Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology

Authors:
Al B. Benson III Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Alan P. Venook UCSF Helen Diller Family Comprehensive Cancer Center

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Mohamed Adam UCSF Helen Diller Family Comprehensive Cancer Center

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George Chang The University of Texas MD Anderson Cancer Center

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Yi-Jen Chen City of Hope National Medical Center

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Kristen K. Ciombor Vanderbilt-Ingram Cancer Center

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Stacey A. Cohen Fred Hutchinson Cancer Center

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Harry S. Cooper Fox Chase Cancer Center

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Dustin Deming University of Wisconsin Carbone Cancer Center

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Ignacio Garrido-Laguna Huntsman Cancer Institute at the University of Utah

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Jean L. Grem Fred & Pamela Buffett Cancer Center

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Paul Haste Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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J. Randolph Hecht UCLA Jonsson Comprehensive Cancer Center

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Sarah Hoffe Moffitt Cancer Center

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Steven Hunt Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Hisham Hussan UC Davis Comprehensive Cancer Center

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Kimberly L. Johung Yale Cancer Center/Smilow Cancer Hospital

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Nora Joseph University of Michigan Rogel Cancer Center

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Natalie Kirilcuk Stanford Cancer Institute

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Smitha Krishnamurthi Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Midhun Malla O’Neal Comprehensive Cancer Center at UAB

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Jennifer K. Maratt Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Wells A. Messersmith University of Colorado Cancer Center

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Jeffrey Meyerhardt Dana-Farber Brigham and Women’s Cancer Center

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Eric D. Miller The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Mary F. Mulcahy Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Steven Nurkin Roswell Park Comprehensive Cancer Center

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Michael J. Overman The University of Texas MD Anderson Cancer Center

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Aparna Parikh Mass General Cancer Center

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Hitendra Patel UC San Diego Moores Cancer Center

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Katrina Pedersen Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Leonard Saltz Memorial Sloan Kettering Cancer Center

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Charles Schneider Abramson Cancer Center at the University of Pennsylvania

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David Shibata The University of Tennessee Health Science Center

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Benjamin Shogan The UChicago Medicine Comprehensive Cancer Center

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John M. Skibber The University of Texas MD Anderson Cancer Center

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Constantinos T. Sofocleous Memorial Sloan Kettering Cancer Center

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Anna Tavakkoli UT Southwestern Simmons Comprehensive Cancer Center

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Christopher G. Willett Duke Cancer Institute

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Christina Wu Mayo Clinic Comprehensive Cancer Center

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Lisa A. Gurski National Comprehensive Cancer Network

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Jenna Snedeker National Comprehensive Cancer Network

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Frankie Jones National Comprehensive Cancer Network

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Full access

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Overview

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2024, an estimated 106,590 new cases of colon cancer and 46,220 cases of rectal cancer will occur. During the same year, an estimated 53,010 people will die of colon and rectal cancer combined.1 Despite these high numbers, the incidence of colon and rectal cancers per 100,000 people decreased from 60.5 in 1976 to 46.4 in 2005 and, more recently, 38.7 in 2016.2,3 In addition, mortality from CRC has been decreasing for decades (since 1947 in females and since 1980 in males) and is currently down by more than 50% from peak mortality rates.1,3 These improvements in incidence of and mortality from CRC are thought to be a result of cancer prevention and earlier diagnosis through screening and better treatment modalities. Recent data show continued rapid declines in incidence among those aged ≥65 years, with a decrease of 3.3% annually between 2011 and 2016.3

Conversely, incidence has increased among those <65 years, with a 1% annual increase in those aged 50 to 64 years and 2% annual increase in those <50 years. CRC death rates also showed age-dependent trends, declining by 3% annually for those ≥65 years, compared with a 0.6% annual decline for individuals aged 50 to 64 years and a 1.3% annual increase for individuals <50 years.3 A retrospective cohort study of the SEER CRC registry also found that the incidence of CRC in patients <50 years has been increasing.4 The authors estimate that the incidence rates for colon and rectal cancers will increase by 90.0% and 124.2%, respectively, for patients 20 to 34 years of age by 2030. The cause of this trend is currently unknown. One review suggests that CRC that occurs in patients <45 years may be clinicopathologically and genetically different from CRC in adults ≥45 years, although this has not been confirmed broadly. If cancer in this population is different, there would be a need to develop specific treatment strategies for this population.5 In a cohort study of 1,959 patients with metastatic CRC (mCRC), patients who developed mCRC at a younger age (<50 years) showed worse survival outcomes and unique adverse event (AE) profiles, which the authors partially attribute to distinct genetic profiles.6

This section of the Discussion summarizes the data supporting the systemic therapy options recommended for mCRC in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer. The full version of these guidelines, available online at NCCN.org, includes additional information on the treatment and management of colon cancer, including clinical presentation and diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship.

Systemic Therapy for Advanced or Metastatic Disease

The current management of disseminated mCRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. Although the specific regimens listed in the guidelines are designated according to whether they pertain to initial therapy, therapy after first progression, or therapy after second progression, it is important to clarify that these recommendations represent a continuum of care and that these lines of treatment are blurred rather than discrete.7 For example, if oxaliplatin is administered as a part of an initial treatment regimen but is discontinued after 12 weeks or earlier for escalating neurotoxicity, continuation of the remainder of the treatment regimen would still be considered initial therapy.

Principles to consider at the start of therapy include (1) preplanned strategies for altering therapy for disease exhibiting a tumor response or for disease characterized as stable or progressive; and (2) plans for adjusting therapy for patients who experience certain toxicities. For example, decisions related to therapeutic choices after first progression of disease should be based, in part, on the prior therapies received (ie, exposing the patient to a range of cytotoxic agents). Furthermore, an evaluation of the efficacy and safety of these regimens for a patient must consider not only the component drugs, but also the doses, schedules, and methods of administration of these agents, and the potential for surgical cure and the performance status of the patient.

For more information on the sequencing and timing of therapies, therapy retreatment/rechallenge, maintenance therapy, and biosimilars, see the full guidelines available online at NCCN.org.

Biomarkers for Systemic Therapy

As the role of targeted therapy for treatment of advanced or mCRC has become increasingly prominent, the NCCN panel has expanded its recommendations regarding biomarker testing. Currently, determination of tumor gene status for KRAS/NRAS and BRAF mutations, as well as HER2 amplifications and microsatellite instability (MSI)/mismatch repair (MMR) status (if not previously done), are recommended for patients with mCRC. Testing may be performed for individual genes or as part of a next-generation sequencing (NGS) panel, with NGS being preferred. NGS panels have the advantage of being able to pick up rare and actionable genetic alterations, such as neurotrophic tyrosine receptor kinase (NTRK) and rearranged during transfection (RET) fusions and may be performed using either a tissue or blood-based (eg, liquid) biopsy.8 Specific information about each of these biomarkers may be found in the subsequent sections.

Repeat molecular testing should not be performed after standard cytotoxic chemotherapy because significant molecular changes are rarely observed. For patients with tumors initially harboring molecular alterations eligible for targeted therapy, repeat testing may be considered to assess for a change in the molecular profile that may guide future targeted therapy decisions. A study of paired plasma samples from patients with RAS/BRAF/EGFR wild-type mCRC who received EGFR inhibitors compared with those who received combination cytotoxic chemotherapy found that those who received the targeted therapy were more likely to develop acquired mutations (46%) than those who received cytotoxic chemotherapy (9%).9

KRAS and NRAS Mutations

The MAPK pathway of RAS/RAF/MEK/ERK is downstream of EGFR; mutations in components of this pathway are now established to be strong negative predictive markers, essentially precluding efficacy of these therapies. A sizable body of literature has shown that tumors with a mutation in exons 2, 3, or 4 of either the KRAS or NRAS genes are essentially insensitive to cetuximab or panitumumab therapy.1020 The panel therefore strongly recommends RAS (KRAS/NRAS) genotyping of tumor (either primary tumor or metastasis) in all patients with mCRC. Patients with known KRAS- or NRAS-mutant tumors should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified. An exception to this is when cetuximab or panitumumab is given in combination with sotorasib or adagrasib for tumors with KRAS G12C mutation (see later section on “Systemic Therapy Options for KRAS G12C Mutation-Positive Disease in the Non-First-Line Setting”). ASCO released a Provisional Clinical Opinion Update on extended RAS testing in patients with mCRC that is consistent with the NCCN panel’s recommendations.21 A guideline on molecular biomarkers for CRC developed by the American Society of Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and ASCO also recommends RAS testing consistent with the NCCN recommendations.22

Studies have reported that around 40% of mCRC have KRAS mutations in codons 12 and 13.23,24 Of these mutations, KRAS G12D was most commonly found (36%), followed by G12V (21.8%), and G13D (18.8%).24 KRAS G12C has been reported in around 17% of KRAS-mutated mCRC cases.25 Results are mixed as far as the prognostic value of KRAS mutations. In the Alliance N0147 trial, patients with KRAS exon 2-mutant tumors experienced a shorter disease-free survival than patients with tumors without such mutations.26 Other studies have also reported worse outcomes with KRAS mutations.23,27,28

In the AGITG MAX study, 10% of patients with tumors with wild-type KRAS exon 2 had mutations in KRAS exons 3 or 4 or in NRAS exons 2, 3, and 4.29 In the PRIME trial, 17% of 641 patients with tumors without KRAS exon 2 mutations were found to have mutations in exons 3 and 4 of KRAS or mutations in exons 2, 3, and 4 of NRAS. A predefined retrospective subset analysis of data from PRIME revealed that progression-free survival (PFS) (hazard ratio [HR], 1.31; 95% CI, 1.07–1.60; P=.008) and overall survival (OS) (HR, 1.21; 95% CI, 1.01–1.45; P=.04) were decreased in patients with tumors with any KRAS or NRAS mutation who received panitumumab plus FOLFOX compared with those who received FOLFOX alone.19 These results show that panitumumab does not benefit patients with KRAS- or NRAS-mutant tumors and may even have a detrimental effect in these patients.

Updated analysis of the FIRE-3 trial (discussed in “Cetuximab or Panitumumab Versus Bevacizumab in First-line Therapy,”) has been published.30 When all RAS (KRAS/NRAS) mutations were considered, PFS was significantly worse in patients with RAS-mutant tumors receiving FOLFIRI plus cetuximab than in patients with RAS-mutant tumors receiving FOLFIRI plus bevacizumab (6.1 vs 12.2 months; P=.004). Conversely, patients with KRAS/NRAS wild-type tumors showed no difference in PFS between the regimens (10.4 vs 10.2 months; P=.54). This result indicates that cetuximab likely has a detrimental effect in patients with KRAS- or NRAS-mutant tumors. The FDA indication for panitumumab was, therefore, updated to state that panitumumab is not indicated for the treatment of patients with KRAS or NRAS mutation-positive disease in combination with oxaliplatin-based chemotherapy.31

A retrospective study by De Roock et al32 raised the possibility that codon 13 mutations (G13D) in KRAS may not be absolutely predictive of nonresponse. Another retrospective study showed similar results.17 However, later retrospective analysis of 3 randomized controlled phase III trials concluded that KRAS G13D-mutant tumors were unlikely to respond to panitumumab.33 Results from a prospective phase II single-arm trial assessed the benefit of cetuximab monotherapy in 12 patients with refractory mCRC whose tumors contained KRAS G13D mutations.34 The primary endpoint of 4-month progression-free rate was not met (25%), and no responses were seen. Preliminary results of the AGITG phase II ICE CREAM trial also failed to see a benefit of cetuximab monotherapy in patients with KRAS G13D-mutant tumors.35 However, partial responses were reported after treatment with irinotecan plus cetuximab in 9% of this irinotecan-refractory population. A meta-analysis of 8 randomized clinical trials (RCTs) came to the same conclusion: that tumors with KRAS G13D mutations are no more likely to respond to EGFR inhibitors than tumors with other KRAS mutations.36

The recommendation for RAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of RAS status is appropriate to plan for the treatment continuum, so that the information may be obtained in a non–time-sensitive manner and the patient and provider can discuss the implications of a RAS mutation, if present, while other treatment options still exist. Note that because anti-EGFR agents have no role in the management of stage I, II, or III disease, RAS genotyping of CRCs at these earlier stages is not recommended.

