from dual therapy, but this is hypothesis generating at most.

PATIENTS WITH REFRACTORY DISEASE

Regorafenib — For patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) agent, anti-epidermal growth factor receptor (EGFR) therapy (if RAS wild-type), and molecularly targeted therapy, if appropriate, and who desire and are eligible for additional cancer therapy, regorafenib is an option. Based upon data from the phase II ReDOS study, we suggest initiating therapy 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 [152]. Patients assigned to regorafenib had a modest though statistically significant improvement in median overall survival (OS; 6.4 versus 5 months, hazard ratio [HR] 0.77, 95% CI 0.64-0.94), and the difference in progression-free survival (PFS), while very small, was statistically significant (HR 0.49, median 1.9 versus 1.7 months). While the disease control rate (DCR) was higher with regorafenib (41 versus 15 percent), only five patients (1 percent) experienced a partial response. The group receiving regorafenib had more grade 3 or 4 hand-foot skin reaction (17 versus 0.4 percent), fatigue (10 versus 5 percent), hypertension (7 versus 1 percent), diarrhea (7 versus 1 percent), and skin rash (6 versus 0 percent). Fatal hepatic failure occurred in 1.6 percent of patients treated with regorafenib versus 0.4 percent in the placebo group. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Largely based on this study, in 2012, regorafenib received approval from the US Food and Drug Administration (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 anti-EGFR therapy. 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 [153]. 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 6 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) [154]. Median OS also trended better in the dose escalation cohort (9.8 versus 6 months), and toxicity was more favorable.

Trifluridine-tipiracil — For patients with mCRC who have been previously treated with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, anti-EGFR therapy (if RAS wild-type), and who desire and are eligible for additional cancer therapy, trifluridine-tipiracil is an option. It is reasonable to add bevacizumab to trifluridine-tipiracil in the setting of multiply refractory disease, as long as there are no contraindications to bevacizumab and third-party payers are willing to pay for combined therapy.

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 [155]. Benefit in refractory mCRC is suggested by the following data:

●Efficacy was initially suggested in a Japanese randomized placebo-controlled phase II trial of 172 patients with refractory mCRC in whom trifluridine-tipiracil significantly prolonged median OS (9 versus 6.6 months); the most common grade 3 or 4 toxicity was hematologic [156].

Based upon these results, trifluridine-tipiracil was approved in Japan for treatment of refractory mCRC.

●Benefit was confirmed in two subsequent placebo-controlled phase III trials (the RECOURSE and TERRA trials) [157,158]. In the larger of the two, 800 patients who were refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and anti-EGFR agents (if KRAS wild-type) were randomly assigned to trifluridine-tipiracil (35 mg/m² orally twice daily on days 1 through 5, and 8 to 12 of each 28-day cycle) or placebo [157]. Trifluridine-tipiracil was associated with a significant prolongation in median OS, the primary endpoint (7.1 versus 5.3 months, HR 0.68, 95% CI 0.58-0.81), and this benefit was irrespective of prior regorafenib use. Although patients treated with trifluridine-tipiracil had a significantly higher DCR (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. Serious adverse events were observed in 30 percent of patients receiving trifluridine-tipiracil compared with 34 percent of the placebo group, 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 relevant to the treatment of patients with longstanding treatment-refractory disease who are often experiencing gastrointestinal distress as a consequence of their disease and are not tolerant of high-grade gastrointestinal toxicity.

Largely based upon these results, trifluridine-tipiracil was approved in the United States for treatment of mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antiangiogenic biologic product, and a monoclonal antibody (MoAb) targeting the EGFR, if RAS wild-type.

Plus bevacizumab — Benefit for combined therapy was suggested in a phase II trial in which 93 patients with chemorefractory mCRC were randomly assigned to standard-dose trifluridine-tipiracil (35 mg/m² orally twice daily on days 1 through 5 and 8 to 12 of each 28-day cycle) without or with bevacizumab (5 mg/kg on days 1 and 15 every 28 days) [159]. Combination therapy was associated with a modest, although statistically significant, improvement in median PFS (4.6 versus 2.6 months, HR 0.45, 95% CI 0.29-0.72) and OS (9.4 versus 6.7 months, HR 0.55, 95% CI 0.32-0.94) and a higher DCR (67 versus 51 percent). From a toxicity standpoint, the fraction of patients experiencing serious adverse events was similar in the two groups, but more patients receiving combined therapy had grade 3 or worse neutropenia (67 versus 37 percent). A biweekly schedule of administration of both trifluridine-tipiracil and bevacizumab might be associated with less toxicity, especially neutropenia [160].

Fruquintinib — Fruquintinib is another potent and highly selective small molecule inhibitor of VEGFR 1, 2, and 3 tyrosine kinases. In the FRESCO trial, 416 Chinese patients who had progressed after two or more lines of therapy that did not include a VEGFR inhibitor (but could have included an agent targeting VEGF) were randomly assigned to fruquintinib (5 mg once daily for 21 days of each 28-day cycle) or placebo [161]. Median OS, the primary endpoint, was significantly better with fruquintinib (9.3 versus 6.6 months, HR 0.65, 95% CI 0.51-0.83), as was median PFS (3.7 versus 1.8 months, HR 0.26, 95% CI 0.21-0.34). Benefit was maintained in those who had previously received an agent targeting VEGF. The most common serious (grade 3 or 4) adverse effects with fruquintinib were hypertension (21 percent), hand-foot skin reaction (11 percent), diarrhea (2.9 percent), and thrombocytopenia (2.5 percent). Overall, 14 percent of the patients receiving fruquintinib required hospitalization or prolongation of an existing hospital stay to manage drug toxicity.