KRAS mutations are early events in CRC formation, and therefore a very tight correlation exists between mutation status in the primary tumor and the metastases.3739 For this reason, RAS genotyping can be performed on archived specimens of either the primary tumor or a metastasis. Fresh biopsies should not be obtained solely for the purpose of RAS genotyping unless an archived specimen from either the primary tumor or a metastasis is unavailable.

BRAF V600E Mutations

Although mutations in RAS indicate a lack of response to EGFR inhibitors, many tumors containing wild-type RAS still do not respond to these therapies. Therefore, studies have addressed factors downstream of RAS as possible additional biomarkers predictive of response to cetuximab or panitumumab. Approximately 5%–9% of CRCs are characterized by a specific mutation in the BRAF gene (V600E).40,41 BRAF mutations are, for all practical purposes, limited to tumors that do not have RAS mutations.4042 Activation of the protein product of the nonmutated BRAF gene occurs downstream of the activated KRAS protein in the EGFR pathway. The mutated BRAF protein product is believed to be constitutively active,4345 thereby putatively bypassing inhibition of EGFR by cetuximab or panitumumab.

Limited data from unplanned retrospective subset analyses of patients with mCRC treated in the first-line setting suggest that although a BRAF V600E mutation confers a poor prognosis regardless of treatment, patients with disease characterized by this mutation may receive some benefit from the addition of cetuximab to front-line therapy.41,46 A planned subset analysis of the PRIME trial also found that mutations in BRAF indicated a poor prognosis but were not predictive of benefit to panitumumab added to FOLFOX in first-line treatment of mCRC.19 Conversely, results from the randomized phase III Medical Research Council (MRC) COIN trial suggest that cetuximab may have no effect or even a detrimental effect in patients with BRAF-mutated tumors treated with CAPEOX or FOLFOX in the first-line setting.42

In subsequent lines of therapy, retrospective evidence suggests that mutated BRAF is a marker of resistance to anti-EGFR therapy in the non–first-line setting of metastatic disease.4749 A retrospective study of 773 primary tumor samples from patients with chemotherapy-refractory disease showed that BRAF mutations conferred a significantly lower response rate to cetuximab (2/24; 8.3%) compared with tumors with wild-type BRAF (124/326; 38.0%; P=.0012).50 Furthermore, data from the multicenter randomized controlled PICCOLO trial are consistent with this conclusion, with a suggestion of harm seen for the addition of panitumumab to irinotecan in the non–first-line setting in the small subset of patients with BRAF-mutant tumors.51

A meta-analysis published in 2015 identified 9 phase III trials and 1 phase II trial that compared cetuximab or panitumumab with standard therapy or best supportive care including 463 patients with metastatic colorectal tumors with BRAF mutations (first-line, second-line, or refractory settings).52 The addition of an EGFR inhibitor did not improve PFS (HR, 0.88; 95% CI, 0.67–1.14; P=.33), OS (HR, 0.91; 95% CI, 0.62–1.34; P=.63), or overall response rate (ORR) (relative risk [RR], 1.31; 95% CI, 0.83–2.08; P=.25) compared with control arms. Similarly, another meta-analysis identified 7 RCTs and found that cetuximab and panitumumab did not improve PFS (HR, 0.86; 95% CI, 0.61–1.21) or OS (HR, 0.97; 95% CI, 0.67–1.41) in patients with BRAF-mutant tumors.53

Although the evidence suggests that BRAF V600E mutation makes response to panitumumab or cetuximab unlikely, the impact of other BRAF mutations was less clear. A multicenter pooled study included 40 patients with mCRC harboring oncogenic non-V600 BRAF mutations (30% class 2 mutations, 70% class 3) who received anti-EGFR antibody treatment.54 Of the patients with class 2 BRAF mutations, only 1 of 12 showed a response to anti-EGFR therapy, compared with 50% of those with class 3 mutations (P=.02). Therefore, it is reasonable to consider anti-EGFR therapy for patients with BRAF mutations other than V600E, especially for class 3 mutations.

In addition to its role as a predictive marker for BRAF-targeted therapy, it is clear that V600E mutations in BRAF are a strong prognostic marker.41,42,5561 A prospective analysis of tissues from patients with stage II and III colon cancer enrolled in the PETACC-3 trial showed that the BRAF mutation is prognostic for OS in patients with low-level MSI (MSI-L) or microsatellite stability (MSS) tumors (HR, 2.2; 95% CI, 1.4–3.4; P=.0003).57 Moreover, an updated analysis of the CRYSTAL trial showed that patients with metastatic colorectal tumors carrying a BRAF mutation have a worse prognosis than those with the wild-type gene.41 Additionally, BRAF mutation status predicted OS in the AGITG MAX trial, with an HR of 0.49 (95% CI, 0.33–0.73; P=.001).56 The OS for patients with BRAF-mutant tumors in the COIN trial was 8.8 months, while those with KRAS exon 2 mutations and wild-type KRAS exon 2 tumors had OS times of 14.4 and 20.1 months, respectively.42 In addition, a secondary analysis of the N0147 and C-08 trials found that BRAF mutations were significantly associated with worse survival after recurrence of resected stage III colon cancer, with a stronger association for primary tumors located in the distal colon.62 Results from a systematic review and meta-analysis of 21 studies, including 9,885 patients, suggest that BRAF mutation may accompany specific high-risk clinicopathologic characteristics.63 In particular, an association was observed between BRAF mutation and proximal tumor location (OR, 5.22; 95% CI, 3.80–7.17; P<.001), T4 tumors (OR, 1.76; 95% CI, 1.16–2.66; P=.007), and poor differentiation (OR, 3.82; 95% CI, 2.71–5.36; P<.001).

Overall, the panel believes that evidence increasingly suggests that BRAF V600E mutation makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely, unless given as part of a BRAF inhibitor regimen (see later section on “Encorafenib Plus Cetuximab or Panitumumab for BRAF V600E Mutation-Positive Disease in the Non–First-line Setting”). The panel recommends BRAF genotyping of tumor tissue (either primary tumor or metastasis64) at diagnosis of stage IV disease. If a tumor is determined to be both MSI-high (MSI-H)/MMR deficient (dMMR) and BRAF V600E, first-line therapy with a checkpoint inhibitor would generally be preferred and a BRAF inhibitor regimen could be used in a later line of therapy, as directed in the algorithm.

HER2 Amplification/Overexpression

HER2 is a member of the same family of signaling kinase receptors as EGFR and has been successfully targeted in breast cancer in both the advanced and adjuvant settings. HER2 is rarely amplified/overexpressed in CRC (approximately 3% overall), but the prevalence is higher in RAS/BRAF–wild type tumors (reported at 5%–14%).65,66 Specific molecular diagnostic methods have been proposed for HER2 testing in CRC,67 and HER2-targeted therapies are now recommended as subsequent therapy options in patients with tumors that have HER2 overexpression (see later section on “Systemic Therapy Options for HER2-Amplified Disease”).65,68 Based on this, the NCCN Guidelines for Colon Cancer recommend testing for HER2 amplifications for all patients with mCRC. More information on HER2 testing methodology can be found in the “Principles of Pathologic and Molecular Review” section of the algorithm.

Evidence does not support a prognostic role of HER2 overexpression.69 In addition to its role as a predictive marker for HER2-targeted therapy, initial results indicate HER2 amplification/overexpression may be predictive of resistance to EGFR-targeting monoclonal antibodies.66,70,71 For example, in a cohort of 98 patients with RAS/BRAF–wild type mCRC, median PFS on therapy without an EGFR inhibitor was similar regardless of HER2 status.71 However, in therapy with an EGFR inhibitor, the PFS was significantly shorter in those with HER2 amplification compared with those without HER2 amplification (2.8 vs 8.1 months; HR, 7.05; 95% CI, 3.4–14.9; P<.001).

dMMR/MSI-H Status

The percentage of stage IV colorectal tumors characterized as MSI-H or dMMR ranged from 3.5% to 5.0% in clinical trials and was 6.5% in the Nurses' Health Study and Health Professionals Follow-up Study.7274 dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. However, programmed death-ligands 1 and 2 (PD-L1 and PD-L2) on tumor cells can suppress the immune response by binding to the programmed cell death protein 1 (PD-1) receptor on T-effector cells. This system evolved to protect the host from an unchecked immune response. Many tumors upregulate PD-L1 and thus evade the immune system.75 It was therefore hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors. Subsequently, this hypothesis was confirmed in clinical trials, leading to the addition of recommendations for checkpoint inhibitors for dMMR/MSI-H disease (see later section on “Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the First-Line Setting and in the Non-First-Line Settings”). The NCCN Guidelines for Colon Cancer recommend universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer. In addition to its role as a predictive marker for immunotherapy use in the advanced CRC setting, MMR/MSI status can also help to identify individuals with Lynch syndrome (see “Lynch Syndrome” in the full guidelines, available online at NCCN.org), and to inform adjuvant therapy decisions for patients with stage II disease (see “Microsatellite Instability” under “Adjuvant Chemotherapy for Resectable Colon Cancer,” in the full guidelines, available online at NCCN.org). It is important to note that there is currently no role for PD-L1 testing in CRC outside a clinical trial and that PD-L1 testing is not recommended.

POLE/POLD1 Mutations

The polymerase genes, POLE and POLD1, encode proteins with proofreading functions that correct mistakes created during DNA replication. Pathologic variants within the endonuclease domain of these proteins results in loss of the proofreading function, leading to subsequent acquisition of downstream mutations.76,77 Germline pathologic variants of POLE or POLD1 are found in polymerase proofreading-associated polyposis, which predisposes patients to colorectal adenomas and carcinomas. Management recommendations for polymerase proofreading-associated polyposis are described in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal (available at NCCN.org). Somatic POLE pathologic variants occur in approximately 2% to 8% of patients with MSS/pMMR CRC although somatic POLD1 pathologic variants are extremely rare.76,78

Similar to dMMR/MSI-H, CRC with POLE/POLD1 pathologic variants has a more favorable prognosis for stage II/III, likely due to enhanced immune response, although this association may be strongest for stage II disease.79 Since POLE/POLD1 pathologic variants also cause a hypermutated phenotype in CRC, similar to dMMR/MSI-H, it was theorized that pMMR CRC with POLE/POLD1 pathologic variants may also benefit from checkpoint inhibitor therapy.80 A retrospective analysis of 458 patients with POLE mutation-positive tumors tested this.81 Of the identified POLE mutations, 15.0% were pathogenic, 15.9% were benign, and 69.1% were of unknown significance. Eighty-two patients received a PD-1/PD-L1 inhibitor, either as monotherapy or in combination. Compared with those with benign variants, patients with POLE pathogenic variants had improved clinical benefit rates (82.4% vs 30.0%; P=.013), improved median PFS (15.1 vs 2.2 months; P<.001), longer OS (29.5 vs 6.8 months; P<.001) and longer treatment duration (15.5 vs 2.5 months).

Based on these results, the NCCN panel recommends that mCRC with functional POLE/POLD1 pathologic variants should be treated consistently with the recommendations for dMMR/MSI-H disease (see “Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the First-Line Setting and the Non-First-Line Settings”).

NTRK Fusions

Three NTRK genes encode the tropomyosin receptor kinase (TRK) proteins. TRK expression is primarily in the nervous system where these kinases help to regulate pain, perception of movement/position, appetite, and memory. NTRK gene fusions lead to overexpression of the TRK fusion protein, resulting in constitutively active downstream signaling.82 Studies have estimated that about 0.2% to 1% of CRCs carry NTRK gene fusions.83,84 A study of 2,314 CRC specimens, of which 0.35% had NTRK fusions, found that NTRK fusions were limited to cancers that were wild-type for KRAS, NRAS, and BRAF. Furthermore, a majority of the CRCs harboring NTRK fusions were also dMMR.85 Similarly, in a smaller study that aimed to characterize the molecular and clinical landscape of ALK, ROS1, and NTRK rearranged mCRC, 76.9% of NTRK rearranged tumors were dMMR.86 NTRK inhibitors are treatment options for patients with mCRC that is NTRK gene fusion-positive (see later section on “Larotrectinib or Entrectinib for NTRK Gene Fusion-Positive Disease in the Non-First-Line Setting”).

RET Fusions

RET is a transmembrane glycoprotein receptor-tyrosine kinase that plays an important role in the homeostasis of several different types of tissues, including neural, hematopoietic, and neuroendocrine tissues.87 RET gene fusions lead to constitutively active, ligand-independent activation of the RET pathway.88 RET gene fusions are implicated in the pathogenesis of several solid tumors, including thyroid and non-small-cell lung cancer, as well as in a small subset (<1%) of CRCs.87,89 A systematic review analyzed data from 24 RET gene fusion–positive mCRC cases from 3 screening sources and found RET gene fusions to be more prevalent with increased age (median age, 66 vs 60 years; P=.052), in those with ECOG performance score (PS) of 1–2 compared with those with ECOG PS of 0 (90% vs 50%; P=.02), in those with right-sided tumors (55% vs 32%; P=.013), and in those with unresected primary tumors (58% vs 21%; P<.001).89 MSI-high status was also found to be more prevalent in RET gene fusion–positive samples compared with RET-negative samples (48% vs 7%; P<.001). All RET gene fusion–positive samples were RAS and BRAF wild-type.89 The highly selective RET kinase inhibitor, selpercatinib, is a treatment option for patients with mCRC that is RET gene fusion-positive (see later section on “Selpercatinib for RET Gene Fusion Positive Disease in the Non-First-Line Setting”).

Tumor Mutational Burden

Tumor mutational burden (TMB) measures the total amount of somatic coding mutations within a given coding area of the tumor genome and can be quantified using NGS techniques.90 Research has identified TMB as a potential biomarker for response to immunotherapy, and pembrolizumab has been FDA-approved for patients with unresectable or metastatic TMB-high (TMB-H) solid tumors that have progressed after prior treatment and have no satisfactory alternative treatment options.91 TMB-H is defined in the label as 10 or more mutations/megabase by an FDA-approved test. This approval was based on results of the phase 2, KEYNOTE-158 study that enrolled patients with advanced solid tumors.92 Patients with TMB-H tumors who were treated with pembrolizumab had an ORR of 29% compared with 6% of those with non-TMB-H tumors. However, of the 796 patients who were evaluated for efficacy on this study, none had CRC.

The phase II TAPUR basket study included a cohort of 28 patients with TMB-H advanced CRC who were treated with pembrolizumab.93 For the CRC cohort, the disease control rate was 31% and the ORR was 11%. Another abstract on the TAPUR study, reporting results for 12 patients with TMB-H advanced CRC treated with nivolumab plus ipilimumab, concluded that the combination therapy does not have sufficient clinical activity in MSS, TMB-H CRC.94

Based on the limited data in the CRC population, the NCCN Panel does not currently recommend TMB biomarker testing, unless measured as part of a clinical trial.

Severe Fluoropyrimidine-Associated Toxicity

Dihydropyrimidine dehydrogenase (DPYD) is the enzyme that catabolizes fluoropyrimidines.95,96 Certain variants of the DPYD gene result in a truncated protein, which may lead to prolonged systemic exposure to fluoropyrimidine97101 and may herald an increased risk of severe toxicity.102104 The actual incidence of specific gene alterations of these variants across different populations is unknown. A systematic review of the published literature found that, across 13,929 patients, such DPYD variants (heterozygous or homozygous) were identified in 4.1% of patients.104 Treatment-related deaths were reported in 0.1% in patients without identified DPYD variants and in 2.3% of those with known DPYD variants (95% CI, 1.3%–3.9%).

Although not all patients known to have DPYD variants are necessarily at increased risk of toxicity, such individuals could receive dose reductions or could be offered nonfluoropyrimidine regimens.96 Prospective studies have shown DPYD genotyping to be feasible in clinical practice and that dose reductions in the setting of variant DPYD genes diminish the risk of substantial toxicity.105107 In a prospective study, 22 patients with the DPYD*2A variant allele (of 2,038 patients screened; 1.1%) received dose-reduced fluoropyrimidine which led to a significant reduction in the risk of grade ≥3 toxicity compared with historic controls (28% vs 73%; P<.001).107 None of the patients died of drug toxicity, compared with a 10% death rate in the historical control group. However, there was great heterogeneity in the specific treatment regimens and dosing decisions within the treated cohorts. Capecitabine was the fluoropyrimidine given to most patients, but the various combinations also included other chemotherapeutics as well as bolus and infusional 5-FU. Also, the protocol left the specific dosing decision to the physician, and fluoropyrimidine dose reductions ranged from 17% to 91% (median 48%).107 A cost-effectiveness modeling within this study concluded that pretreatment testing was cost-effective, largely based on the assumptions that intensive care unit hospitalizations and the cost of uridine triacetate (approximately $75,000 per cycle) as a rescue treatment in very ill patients could be avoided. Efficacy was not an endpoint in this study. Another prospective study identified 85 patients with any of the 4 most common DPYD variant alleles (8% of 1,103 patients screened) who received an initial fluoropyrimidine dose reduction of either 25% or 50% depending on the specific allele.106 This study reported that the RR of severe fluoropyrimidine-related toxicity was reduced for genotype-guided dosing for all studied alleles compared with the historical cohorts.

In an effort to standardize the dose adjustments indicated by the specific variants, the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing provides dosing recommendations for 5-FU and 5-FU prodrug-based regimens based on DPYD.108 A reduced starting dose of fluoropyrimidines is recommended for intermediate metabolizers (those who are heterozygous for DPYD decreased/no function variants). Some patients with decreased/no function variants tolerate normal doses of fluoropyrimidines; thus the CPIC Guidelines recommend increasing doses in subsequent cycles for patients with minimal or no toxicity in the first 2 cycles of treatment. Further dose reduction is recommended for those who do not tolerate the reduced starting dose. For those classified as poor metabolizers, the CPIC Guidelines recommend avoiding fluoropyrimidines. These guidelines reflect common sense dose adjustments rather than methodically derived dosing based on actual pharmacokinetics. Also, the dose adjustment paradigm does not distinguish between intravenous bolus or infusional 5-FU or the prodrug capecitabine. The pharmacokinetics of intravenous 5-FU vary greatly based on the rate of infusion, and there are many more factors involved in determining an individual’s tolerance of capecitabine, which is uniformly used at reduced dose in the United States compared with Europe.109

Although dose adjustment of fluoropyrimidines based on DPYD genotype has been shown to diminish toxicity, it is not certain that dose reductions do not result in inferior efficacy. A prospective multicenter study of 156 DPYD variant carriers and 775 DPYD wild-type controls, most with advanced or metastatic disease, sought to test this.110 In this study, DPYD variant carriers received either a 25% or 50% fluoropyrimidine dose reduction, depending on the exact variant. Each DPYD variant carrier was matched to 3 wild-type controls treated with the standard dose. For pooled DPYD variant carriers, PFS and OS were not significantly affected by these lower fluoropyrimidine doses, although a shorter PFS (HR, 1.43; 95% CI, 1.10–1.86; P=.007) was found in the 61 carriers of the c.1236G>A variant who were treated with the reduced dose. These findings raise the possibility that dose reduction may diminish the efficacy of the fluoropyrimidine with at least this variant of DPYD. Although the impact in patients with advanced CRC may not be significant, reduced efficacy of fluoropyrimidines when used in the adjuvant setting could be very meaningful. Because fluoropyrimidines are a pillar of therapy in CRC and it is not known with certainty that given DPYD variants are associated with this risk and/or that dose adjustments do not impact efficacy, the NCCN Panel does not recommend universal pretreatment DPYD genotyping at this time. However, as with all guideline decisions, the panel reviews all new data and considers input from stakeholders in real time and guidelines are continuously reassessed.

Uridine triacetate is an orally administered pyrimidine analog that is believed to compete for receptors on normal cells and, as such, decreases the toxic effects of excessive fluoropyrimidines. It is FDA approved for the emergency treatment of both adult and pediatric patients exhibiting early-onset, severe or life-threatening toxicity within 96 hours of the completion of 5-FU or capecitabine administration.111 Uridine triacetate was evaluated in 2 single-arm, multicenter open-label trials in which a total of 135 patients were treated with uridine triacetate following 5-FU or capecitabine overdose or upon early onset of severe toxicities.112,113 In these studies, a total of 96% of the patients treated with uridine triacetate survived and exhibited rapid reversal of severe cardiac and neurologic toxicities. Thirty-eight percent of these patients were able to resume chemotherapy within 30 days, with a mean time to resumption of chemotherapy of 19.6 days.112 The importance of administration of uridine triacetate within the first 96 hours must be noted. While most patients on these trials were treated within the first 96 hours, 50% of the 4 patients who were treated beyond 96 hours died.113

First-Line Systemic Therapy

The focus of this publication is on some of the newer regimens recommended for systemic therapy for mCRC, especially the targeted therapy options (see Figure 1). Therefore, for data supporting FOLFOX, CAPEOX, FOLFIRI, infusional 5-FU, capecitabine, or FOLFIRINOX for first-line therapy, please see the full guidelines available online at NCCN.org.

Figure 1.
Figure 1.

COL-D 1 of 11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0029

Bevacizumab for First-line Therapy

Bevacizumab is a humanized monoclonal antibody that blocks the activity of VEGF, a factor that plays an important role in tumor angiogenesis.114 The NCCN Panel notes that FDA-approved biosimilars may be substituted for bevacizumab wherever the therapy is recommended within these guidelines (see “Biosimilars” in the full guidelines, available online at NCCN.org, for more information). Pooled results from several randomized phase II studies have shown that the addition of bevacizumab to first-line 5-FU/LV improved OS in patients with unresectable mCRC compared with those receiving these regimens without bevacizumab.115117 A combined analysis of the results of these trials showed that the addition of bevacizumab to 5-FU/LV was associated with a median survival of 17.9 versus 14.6 months for regimens consisting of 5-FU/LV or 5-FU/LV plus irinotecan without bevacizumab (P=.008).118 A study of previously untreated patients receiving bevacizumab plus IFL also provided support for the inclusion of bevacizumab in initial therapy.115 In that pivotal trial, a longer survival time was observed with the use of bevacizumab (20.3 vs 15.6 months; HR, 0.66; P<.001).

Results have also been reported from a large, head-to-head, randomized, double-blind, placebo-controlled, phase III study (NO16966) in which CAPEOX (capecitabine dose, 1,000 mg/m2, twice daily for 14 days) with bevacizumab or placebo was compared with FOLFOX with bevacizumab or placebo in 1,400 patients with unresectable metastatic disease.119 The addition of bevacizumab to oxaliplatin-based regimens was associated with a more modest increase of 1.4 months in PFS compared with these regimens without bevacizumab (HR, 0.83; 97.5% CI, 0.72–0.95; P=.0023), and the difference in OS, which was also a modest 1.4 months, did not reach statistical significance (HR, 0.89; 97.5% CI, 0.76–1.03; P=.077).119 Researchers have suggested that differences observed in cross-study comparisons of NO16966 with other trials might be related to differences in the discontinuation rates and durations of treatment between trials, although these hypotheses are conjectural.119 However, in this 1,400-patient randomized study, absolutely no difference in response rate was seen with and without bevacizumab, and this finding could not have been influenced by the early withdrawal rates, which would have occurred after the responses would have occurred. Results of subset analyses evaluating the benefit of adding bevacizumab to either FOLFOX or CAPEOX indicated that bevacizumab was associated with improvements in PFS when added to CAPEOX but not FOLFOX.119

The combination of FOLFIRI and bevacizumab in the first-line treatment of advanced CRC has been studied, although no RCTs have compared FOLFIRI with and without bevacizumab. A systematic review with a pooled analysis (29 prospective and retrospective studies, 3,502 patients) found that the combination gave a response rate of 51.4%, a median PFS of 10.8 months (95% CI, 8.9–12.8), and a median OS of 23.7 months (95% CI, 18.1–31.6).120 FOLFIRINOX with bevacizumab is also an accepted combination (see “FOLFOXIRI or FOLFIRINOX,” in the full guidelines, available online at NCCN.org), although no RCTs have compared FOLFIRINOX with and without bevacizumab.