A follow-up study of fruquintinib monotherapy, the double-blind placebo-controlled FRESNO-2 trial, was conducted at 153 sites in the United States, Europe, Japan, and Australia [162]. In a preliminary report presented at the 2022 European Society for Medical Oncology meeting, median OS was significantly better with fruquintinib (7.4 versus 4.8 months), and the disease control rate (objective response plus stable disease) was also higher (56 versus 16 percent). The most frequent grade 3 or 4 adverse events with fruquintinib were hypertension (14 percent), asthenia (8 percent), and hand-foot syndrome (6.4 percent). Fruquintinib is only approved and available in China [163].

SIRT — Another option for chemotherapy-refractory disease, in patients whose disease is either limited to liver or predominantly progressing in liver, is selective internal radiotherapy (SIRT) using radioactive isotopes (eg, 131-labeled lipiodol or yttrium 90 [90Y]-tagged glass or resin microspheres) that are delivered selectively to the tumor via the hepatic artery. This subject is discussed in detail elsewhere. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Radioembolization'.)

Rechallenge with previously used drugs — After failure of all conventional agents/combinations, if performance status is adequate and a tumor-directed therapeutic approach is still warranted (and desired, after a realistic discussion with the patient and/or family about the risks and benefits), we prefer enrollment in a phase I or II trial testing novel agents/combinations. If protocol treatment is not available or participation is not feasible, reutilizing a regimen initially used in the treatment sequence (eg, FOLFOX or CAPOX) is a reasonable option, especially if the regimen was abandoned because of toxicity and not disease progression [164]. Caution is warranted during oxaliplatin rechallenge, as rates of infusion reaction appear to more than double in patients with prior exposure, and tend to occur earlier (eg, cycles 2 to 3) rather than later in the treatment course [165,166]. During the often lengthy phase of sequential therapy, tumors may retain or regain sensitivity to previously used drugs, including anti-EGFR agents. (See 'Subsequent treatment and the continuum of care model' above.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas with persistently high rates of viral transmission include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. Specific considerations for patients undergoing palliative chemotherapy for stage IV CRC include establishing goals of care and discussing advance care planning, utilizing oral rather than intravenous therapy, where appropriate, transitioning outpatient care (eg, pump disconnection) to home whenever possible, and using intermittent rather than continuous therapy (with or without maintenance therapy), where feasible. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)

These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General considerations – Understanding of how to combine and sequence drugs for metastatic colorectal cancer (mCRC) is evolving. In general, ensuring exposure to all active drugs is more important than the specific sequence of administration. (See 'Available agents and overview of the therapeutic approach' above.)

Multipanel genomic testing of tumor tissue is essential for optimal care. (See 'Multipanel somatic (tumor) and germline genomic testing' above.)

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.)

Chemotherapy regimens are presented elsewhere. (See "Treatment protocols for small and large bowel cancer".)

●Treatment selection – Our 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.

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

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

•HER2 overexpressors – For HER2-overexpressing mCRC progressing after conventional chemotherapy, we suggest HER2-targeted therapy (Grade 2B). Options include trastuzumab plus lapatinib, trastuzumab plus pertuzumab, trastuzumab plus tucatinib, or, for individuals who previously received trastuzumab and have progressed on two or more cytotoxic regimens, fam-trastuzumab deruxtecan. (See 'HER2 overexpressors' above.)

•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 – Patients with a RAS mutation do not benefit from treatments targeting the EGFR.

The best way to manage patients with the specific RAS G12C mutation is unclear. For most, we encourage participation in a clinical trial testing new strategies. (See 'RAS mutated tumors' above.)

•No molecular marker (RAS/BRAF wild-type), and patients not eligible for, or progressing during targeted treatments – For fit patients initially treated with an oxaliplatin-containing chemotherapy doublet (ie, FOLFOX or CAPOX/XELOX), we switch to FOLFIRI (table 9) or irinotecan alone at the time of disease progression. For patients initially treated with FOLFIRI, we switch to an oxaliplatin-based regimen. (See 'The cytotoxic chemotherapy backbone' above.)

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

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

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

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

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.)

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 'Patients not initially treated 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. (See 'Patients not initially treated with cetuximab/panitumumab' above.)

For patients initially treated with cetuximab or panitumumab plus cytotoxic chemotherapy, we typically prefer a second-line fluoropyrimidine-based chemotherapy regimen with or without bevacizumab rather than continuation of an anti-EGFR agent at progression. (See 'Rechallenge with an anti-EGFR agent' above.)

•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.)

•Multiply relapsed disease – 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 anti-EGFR agent, and who require additional therapy, options include single-agent regorafenib, trifluridine-tipiracil with or without bevacizumab, or, where available, fruquintinib. (See 'Patients with refractory disease' above.)

After failure of all conventional agents/combinations, if performance status is adequate and a tumor-directed therapeutic approach is still warranted, we prefer enrollment in a phase I or II trial testing novel agents/combinations. Alternatives include retreatment with a prior regimen and selective internal radiotherapy for patients whose disease is either limited to liver or predominantly progressing in liver. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Radioembolization'.)

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