A prospective observational cohort study (ARIES) included 1,550 patients who received first-line therapy with bevacizumab with chemotherapy for mCRC and 482 patients treated with bevacizumab in second-line.121 Median OS was 23.2 months (95% CI, 21.2–24.8) for the first-line cohort and 17.8 months (95% CI, 16.5–20.7) in the second-line group. A similar cohort study (ETNA) of first-line bevacizumab use with irinotecan-based therapy reported a median OS of 25.3 months (95% CI, 23.3–27.0).122

Several meta-analyses have shown a benefit for the use of bevacizumab in first-line therapy for mCRC.123131 A meta-analysis of 6 RCTs (3,060 patients) that assessed the efficacy of bevacizumab in first-line treatment of mCRC found that bevacizumab gave a PFS (HR, 0.72; 95% CI, 0.66–0.78; P<.00001) and OS (HR, 0.84; 95% CI, 0.77–0.91; P<.00001) advantage.132 However, subgroup analyses showed that the advantage was limited to irinotecan-based regimens. In addition, an analysis of the SEER-Medicare database found that bevacizumab added a modest improvement to OS of patients with stage IV CRC diagnosed between 2002 and 2007 (HR, 0.85; 95% CI, 0.78–0.93).133 The survival advantage was not evident when bevacizumab was combined with oxaliplatin-based chemotherapy but was evident in irinotecan-based regimens. Limitations of this analysis have been discussed,134,135 but, overall, the addition of bevacizumab to first-line chemotherapy appears to offer a modest clinical benefit.

A meta-analysis of RCTs showed that the addition of bevacizumab to chemotherapy is associated with a higher incidence of treatment-related mortality than chemotherapy alone (RR, 1.33; 95% CI, 1.02–1.73; P=.04), with hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal perforation (7.1%) being the most common causes of fatality.136 Venous thromboembolisms, conversely, were not increased in patients receiving bevacizumab with chemotherapy versus those receiving chemotherapy alone.137 Another meta-analysis showed that bevacizumab was associated with a significantly higher risk of hypertension, gastrointestinal hemorrhage, and perforation, although the overall risk for hemorrhage and perforation is quite low.138 The risk of stroke and other arterial events is increased in patients receiving bevacizumab, especially in those ≥65 years. Gastrointestinal perforation is a rare but important side effect of bevacizumab therapy in patients with CRC.139,140 Extensive prior intra-abdominal surgery, such as peritoneal stripping, may predispose patients to gastrointestinal perforation. A small cohort of patients with advanced ovarian cancer had an unacceptably high rate of gastrointestinal perforation when treated with bevacizumab.141 This result illustrated that peritoneal debulking surgery may be a risk factor for gastrointestinal perforation, whereas the presence of an intact primary tumor does not seem to increase the risk for gastrointestinal perforation. The FDA approved a safety label warning of the risk for necrotizing fasciitis, sometimes fatal and usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation after bevacizumab use.114

Use of bevacizumab may interfere with wound healing.114,139,140 A retrospective evaluation of data from 2 randomized trials of 1,132 patients undergoing chemotherapy with or without bevacizumab as initial therapy for mCRC indicated that the incidence of wound healing complications was increased for the group of patients undergoing a major surgical procedure while receiving a bevacizumab-containing regimen compared with the group receiving chemotherapy alone while undergoing major surgery (13% vs 3.4%, respectively; P=.28).140 However, when chemotherapy plus bevacizumab or chemotherapy alone was administered after surgery, with a delay between surgery and bevacizumab administration of at least 6 weeks, the incidence of wound healing complications in either group of patients was low (1.3% vs 0.5%; P=.63). Similarly, results of a single-center, nonrandomized phase II trial of patients with potentially resectable liver metastases showed no increase in bleeding or wound complications when the bevacizumab component of CAPEOX plus bevacizumab therapy was stopped 5 weeks before surgery (ie, bevacizumab excluded from the sixth cycle of therapy).142 In addition, no significant differences in bleeding, wound, or hepatic complications were seen in a retrospective trial evaluating the effects of preoperative bevacizumab stopped at 8 weeks or less versus at more than 8 weeks before resection of liver colorectal metastases in patients receiving oxaliplatin- or irinotecan-containing regimens.143 The panel recommends an interval of at least 6 weeks (which corresponds to 2 half-lives of the drug114) between the last dose of bevacizumab and any elective surgery. Additionally, reinitiation of bevacizumab should be delayed at least 6 to 8 weeks postoperatively.

Preclinical studies suggested that cessation of anti-VEGF therapy might be associated with accelerated recurrence, more aggressive tumors on recurrence, and increased mortality. A retrospective meta-analysis of 5 placebo-controlled, randomized phase III trials including 4,205 patients with metastatic colorectal, breast, renal, or pancreatic cancer found no difference in time to disease progression and mortality with discontinuation of bevacizumab versus discontinuation of placebo.144 Although this meta-analysis has been criticized,145,146 the results are supported by results from the NSABP Protocol C-08 trial.147 This trial included patients with stage II and stage III CRC, and no differences in recurrence, mortality, or mortality 2 years after recurrence were seen between patients receiving bevacizumab versus patients in the control arm. These results suggest that no “rebound effect” is associated with bevacizumab use.

Cetuximab or Panitumumab for First-Line Therapy in KRAS/NRAS Wild-Type Disease

Cetuximab and panitumumab are monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways. Panitumumab is a fully human monoclonal antibody, whereas cetuximab is a chimeric monoclonal antibody.148 Cetuximab and panitumumab have been studied in combination with FOLFIRI and FOLFOX as initial therapy options for treatment of mCRC. The randomized, phase II PLANET-TTD trial comparing patients treated with panitumumab plus either FOLFOX or FOLFIRI found no significant differences in efficacy between the 2 regimens.149

Meta-analyses of RCTs have concluded that EGFR inhibitors provide a clear clinical benefit in the treatment in patients with RAS wild-type mCRC.20,150 Patients with known KRAS- or NRAS-mutant tumors should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified (see previous sections on “Biomarkers for Systemic Therapy,” and “KRAS and NRAS Mutations,” for more information). Individual trials are discussed subsequently.

Administration of either cetuximab or panitumumab has been associated with severe infusion reactions, including anaphylaxis, in 3% and 1% of patients, respectively.148 Based on case reports and a small trial, administration of panitumumab seems to be feasible for patients experiencing severe infusion reactions to cetuximab.151153 Skin toxicity is a side effect of both of these agents and is not considered part of the infusion reactions. The incidence and severity of skin reactions with cetuximab and panitumumab seem to be very similar. Furthermore, the presence and severity of skin rash in patients receiving either of these drugs have been shown to predict increased response and survival.16,18,154157 An NCCN task force addressed the management of dermatologic and other toxicities associated with EGFR inhibitors.158 Cetuximab and panitumumab have also been associated with a risk for venous thromboembolic and other serious AEs.159,160

Based on the results of the PACCE and CAIRO2 trials, the panel strongly advises against the concurrent use of bevacizumab with either cetuximab or panitumumab (see previous section on “Bevacizumab”).161,162 Several trials that assessed EGFR inhibitors in combination with various chemotherapy agents are discussed subsequently.

Cetuximab/Panitumumab and Primary Tumor Sidedness

A growing body of data has shown that the location of the primary tumor can be both prognostic and predictive of response to EGFR inhibitors in mCRC.163171 For example, outcomes for 75 patients with mCRC treated with cetuximab, panitumumab, or cetuximab/irinotecan in first-line or subsequent lines of therapy at 3 Italian centers were analyzed based on sidedness of the primary tumor.164 No responses were seen in the patients with right-sided primary tumors compared with a response rate of 41% in those with left-sided primaries (P=.003). The median PFS was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (HR, 3.97; 95% CI, 2.09–7.53; P<.0001).

The strongest evidence for the predictive value of primary tumor sidedness and response to EGFR inhibitors is in the first-line treatment of patients in the phase III CALGB/SWOG 80405 trial.168 The study showed that patients with RAS wild-type, right-sided primary tumors (cecum to hepatic flexure) had longer OS if treated with bevacizumab than if treated with cetuximab in first line (HR, 1.36; 95% CI, 0.93–1.99; P=.10), whereas patients with all RAS wild-type, left-sided primary tumors (splenic flexure to rectum) had longer OS if treated with cetuximab than if treated with bevacizumab (HR, 0.77; 95% CI, 0.59–0.99; P=.04).172 OS was prolonged with cetuximab versus bevacizumab in the left-sided primary group (39.3 vs 32.6 months) but shortened in the right-sided primary group (13.6 vs 29.2 months). Retrospective analyses of other contemporary studies have confirmed this finding.171

These and other data suggest that cetuximab and panitumumab confer little if any benefit to patients with mCRC if the primary tumor originated on the right side. The panel believes that primary tumor sidedness is a surrogate for the nonrandom distribution of molecular subtypes across the colon and that the ongoing analysis of genomic differences between right- and left-sided tumors173 will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy,163,164,166 but the panel awaits more definitive studies. Until such data are available, all patients with RAS/BRAF wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given.

Cetuximab With FOLFIRI

Use of cetuximab as initial therapy for metastatic disease was investigated in the CRYSTAL trial, in which patients were randomly assigned to receive FOLFIRI with or without cetuximab.18 Retrospective analyses of the subset of patients with known KRAS exon 2 tumor status showed a statistically significant improvement in median PFS with the addition of cetuximab in the wild-type setting (9.9 vs 8.7 months; HR, 0.68; 95% CI, 0.50–0.94; P=.02).18 The statistically significant benefit in PFS for patients with KRAS exon 2 wild-type tumors receiving cetuximab was confirmed in a publication of an updated analysis of the CRYSTAL data.41 This study included a retrospective analysis of OS in the KRAS exon 2 wild-type population and found an improvement with the addition of cetuximab (23.5 vs 20.0 months; P=.009). Importantly, the addition of cetuximab did not affect the quality of life of participants in the CRYSTAL trial.174 As has been seen with other trials, when DNA samples from the CRYSTAL trial were reanalyzed for additional KRAS and NRAS mutations, patients with RAS wild-type tumors derived a clear OS benefit (HR, 0.69; 95% CI, 0.54–0.88), whereas those with any RAS mutation did not (HR, 1.05; 95% CI, 0.86–1.28).175

Panitumumab With FOLFIRI

FOLFIRI with panitumumab is listed as an option for first-line therapy in mCRC based on extrapolation from data in second-line treatment.51,176178

Cetuximab With FOLFOX

Several trials have assessed the combination of FOLFOX and cetuximab in first-line treatment of mCRC. In a retrospective evaluation of the subset of patients with known tumor KRAS exon 2 status enrolled in the randomized phase II OPUS trial, addition of cetuximab to FOLFOX was associated with an increased objective response rate (61% vs 37%; OR, 2.54; P=.011) and a very slightly lower risk of disease progression (7.7 vs 7.2 months [a 15-day difference]; HR, 0.57; 95% CI, 0.36–0.91; P=.016) compared with FOLFOX alone in the subset of patients with KRAS exon 2 wild-type tumors.12 Although data supporting the statistically significant benefits in objective response rate and PFS for patients with tumors characterized by KRAS wild-type exon 2 were upheld in an update of this study, no median OS benefit was observed for the addition of cetuximab to chemotherapy (22.8 months in the cetuximab arm vs 18.5 months in the arm undergoing chemotherapy alone; HR, 0.85; P=.39).179

Furthermore, in the randomized phase III MRC COIN trial, no benefit in OS (17.9 vs 17.0 months; P=.067) or PFS (8.6 months in both groups; P=.60) was seen with the addition of cetuximab to FOLFOX or CAPEOX as first-line treatment of patients with locally advanced or mCRC and wild-type KRAS exon 2.42 Exploratory analyses of the COIN trial, however, suggest that there may be a benefit to the addition of cetuximab in patients who received FOLFOX instead of CAPEOX.42

Notably, additional trials examining the efficacity of the addition of cetuximab to oxaliplatin-containing regimens in the first-line treatment of patients with advanced or mCRC and wild-type KRAS exon 2 have not shown any benefit. The addition of cetuximab to the Nordic FLOX regimen showed no benefit in OS or PFS in this population of patients in the randomized phase III NORDIC VII study of the Nordic Colorectal Cancer Biomodulation Group.180

However, results from the randomized phase III CALGB/SWOG 80405 trial of greater than 1,000 patients (discussed in the “Cetuximab or Panitumumab vs Bevacizumab in First-line Therapy,” section, later in the discussion) showed that the combination of FOLFOX with cetuximab can be effective in first-line treatment of mCRC.181 The phase III open-label, randomized TAILOR trial confirmed this result, reporting benefits in PFS (9.2 vs 7.4 months; P=.004), OS (20.7 vs 17.8 months; P=.02), and ORR (61.1% vs 39.5%; P<.001) with first-line cetuximab plus FOLFOX compared with FOLFOX alone in patients with RAS wild-type mCRC.182 Therefore, the panel recommends cetuximab plus FOLFOX as an initial therapy option for RAS/BRAF wild-type patients with advanced or metastatic disease.

Panitumumab With FOLFOX

Panitumumab in combination with either FOLFOX19,183 or FOLFIRI184 has also been studied in the first-line treatment of patients with mCRC. Results from the large, open-label, randomized PRIME trial comparing panitumumab plus FOLFOX versus FOLFOX alone in patients with KRAS/NRAS wild-type advanced CRC showed a statistically significant improvement in PFS (HR, 0.72; 95% CI, 0.58–0.90; P=.004) and OS (HR, 0.77; 95% CI, 0.64–0.94; P=.009) with the addition of panitumumab.19 Therefore, the combination of FOLFOX and panitumumab remains an option as initial therapy for patients with advanced or metastatic disease. Importantly, the addition of panitumumab had a detrimental impact on PFS for patients with tumors characterized by mutated KRAS/NRAS in the PRIME trial (discussed further in the previous section, “KRAS and NRAS Mutations” within the section on “Biomarkers for Systemic Therapy”).19

The phase III randomized GONO TRIPLETE study compared mFOLFOXIRI plus panitumumab with mFOLFOX6 plus panitumumab as initial therapy in patients with unresectable RAS/BRAF wild-type mCRC and found that more intensive mFOLFOXIRI plus panitumumab did not provide additional benefit and resulted in nonnegligible increases in gastrointestinal toxicity.185 The 2 groups had similar OR rates, at 76% for mFOLFOX6 plus panitumumab versus 73% for mFOLFOXIRI plus panitumumab (odds ratio, 0.87; 95% CI, 0.56–1.34; P=.526). Median PFS was also similar at a median follow up of 26.5 months, at 12.7 months for mFOLFOX6 plus panitumumab versus 12.3 months for mFOLFOXIRI plus panitumumab (HR, 0.88; 95% CI, 0.70–1.11; P=.277). There were also no significant differences in early tumor shrinkage (58% vs 57%; P=.878) or deepness of response (47% vs 48%; P=.845) noted. Grade >2 diarrhea occurred in 7% of patients in the mFOLFOX6 plus panitumumab versus 23% of patients in the mFOLFOXIRI plus panitumumab group.

Cetuximab With CAPEOX

In a trial comparing CAPEOX/cetuximab versus FOLFOX/cetuximab, 88 patients with extended RAS/BRAF/PIK3CA wild-type mCRC were evaluated.186 There was no significant difference in response rate between the CAPEOX/cetuximab versus FOLFOX/cetuximab arms, at 61.5% and 66.7%, respectively (P=.298). Disease control rates were also similar, at 86.5% (95% CI, 74.2%–94.4%) for the CAPEOX/cetuximab group versus 88.9% (95% CI, 73.9%–96.9%) for the FOLFOX/cetuximab roup. Based on these data, the panel now recommends CAPEOX plus cetuximab or panitumumab in addition to FOLFOX plus cetuximab or panitumumab for initial therapy for advanced or mCRC.

Cetuximab or Panitumumab Versus Bevacizumab in First-Line Therapy

The randomized, open-label, multicenter FIRE-3 trial from the German AIO group compared the efficacy of FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in first-line, KRAS exon 2 wild-type, metastatic disease.30 This trial did not meet its primary endpoint of investigator-read objective response rate in the 592 patients (62.0% vs 58.0%; P=.18). PFS was nearly identical between the arms of the study, but a statistically significant improvement in OS was reported in the cetuximab arm (28.7 vs 25.0 months; HR, 0.77; 95% CI, 0.62–0.96; P=.017). The panel has several criticisms of the trial, including the lack of third-party review and low rates of second-line therapy.187,188 While the rate of AEs was similar between the arms, more skin toxicity was observed in those receiving cetuximab. A final survival analysis of the FIRE-3 study reported a median OS in the RAS wild-type population of 31 months with cetuximab versus 26 months with bevacizumab, along with improved outcomes for ORR and median OS in the per-protocol population with cetuximab.189 PFS was similar between the groups and the advantage for cetuximab only occurred in patients with left-sided primary tumors.

The phase III PARADIGM trial evaluated the use of panitumumab versus bevacizumab when combined with FOLFOX as first-line therapy in 823 patients with RAS wild-type mCRC.190 In the as-treated population, 75.3% had left-sided tumors. After a median follow-up of 61 months, panitumumab showed a significantly higher median OS when used as part of the first-line regimen compared with bevacizumab. This was true for both the left-sided tumor population (37.9 vs 34.3 months; P=.03) as well as the full analysis set (36.2 vs 31.3 months; P=.03). Although PFS was similar between the treatment groups, RR and R0 resection rates were higher with panitumumab. The panel notes that since the OS curves do not separate until well after the median PFS, the improvement in OS with panitumumab may be related to what the patients received in later lines of therapy rather than the choice of first-line therapy.

Results of the phase III CALGB/SWOG 80405 trial, comparing FOLFOX/FOLFIRI with cetuximab or bevacizumab, were reported.181 In this study, patients with wild-type KRAS exon 2 tumors received either FOLFOX (73%) or FOLFIRI (27%) and were randomized to receive cetuximab or bevacizumab. The primary endpoint of OS was equivalent between the arms, at 29.0 months in the bevacizumab arm versus 30.0 months in the cetuximab arm (HR, 0.88; 95% CI, 0.77–1.01; P=.08).

Results for the randomized multicenter phase II PEAK trial, which compared FOLFOX/panitumumab with FOLFOX/bevacizumab in first-line treatment of patients with wild-type KRAS exon 2 tumors, were also published.191 In the subset of 170 participants with wild-type KRAS/NRAS based on extended tumor analysis, PFS was better in the panitumumab arm (13.0 vs 9.5 months; HR, 0.65; 95% CI, 0.44–0.96; P=.03). A trend toward improved OS was seen (41.3 vs 28.9 months; HR, 0.63; 95% CI, 0.39–1.02; P=.06). The final analysis of the PEAK trial confirmed that FOLFOX/panitumumab showed a longer PFS compared with FOLFOX/bevacizumab in patients with wild-type RAS tumors (12.8 vs 10.1 months; HR, 0.68; 95% CI, 0.48–0.96; P=.029).192 Although these data are intriguing, definitive conclusions are hindered by the small sample size and limitations of subset analyses.193

Economic analyses suggest that bevacizumab may be more cost-effective than EGFR inhibitors in first-line therapy for mCRC,194 although more recent analyses have shown the opposite.195,196

At this time, the panel considers the addition of cetuximab, panitumumab, or bevacizumab to chemotherapy as equivalent choices in the first-line, left-sided, RAS/BRAF wild-type, metastatic setting.

Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or Functional POLE/POLD1 Mutation-Positive Disease in the First-Line Setting

The phase III, randomized open-label KEYNOTE-177 study evaluated the use of pembrolizumab compared with chemotherapy with or without bevacizumab or cetuximab as first-line therapy for 307 patients with MSI-H/dMMR mCRC.197 Median PFS was found to be longer with pembrolizumab compared with chemotherapy (16.5 vs 8.2 months; HR, 0.60; 95% CI, 0.45–0.80; P=.0002). Confirmed ORR was 43.8% with pembrolizumab versus 33.1% with chemotherapy. Grade ≥3 treatment-related AEs were reported in 22% of patients treated with pembrolizumab compared with 66% of those treated with chemotherapy. In an updated final analysis of KEYNOTE-177, with a median follow up of 44.5 months, median OS was not reached (NR) with pembrolizumab (NR; 95% CI, 49.2–NR) compared with 36.7 months (NR; 95% CI, 27.6–NR) with chemotherapy (HR, 0.74; 95% CI, 0.53–1.03; P=.036).198 Altough the survival difference was not significant between the 2 arms, the study did report a 60% crossover rate, with 60% of patients on the chemotherapy-first arm crossing over to pembrolizumab or another checkpoint inhibitor during the course of the study.

A follow up health-related quality of life analysis of 294 patients treated as part of KEYNOTE-177 revealed a clinically meaningful improvement in quality of life with pembrolizumab versus chemotherapy based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (P=.0002).199

Likewise, the phase II CheckMate-142 trial evaluated the role of nivolumab in combination with ipilimumab for first-line treatment of dMMR/MSI-H mCRC.200 In the first-line cohort, ORR was found to be 69% (95% CI, 53%–82%) and disease control rate was 84% (95% CI, 70.5%–93.5%), with a median follow-up of 29 months. Thirteen percent of patients had complete disease response and the median duration of response, median PFS, and median OS had not been reached. Twenty percent of patients had grade 3 or 4 treatment-related AEs, and AEs led to discontinuation in 13% of patients. A 2022 abstract reported 5-year follow up results of CheckMate-142.201 ORR by investigator assessment increased to 71% (95% CI, 56–84), with progressive disease rate of 16%. PFS and OS rates at 48 months were 51% and 72%, respectively. Additional results from CheckMate-142 (including nivolumab alone or in combination with ipilimumab as subsequent therapy) are discussed in “Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the Non-First-Line Setting,” below.

CheckMate 8HW is an ongoing phase III study comparing nivolumab in combination with ipilimumab to nivolumab alone or chemotherapy for dMMR/MSI-H mCRC. In a prespecified interim analysis, PFS was compared between nivolumab plus ipilimumab (202 patients) and chemotherapy (101 patients) in the first-line setting.202 With a median follow-up of 24.3 months, the combination of nivolumab plus ipilimumab showed a significant improvement in PFS compared with chemotherapy, with a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.14–0.32; P<.0001). No new safety signals were observed, and nivolumab plus ipilimumab had a lower percentage of grade ≥3 treatment-related AEs compared with chemotherapy (23% vs 48%), although there were 2 treatment-related deaths on the immunotherapy combination and none with chemotherapy. OS data have not yet been presented.

Although PD-1 immune checkpoint inhibitors are generally well tolerated, serious adverse reactions—many immune-mediated—occur in as many as 21% to 41% of patients.203206 The most common immune-mediated side effects are to the skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems.207209 Pneumonitis, occurring in approximately 3% to 7% of patients on checkpoint inhibitor therapy, is one of the most serious side effects of PD-1 inhibitors.207,210212

Based on these data, the panel recommends pembrolizumab; dostarlimab-gxly; or nivolumab, alone or in combination with ipilimumab, as first-line treatment options for patients with MSI-H/dMMR mCRC, regardless of whether intensive therapy is recommended (see Figure 2). The recommendation for nivolumab plus ipilimumab is category 2B when intensive therapy is not recommended due to concerns about potential toxicity from the combination therapy. While dostarlimab-gxly does not have clinical trial data for untreated mCRC, the panel feels that the checkpoint inhibitors may be used interchangeably for dMMR/MSI-H mCRC and the clinical trial data for dostarlimab-gxly in both the previously untreated, locally advanced and the previously treated mCRC settings support its use in the first-line setting. As discussed in the previous “Biomarkers for Systemic Therapy” section, checkpoint inhibitor immunotherapy is also recommended for mCRC with functional POLE/POLD1 mutations.

Figure 2.
Figure 2.

COL-D 3 of 11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0029

Second-Line or Subsequent Systemic Therapy

The recommended therapy options after first progression for patients who have received prior therapy are dependent on the initial treatment regimen and are outlined in the guidelines (see Figure 3). Single-agent irinotecan administered after first progression has been shown to significantly improve OS relative to best supportive care213 or infusional 5-FU/LV.214 In the study of Rougier et al,214 median PFS was 4.2 months for irinotecan versus 2.9 months for 5-FU (P=.030), whereas Cunningham et al213 reported a survival rate at 1 year of 36.2% in the group receiving irinotecan versus 13.8% in the supportive care group (P=.0001). A meta-analysis of 5 RCTs showed that there was no OS benefit to FOLFIRI over that obtained with irinotecan alone.215 Furthermore, no significant differences in OS were observed in the Intergroup N9841 trial when FOLFOX was compared with irinotecan monotherapy after first progression of mCRC.216

Figure 3.
Figure 3.

COL-D 2 of 11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 2D; 10.6004/jnccn.2024.0029

A meta-analysis of randomized trials found that the addition of a targeted agent after first-line treatment improves outcomes but also increases toxicity.217 Another meta-analysis showed an OS and PFS benefit to continuing an antiangiogenic agent after progression on an antiangiogenic agent in first-line treatment.218 Data relating to specific biologic therapies are discussed subsequently.

Cetuximab and Panitumumab in the Non–First-Line Setting

For patients with wild-type KRAS/NRAS/BRAF tumors who experienced progression on therapies not containing an EGFR inhibitor, cetuximab or panitumumab plus irinotecan, cetuximab or panitumumab plus FOLFIRI, or single-agent cetuximab or panitumumab14 is recommended. For patients with wild-type KRAS/NRAS/BRAF tumors progressing on therapies that did contain an EGFR inhibitor, administration of an EGFR inhibitor is not recommended in subsequent lines of therapy, except for anti-EGFR rechallenge. No data support switching to either cetuximab or panitumumab after failure of the other drug, and the panel recommends against this practice. While there is limited evidence suggesting that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy, the panel awaits more definitive studies to set this limitation. Until such data are available, all patients with RAS/BRAF wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given. See previous section on “Cetuximab/Panitumumab and Primary Tumor Sidedness,” for discussion of data.

Panitumumab has been studied as a single agent in the setting of mCRC for patients with disease progression on oxaliplatin/irinotecan-based chemotherapy in an open-label phase III trial.219 In a retrospective analysis of the subset of patients in this trial with known KRAS exon 2 tumor status, the benefit of panitumumab versus best supportive care was shown to be enhanced in patients with KRAS exon 2 wild-type tumors.10 PFS was 12.3 weeks versus 7.3 weeks in favor of the panitumumab arm. Response rates to panitumumab were 17% versus 0% in the wild-type and mutant arms, respectively.10 A more recent phase III trial compared single-agent panitumumab to best supportive care in patients with wild-type KRAS exon 2 mCRC and disease progression on oxaliplatin- and irinotecan-based chemotherapy.220 The primary endpoint of OS was improved with panitumumab (10.0 vs 7.4 months; HR, 0.73; 95% CI, 0.57–0.93; P<.01).

Panitumumab has also been studied in combination therapy in the setting of progressing mCRC. Among patients with KRAS exon 2 wild-type tumors enrolled in the large Study 181 comparing FOLFIRI alone versus FOLFIRI plus panitumumab as second-line therapy for mCRC, addition of the biologic agent was associated with improvement in median PFS (5.9 vs 3.9 months; HR, 0.73; 95% CI, 0.59–0.90; P=.004), although differences in OS between the arms did not reach statistical significance.176 These results were confirmed in the final results of Study 181.178 Furthermore, reanalysis of samples from the trial showed that the benefit of the combination was limited to participants with no RAS mutations.221 In addition, secondary analysis from the STEPP trial showed that panitumumab in combination with irinotecan-based chemotherapy in second-line therapy has an acceptable toxicity profile.177 The randomized multicenter PICCOLO trial, which assessed the safety and efficacy of irinotecan/panitumumab, did not meet its primary endpoint of improved OS in patients with wild-type KRAS/NRAS tumors.51

Cetuximab has been studied both as a single agent14,154,222,223 and in combination with irinotecan222 in patients experiencing disease progression on initial therapy not containing cetuximab or panitumumab for metastatic disease. Results of a large phase III study comparing irinotecan with or without cetuximab did not show a difference in OS, but showed significant improvement in response rate and in median PFS with irinotecan and cetuximab compared with irinotecan alone.224 Importantly, KRAS status was not determined in this study and toxicity was higher in the cetuximab-containing arm (eg, rash, diarrhea, electrolyte imbalances).224 In a reanalysis of RAS status, median PFS (5.4 vs 2.6 months; HR, 0.57; 95% CI, 0.46–0.69; P<.0001) and objective response rate (29.4% vs 5.0%; odds ratio, 8.12; 95% CI, 4.04–17.40; P<.0001) were improved with cetuximab plus irinotecan compared with irinotecan alone.225 Median OS was similar between the 2 groups (12.3 months for cetuximab plus irinotecan vs 12.0 months for irinotecan alone [HR, 0.91; 95% CI, 0.71–1.17; P=.4645]). Almost 50% of patients in the irinotecan alone arm received cetuximab poststudy, potentially masking an OS benefit with the addition of cetuximab.

In a retrospective analysis of the subset of patients with known KRAS exon 2 tumor status receiving cetuximab monotherapy as second-line therapy,154 the benefit of cetuximab versus best supportive care was shown to be enhanced in patients with KRAS exon 2 wild-type tumors.14 For those patients, median PFS was 3.7 versus 1.9 months (HR, 0.40; 95% CI, 0.30–0.54; P<.001) and median OS was 9.5 versus 4.8 months (HR, 0.55; 95% CI, 0.41–0.74; P<.001), in favor of the cetuximab arm.14

The randomized, multicenter, open-label, noninferiority phase III ASPECCT trial compared single-agent cetuximab with single-agent panitumumab in the chemotherapy-refractory metastatic setting.226 The primary noninferiority OS endpoint was reached, with a median OS of 10.4 months (95% CI, 9.4–11.6) with panitumumab and 10.0 months (95% CI, 9.3–11.0) with cetuximab (HR, 0.97; 95% CI, 0.84–1.11). The incidence of AEs was similar between the groups. The final analysis of ASPECCT came to the same conclusion, reporting a median OS of 10.2 months with panitumumab and 9.9 months with cetuximab (HR, 0.98; 95% CI, 0.82–1.07).227

The randomized, multicenter, phase II SPIRITT trial randomized 182 patients with KRAS wild-type tumors whose disease progressed on first-line oxaliplatin-based therapy plus bevacizumab to FOLFIRI plus bevacizumab or FOLFIRI plus panitumumab.228 No difference was seen in the primary endpoint of PFS between the arms (7.7 months in the panitumumab arm vs 9.2 months in the bevacizumab arm; HR, 1.01; 95% CI, 0.68–1.50; P=.97).

A pooled analysis of the TRIBE and TRIBE2 studies assessed treatments administered after second disease progression in 1,187 patients with mCRC who received upfront FOLFOXIRI/bevacizumab vs FOLFOX or FOLFIRI/bevacizumab.229 In third-line therapy, patients with RAS/BRAF wild type tumors achieved longer PFS with EGFR inhibitors compared with other therapies (6.4 vs 3.9 months, P=.02).

Bevacizumab in the Non–First-Line Setting

In the TML (ML18147) trial, patients with mCRC who progressed on regimens containing bevacizumab received second-line therapy consisting of a different chemotherapy regimen with or without bevacizumab.230 This study met its primary endpoint, with patients continuing on bevacizumab having a modest improvement in OS (11.2 vs 9.8 months; HR, 0.81; 95% CI, 0.69–0.94; P=.0062). Subgroup analyses from this trial found that these treatment effects were independent of KRAS exon 2 status.231

Similar results were reported from the GONO group’s phase III randomized BEBYP trial, in which the PFS of patients who continued on bevacizumab plus a different chemotherapy regimen after progression on bevacizumab was 6.8 months compared with 5.0 months in the control arm (HR, 0.70; 95% CI, 0.52–0.95; P=.001).232 An improvement in OS was also seen in the bevacizumab arm (HR, 0.77; 95% CI, 0.56–1.06; P=.04). The EAGLE trial randomized 387 patients with disease progression after oxaliplatin-based therapy with bevacizumab to second-line therapy with FOLFIRI plus either 5 or 10 mg/kg bevacizumab.233 No difference was seen in PFS or time to treatment failure between the arms, indicating that 5 mg/kg of bevacizumab is an appropriate dose in second-line treatment of mCRC.

The continuation of bevacizumab after progression on bevacizumab was also studied in a community oncology setting through a retrospective analysis of 573 patients from the US Oncology iKnowMed electronic medical record system.234 Bevacizumab beyond progression was associated with a longer OS (HR, 0.76; 95% CI, 0.61–0.95) and a longer postprogression OS (HR, 0.74; 95% CI, 0.60–0.93) on multivariate analysis. Analyses of the ARIES observational cohort found similar results, with longer postprogression survival with continuation of bevacizumab (HR, 0.84; 95% CI, 0.73–0.97).235

Overall, these data (along with data from the VELOUR trial, discussed subsequently) show that the continuation of VEGF blockade in second-line therapy offers a very modest but statistically significant OS benefit. The panel added the continuation of bevacizumab to the second-line treatment options in the 2013 versions of the NCCN Guidelines for Colon and Rectal Cancers. It may be added to any regimen that does not contain another targeted agent. The panel recognizes the lack of data suggesting a benefit to bevacizumab with irinotecan alone in this setting, but believes that the option is acceptable, especially in patients whose disease progressed on a 5-FU– or capecitabine-based regimen. When an angiogenic agent is used in second-line therapy, bevacizumab is preferred over ziv-aflibercept and ramucirumab (discussed subsequently), based on toxicity and/or cost.236 Beyond the second-line setting, bevacizumab may be combined with trifluridine-tipiracil [see the later section on “Trifluridine-Tipiracil (TAS-102),” for more information].

It may also be appropriate to consider using bevacizumab with second-line therapy after progression on a first-line regimen that did not contain bevacizumab.237 However, no data are available to support adding bevacizumab to a regimen after progression on that same regimen. The randomized phase III ECOG E3200 study in patients who experienced disease progression through a first-line non–bevacizumab-containing regimen showed that the addition of bevacizumab to second-line FOLFOX modestly improved survival.237 Median OS was 12.9 months for patients receiving FOLFOX plus bevacizumab compared with 10.8 months for patients treated with FOLFOX alone (P=.0011).237 Use of single-agent bevacizumab is not recommended because it was shown to have inferior efficacy compared with the FOLFOX alone or FOLFOX plus bevacizumab treatment arms.237

Ziv-Aflibercept

Ziv-aflibercept is a recombinant protein that has part of the human VEGF receptors (VEGFR) 1 and 2 fused to the Fc portion of human immunoglobulin G1 (IgG1).238 It is designed to function as a VEGF trap to prevent activation of VEGFR and thus inhibit angiogenesis. The VELOUR trial tested second-line ziv-aflibercept in patients with mCRC that progressed after one regimen containing oxaliplatin. The trial met its primary endpoint with a small improvement in OS (13.5 months for FOLFIRI/ziv-aflibercept vs 12.1 months for FOLFIRI/placebo; HR, 0.82; 95% CI, 0.71–0.94; P=.003).239 A prespecified subgroup analysis from the VELOUR trial found that median OS in the ziv-aflibercept arm versus the placebo arm was 12.5 months (95% CI, 10.8–15.5) versus 11.7 months (95% CI, 9.8–13.8) in patients with prior bevacizumab treatment and 13.9 months (95% CI, 12.7–15.6) versus 12.4 months (95% CI, 11.2–13.5) in patients with no prior bevacizumab treatment.240

AEs associated with ziv-aflibercept treatment in the VELOUR trial led to discontinuation in 26.6% of patients compared with a 12.1% discontinuation in the placebo group.239 The most common causes for discontinuation were asthenia/fatigue, infections, diarrhea, hypertension, and venous thromboembolic events.

Ziv-aflibercept has only shown activity when given in conjunction with FOLFIRI in patients without prior exposure to FOLFIRI. No data suggest activity of FOLFIRI plus ziv-aflibercept in patients whose disease progressed on FOLFIRI plus bevacizumab or vice-versa, and no data suggest activity of single-agent ziv-aflibercept. Furthermore, the addition of ziv-aflibercept to FOLFIRI in first-line therapy of patients with mCRC in the phase II AFFIRM study had no benefit and increased toxicity.241 Thus, the panel added ziv-aflibercept as a second-line treatment option in combination with FOLFIRI or irinotecan only after progression on therapy not containing irinotecan. However, the panel prefers bevacizumab over ziv-aflibercept and ramucirumab in this setting, based on toxicity and/or cost.236

Ramucirumab

Another antiangiogenic agent, ramucirumab, is a human monoclonal antibody that targets the extracellular domain of VEGFR 2 to block VEGF signaling.242 In the multicenter, phase III RAISE trial, 1,072 patients with mCRC whose disease progressed on first-line therapy with fluoropyrimidine/oxaliplatin/bevacizumab were randomized to FOLFIRI with either ramucirumab or placebo.243 The primary endpoint of OS in the ITT population was met at 13.3 months and 11.7 months in the ramucirumab and placebo groups, respectively, for an HR of 0.84 (95% CI, 0.73–0.98; P=.02). PFS was also improved with the addition of ramucirumab, at 5.7 months and 4.5 months for the 2 arms (HR, 0.79; 95% CI, 0.70–0.90; P<.0005). A subgroup analysis of the RAISE trial subsequently reported similar efficacy and safety among patient subgroups with different KRAS mutation tumor status, time to progression on first-line therapy, and age.244

Rates of discontinuation due to AEs in the RAISE trial were 11.5% in the ramucirumab arm and 4.5% in the placebo arm. The most common grade 3 or worse AEs were neutropenia, hypertension, diarrhea, and fatigue. In addition, a meta-analysis of 6 phase III trials showed that ramucirumab did not increase the risk of arterial thromboembolic events, venous thromboembolic events, high-grade bleeding, or high-grade gastrointestinal bleeding compared with placebo.245 These results suggest that ramucirumab may be distinct among antiangiogenic agents in that it does not increase the risk of these events.

Considering the results of the RAISE trial, the panel added ramucirumab as a second-line treatment option in combination with FOLFIRI or irinotecan after progression on therapy not containing irinotecan. As with ziv-aflibercept, no data suggest activity of FOLFIRI plus ramucirumab in patients whose disease progressed on FOLFIRI plus bevacizumab or vice-versa, and no data suggest activity of single-agent ramucirumab. When an angiogenic agent is used in this setting, the panel prefers bevacizumab over ziv-aflibercept and ramucirumab, because of toxicity and/or cost.236

Encorafenib Plus Cetuximab or Panitumumab for BRAF V600E Mutation-Positive Disease in the Non–First-Line Setting

A combination of the BRAF inhibitor, encorafenib, and the MEK inhibitor, binimetinib, with cetuximab has been investigated in the randomized phase III BEACON trial for metastatic, BRAF V600E mutant CRC.246,247 The safety lead-in of the BEACON trial showed promising efficacy results with an ORR of 48% (95% CI, 29.4%–67.5%) among the 29 patients included in the efficacy analysis. Among the 30 treated patients in the safety lead-in, the most common grade 3 or 4 AEs were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate transaminase (10%), and urinary tract infections (10%).246

Subsequently, the randomized portion of the BEACON trial reported similarly encouraging results, including a positive OS result.247 Within this portion of the study, 665 patients were randomized to receive either the triplet combination, an encorafenib and cetuximab doublet, or a control regimen of cetuximab plus either irinotecan or FOLFIRI. Updated results of BEACON reported a median OS of 5.9 months, 9.3 months, and 9.3 months for the control, doublet, and triplet arms, respectively.248 The confirmed ORRs were 1.8%, 19.5%, and 26.8%, respectively, and grade 3 or higher AE rates were highest in the triplet arm, although the addition of binimetinib did not improve OS over the doublet. Quality-of-life assessments showed that the doublet and triplet regimens led to a similarly longer maintenance of quality of life compared with control.249 Based on these reports, the NCCN Panel concluded that only the doublet regimen of encorafenib with either cetuximab or panitumumab should be recommended for patients with BRAF V600E-mutated mCRC.

Data exist on the use of cetuximab or panitumumab in combination with irinotecan and vemurafenib250 or dabrafenib plus trametinib251 for BRAF V600E mutant mCRC. However, based on superior data and/or lower toxicity with the encorafenib-containing doublets, the panel voted to not include recommendations for these regimens within the current version of the guidelines.

Systemic Therapy Options for HER2-Amplified Disease

Four different regimens are recommended by the panel as options for subsequent treatment of mCRC with HER2 amplifications: fam-trastuzumab deruxtecan-nxki (T-DXd) monotherapy or trastuzumab in combination with pertuzumab, lapatinib, or tucatinib. These regimens (with the exception of T-DXd) may also be appropriate for patients with previously untreated HER2-amplified mCRC when intensive therapy is not recommended. The NCCN panel notes that FDA-approved biosimilars may be substituted for trastuzumab wherever the therapy is recommended within these guidelines (see the section on “Biosimilars”, in the full guidelines, available online at NCCN.org, for more information). The results of clinical trials supporting each of these regimens are detailed subsequently.

Trastuzumab Plus Pertuzumab

A combination regimen of the HER2 inhibitors trastuzumab and pertuzumab was studied in a subset analysis of MyPathway, a phase IIa multiple basket study.252 This subset included 57 patients with previously treated, HER2-amplified mCRC who were treated with the combination of pertuzumab and trastuzumab. ORR was 32% (95% CI, 20–45), with 1 complete response and 17 partial responses. Thirty-seven percent of patients treated with trastuzumab plus pertuzumab had grade 3 or 4 AEs, with hypokalemia and abdominal pain being most common. Another phase II basket study, TAPUR, also investigated the combination of trastuzumab and pertuzumab in HER2-amplified mCRC.253 In this study, 28 patients with heavily pretreated, HER2-amplified advanced CRC were treated with the combination. The disease control rate was 54% and objective response was observed in 25% of patients. The median PFS and median OS were 9.6 weeks and 28.8 weeks, respectively. Four patients had at least one grade 3 AE or serious AE, including anemia, infusion reaction, left ventricular dysfunction, and decreased lymphocyte count.

Trastuzumab Plus Lapatinib

The combination of trastuzumab plus the dual HER2/EGFR inhibitor, lapatinib, was studied in the multicenter, phase II HERACLES trial.65 This trial included 27 patients with previously treated, HER2-positive tumors that were treated with trastuzumab and lapatinib. ORR was 30% (95% CI, 14–50), with 1 patient with complete response, 7 patients with partial responses, and 12 patients with stable disease. Twenty-two percent of patients treated with trastuzumab plus lapatinib had grade 3 AEs, including fatigue (4 patients), skin rash (1 patient), and increased bilirubin (1 patient).65

Trastuzumab Plus Tucatinib

A combination regimen of the HER2 inhibitors trastuzumab and tucatinib was studied in the multicenter, phase II MOUNTAINEER trial.254 This trial included 117 patients with chemotherapy-refractory, HER2-positive, RAS wild-type mCRC. Initially, all patients on this study were treated with the combination (cohort A), while later, patients were randomized to receive either tucatinib monotherapy (cohort C) or the combination of tucatinib and trastuzumab (cohort B). Of the 84 patients who received the combination in cohorts A and B, the confirmed ORR was 38.1% (95% CI, 27.7–49.3), with 3 patients experiencing a complete response to the treatment. In all 3 cohorts, the most common AE was diarrhea. Three percent of patients who received the combination had tucatinib-related serious AEs (acute kidney injury, colitis, and fatigue).

Fam-Trastuzumab Deruxtecan-nxki

The HER2-directed antibody and topoisomerase inhibitor conjugate was studied in the phase 2, multicenter DESTINY-CRC01 trial of 78 patients with HER2-expressing, RAS/BRAF wild-type unresectable and/or mCRC that had already progressed on at least 2 prior regimens.255 Patients were split into 3 cohorts based on the level of tumor HER2 expression (cohort A: immunohistochemistry [IHC ]3+or IHC 2+/ in situ hybridization [ISH]+; cohort B: IHC 2+/ISH-; cohort C: IHC 1+). In cohort A, the primary endpoint of ORR was 45.3%, with 1 complete response and 23 partial responses. Median PFS in this group was 6.9 months, and median OS had not yet been reached at the time of data cutoff. No responses were reported in cohorts B or C. Thirty percent of patients in cohort A had received prior anti-HER2 therapy; for these patients ORR was 43.8%. The most common grade ≥3 treatment-emergent AEs were decreased neutrophil count (22%) and anemia (14%). In the final analysis of DESTINY-CRC01, no responses occurred in cohorts B or C.256 In cohort A, confirmed ORR was 45.3%, all of which were partial responses, with a median duration of response of 7.0 months. Median PFS and OS were 6.9 and 15.5 months, respectively. Of note, across all 3 cohorts, 8 patients on this trial developed interstitial lung disease or pneumonitis related to T-DXd, including 3 patients who died due to this complication (3.5% of all patients).

The ongoing DESTINY-CRC02 trial includes patients with HER2-positive (IHC 3+or IHC 2+/ISH+) mCRC, with either RAS wild-type or mutant disease.257 Patients were randomized to either 5.4 or 6.4 mg/kg T-DXd. An abstract presented primary results, reporting an ORR of 37.8% for the 5.4 mg/kg dose and 27.5% for 6.4 mg/kg. T-DXd showed antitumor activity irrespective of RAS mutation status and in those who were previously treated with anti-HER2 therapy, suggesting that this agent may be considered as an option for HER2-amplified mCRC regardless of RAS mutation status or previous HER2 targeted therapy.

Systemic Therapy Options for KRAS G12C Mutation-Positive Disease in the Non–First-Line Setting

Two KRAS G12C inhibitors, sotorasib and adagrasib, are recommended for treatment of previously treated metastatic colorectal cancer that harbors this mutation. Sotorasib or adagrasib should be given in combination with cetuximab or panitumumab or may be considered as a single agent if toxicities from EGFR inhibitors are a concern. Mechanisms for acquired resistance to adagrasib and sotorasib have been described.258

The phase I portion of the CodeBreaK 100 trial was a basket study of sotorasib monotherapy. It included 129 patients with solid tumors harboring the KRAS G12C mutation, 42 with colorectal cancer.259 Of the subgroup with CRC, 7.1% had a confirmed response and 73.8% had disease control. A prespecified subset analysis of the phase II portion of CodeBreaK 100 investigated sotorasib monotherapy for previously treated mCRC with KRAS G12C mutation.260 Objective response was observed in 9.7% of the 62 treated patients. Grade ≥3 treatment-related AEs occurred in 11.6% of patients treated with sotorasib monotherapy. The phase Ib/II CodeBreaK 101 trial looked at various doublets including sotorasib. One cohort of this trial investigated the combination of sotorasib plus panitumumab in 40 patients with previously treated KRAS G12C-mutated mCRC. Results from the dose expansion cohort reported a confirmed ORR of 30% (95% CI, 16.6%–46.5%).261 Median PFS and OS were 5.7 and 15.2 months, respectively. Grade ≥3 treatment-related AEs occurred in 27% of patients who received the combination therapy.

KRYSTAL-1 is a phase I/II clinical trial evaluating the safety and efficacy of adagrasib, alone or in combination with other anticancer therapies, in patients with advanced solid tumors that had been previously treated. One publication of this study reported results for patients with KRAS G12C-mutated mCRC treated with adagrasib alone (n=44) or adagrasib in combination with cetuximab (n=32).262 In this subgroup, disease response was reported in 19% of patients treated with adagrasib monotherapy, with a median duration of response of 4.3 months (95% CI, 8–33) and median PFS of 5.6 months (95% CI, 2.3–8.3). For the combination of adagrasib and cetuximab, responses were noted in 46% of patients, with a median response duration of 7.6 months (95% CI, 5.7–not estimable) and median PFS of 6.9 months (95% CI, 5.4–8.1). Grade ≥3 treatment-related AEs were reported in 34% of patients who received the monotherapy and 16% of those who received the combination. A 2024 AACR abstract on this study presented updated results from 94 patients who received the combination of adagrasib and cetuximab.263 With a median follow-up of 11.9 months, the ORR was 34.0%, DCR was 85.1%, and median duration of response was 5.8 months. Median PFS was 6.9 months and median OS was 15.9 months.

Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or Functional POLE/POLD1 Mutation-Positive Disease in the Non–First-Line Setting

The panel currently recommends that dMMR/MSI-H or POLE/POLD1 mutation-positive mCRC be treated with a checkpoint inhibitor as first-line therapy if no prior immunotherapy has been received and the patient is a candidate for immunotherapy. However, if a different therapy was used in the first-line setting, checkpoint inhibitor immunotherapy is also appropriate for use in the non–first-line setting.

Pembrolizumab is a humanized, IgG4 monoclonal antibody that binds to PD-1 with high affinity, preventing its interaction with PD-L1 and PD-L2 and thus allowing immune recognition and response.91 A phase II study evaluated the activity of pembrolizumab in 11 patients with dMMR CRC, 21 patients with pMMR CRC, and 9 patients with dMMR noncolorectal carcinomas.203 All patients had progressive metastatic disease; the patients in the colorectal arms had progressed through 2 to 4 previous therapies. The primary endpoints were the immune-related objective response rate and the 20-week immune-related PFS rate. The immune-related objective response rates were 40% (95% CI, 12–74) in the dMMR CRC group, 0% (95% CI, 0–20) in the pMMR CRC group, and 71% (95% CI, 29–96) in the dMMR noncolorectal group. The 20-week immune-related PFS rates were 78% (95% CI, 40–97), 11% (95% CI, 1–35), and 67% (95% CI, 22–96), respectively. These results indicate that MSI is a predictive marker for the effectiveness of pembrolizumab across tumor types. Furthermore, the median PFS and OS were not reached in the arm with dMMR CRC and were 2.2 and 5.0 months, respectively, in the pMMR CRC group (HR for disease progression or death, 0.10; P<.001). Another phase II study, KEYNOTE-164, investigated the efficacy of pembrolizumab in 124 patients with MSI-H/dMMR mCRC that had been treated with at least 1 previous line of therapy.264 The patients on this study were divided into 2 cohorts based on whether they had received 2 lines or more of therapy including fluoropyrimidine, oxaliplatin, and irinotecan (cohort A) or 1 or more lines of therapy (cohort B). ORR was reported as 33% for both cohorts, with the median duration of response not reached at the time of publication. Median PFS was 2.3 months and 4.1 months, for cohorts A and B, respectively. Median OS was 31.4 months for cohort A and had not been reached for cohort B. Treatment-related AEs of grade ≥3 occurred in 16% of patients in cohort A and 13% in cohort B, with pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase being most common.

Nivolumab is another humanized IgG4 PD-1 blocking antibody,265 which was studied with or without ipilimumab in patients with mCRC in the phase II, multicohort CheckMate-142 trial.205,206 One cohort of this trial included 74 patients with dMMR CRC who were treated with nivolumab. ORR for these patients was 31.1% (95% CI, 20.8–42.9) with 69% of patients having disease control for at least 12 weeks. Median duration of response had not yet been reached at the time of data collection. PFS and OS were 50% and 73%, respectively, at 1 year. Grade 3 or 4 drug-related AEs occurred in 20% of patients, with increased amylase and increased lipase being most common.205 Emerging 5-year long term data revealed an ORR of 39% (95% CI, 28–51).201 PFS and OS at 48 months were 36% and 49%, respectively.

Another cohort of the CheckMate-142 included 119 patients with dMMR CRC who were treated with nivolumab in combination with ipilimumab. For this cohort, ORR was 55% (95% CI, 45.2–63.8) and the disease control rate for at least 12 weeks was 80%. PFS and OS were 71% and 85%, respectively, at 1 year. In addition, significant, clinically meaningful improvements were observed in patient-reported outcomes of functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related AEs occurred in 32% of patients, but were manageable.206 An in-depth analysis of the safety profile of nivolumab plus ipilimumab on the CheckMate-142 trial reported that AEs predefined in the study protocol as being of special clinical interest (eg, endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin events) tended to occur early in treatment, were managed using evidence-based treatment algorithms, and resolved.266 Emerging 5-year long-term data from this cohort revealed an ORR of 65% (95% CI, 55–73).201 PFS and OS at 48 months were 54% and 71%, respectively.

A third humanized IgG4 PD-1 blocking antibody, dostarlimab-gxly, has been FDA-approved for the treatment of adult patients with dMMR recurrent or advanced solid tumors that have progressed on or following treatment and who have no satisfactory alternative treatment options.267 The safety and efficacy of dostarlimab-gxly was evaluated in the phase I GARNET study of patients with advanced solid tumors who had previously received systemic therapy for advanced disease.268 Cohort F of this trial enrolled patients with dMMR or POLE mutant nonendometrial solid tumors, the majority of which were gastrointestinal cancers. Of the 115 patients with colorectal cancer in the efficacy analysis, confirmed ORR was 43.5% (95% CI, 34.3–53.0), with 12.2% experiencing complete response. Median PFS for this group was 8.4 months and median DOR and OS were not yet reached. Treatment-related AEs grade ≥3 were reported in 16.3% of 363 patients included in the safety analysis. Dostarlimab-gxly was discontinued in 25 patients due to a treatment-related AE.

Based on these data, the panel recommends pembrolizumab, nivolumab, nivolumab plus ipilimumab, or dostarlimab-gxly as subsequent-line treatment options in patients with metastatic dMMR/MSI-H CRC who have not previously received checkpoint inhibitor immunotherapy. As discussed in the earlier “Biomarkers for Systemic Therapy,” section, checkpoint inhibitor immunotherapy is also recommended for mCRC with functional POLE/POLD1 mutations.

Larotrectinib or Entrectinib for NTRK Gene Fusion-Positive Disease in the Non–First-Line Setting

Studies have estimated that about 0.2%–1% of CRCs carry NTRK gene fusions.83,84 Two targeted therapies, larotrectinib and entrectinib, have been FDA-approved for the treatment of patients with metastatic, unresectable solid tumors that have an NTRK gene fusion and no satisfactory alternative treatment options, regardless of the location of the primary tumor.269,270

A pooled analysis of 3 studies (a phase I including adults, a phase I/II involving children, and the phase II NAVIGATE study involving adolescents and adults) studied the safety and efficacy of larotrectinib in 55 patients with NTRK gene fusion-positive tumors, including 4 patients with colon cancer.82 For the whole population, the ORR was 75% (95% CI, 61–85) by independent review and 80% (95% CI, 67–90) by investigator assessment,82 although the package insert cites a 25% ORR for colon tumors specifically.270 Larotrectinib was found to be well-tolerated as the majority (93%) of AEs were grades 1 or 2 and no treatment-related AEs of grades 3 or 4 occurred in more than 5% of patients.82 A subsequent analysis of these 3 studies included 159 patients, 8 with colon cancer, and reported similar results compared with the earlier analysis.271 In this later analysis, the ORR was 79% (95% CI, 72–85) by investigator assessment with 16% complete responses. An analysis of 14 patients with gastrointestinal cancer who were treated with larotrectinib in the NAVIGATE study reported a median PFS of 5.3 months (95% CI, 2.2–9.0) and a median OS of 33.4 months (95% CI, 2.8–36.5).272 Responses were ongoing for 5 patients, leading their results to be censored. Of the 8 patients with colon cancer, 50% showed a partial response and 50% had stable disease.

An integrated analysis of 3 global phase I/II studies (ALKA-372-001, STARTRK-1, and STARTRK-2) tested the efficacy and safety of entrectinib in 54 adult patients with advanced or metastatic NTRK gene fusion-positive solid tumors.273 For the whole population, ORR was 57% (95% CI, 43.2–70.8), median PFS was 11 months (95% CI, 8.0–14.9), and median OS was 21 months (95% CI, 14.9–not estimable) by independent review. Median duration of response was 10 months (95% CI, 7.1–not estimable). Of the 4 patients with CRC in this study, 1 was recorded as having a response. Notably, a similar ORR (50% vs 60%) was observed among those with central nervous system metastasis, indicating that entrectinib has activity in this population. Entrectinib was found to be well-tolerated because most treatment-related AEs were grade 1 or 2 and managed with dose reduction, leading few (4%) patients to discontinue therapy due to treatment-related AEs.

Based on these results the panel added larotrectinib and entrectinib as subsequent treatment options for patients with NTRK gene fusion-positive disease, acknowledging that these therapies will not be appropriate for most patients due to the rarity of the NTRK fusion in CRC.

Selpercatinib for RET Gene Fusion-Positive Disease in the Non–First-Line Setting

In the ongoing phase 1/2 LIBRETTO-001 trial, the efficacy and safety of the highly selective RET kinase inhibitor selpercatinib is being investigated in a diverse group of patients with RET gene fusion-positive tumors, including 10 patients with colon cancer.88 Patients in this trial had received a median of 2 prior lines of systemic therapy, and 31% of patients received 3 or more prior lines of treatment. Of a total of 41 efficacy-evaluable patients, the ORR for the entire cohort by independent review was 43.9% (95% CI, 28.5–60.3) and 20% in the colon cancer subgroup (95% CI, 2.5–55.6). There were 2 complete responses (5%), although neither patient had colon cancer. For the entire cohort, median PFS was 13.2 months (95% CI, 7.4–26.2) by independent review, median OS was 18 months (95% CI, 10.7–not evaluable), and median duration of response was 24.5 months (95% CI, 9.2–not evaluable). For the colon cancer subgroup, median duration of response was 9.4 months (95% CI, 5.6–13.3). The most common grade 3 or higher treatment-emergent AEs were hypertension and transaminitis. The most common treatment-related serious AEs were drug-induced livery injury, fatigue, and hypersensitivity. One patient had to permanently discontinue selpercatinib due to drug-induced liver injury.

Based on these data, the FDA has approved selpercatinib for locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.274

Regorafenib

Regorafenib is a small-molecule inhibitor of multiple kinases (including VEGFR, fibroblast growth factor receptors, platelet-derived growth factor receptors, BRAF, KIT, and RET) that are involved with various processes including tumor growth and angiogenesis.275 The phase III CORRECT trial randomized 760 patients whose disease progressed on standard therapy to best supportive care with placebo or regorafenib.276 The trial met its primary endpoint of OS (6.4 months for regorafenib vs 5.0 months for placebo; HR, 0.77; 95% CI, 0.64–0.94; P=.005). PFS was also significantly but modestly improved (1.9 vs 1.7 months; HR, 0.49; 95% CI, 0.42–0.58; P<.000001).

The randomized, double-blind, phase III CONCUR trial was performed in China, Hong Kong, South Korea, Taiwan, and Vietnam.277 Patients with progressive mCRC were randomized 2:1 to receive regorafenib or placebo after 2 or more previous treatment regimens. After a median follow-up of 7.4 months, the primary endpoint of OS was met in the 204 randomized patients (8.8 months in the regorafenib arm vs 6.3 months in the placebo arm; HR, 0.55; 95% CI, 0.40–0.77; P<.001).

The most common grade 3 or higher AEs in the regorafenib arm of the CORRECT trial were hand–foot skin reaction (17%), fatigue (10%), hypertension (7%), diarrhea (7%), and rash/desquamation (6%).276 Severe and fatal liver toxicity occurred in 0.3% of 1,100 patients treated with regorafenib across all trials.275 In a meta-analysis of 4 studies that included 1,078 patients treated with regorafenib for CRC, gastrointestinal stromal tumor, renal cell carcinoma, or hepatocellular carcinoma, the overall incidence of all-grade and high-grade hand–foot skin reactions was 60.5% and 20.4%, respectively.278 In the subset of 500 patients with CRC, the incidence of all-grade hand–foot skin reaction was 46.6%.

Other studies have also investigated regorafenib for treatment of refractory mCRC. The phase IIIb CONSIGN trial assessed the safety of regorafenib in 2,872 patients from 25 countries with refractory mCRC.279 The REBECCA study assessed the safety and efficacy of regorafenib in a cohort of 654 patients with mCRC within a compassionate use program.280 The prospective, observational CORRELATE study assessed the safety and efficacy of regorafenib in 1,037 patients with mCRC in real-world clinical practice.281 The safety and efficacy profiles of regorafenib in all of these trials were consistent with that seen in the CORRECT trial.

The randomized, phase II ReDOS trial investigated the use of an alternative dose schedule to reduce the toxicities related to regorafenib treatment.282 Of the 116 evaluable patients, the dose-escalation group had a higher percentage of patients who initiated cycle 3 of regorafenib (43%) compared with the standard dosing group (26%). Rates of several of the most common AEs were also lower among the dose-escalation group compared with the standard dosing group. Based on these results, the panel agreed that a dose-escalation strategy is an appropriate alternative approach for regorafenib dosing. The phase II REARRANGE study has also supported alternative dosing schedules for regorafenib as feasible and safe in patients with previously treated mCRC.283

Regorafenib has only shown activity in patients whose disease has progressed on all standard therapy. Therefore, the panel added regorafenib as an additional line of therapy for patients with mCRC refractory to chemotherapy. It can be given before or after trifluridine-tipiracil, with or without bevacizumab, or fruquintinib; no data inform the best order of these therapies.

Trifluridine-Tipiracil (TAS-102)

Trifluridine-tipiracil is an oral combination drug, consisting of a cytotoxic thymidine analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride, which prevents the degradation of trifluridine. Early clinical studies of the drug in patients with CRC were promising.284,285

Results of the double-blind, randomized, controlled, international phase III RECOURSE trial were published in 2015,286 followed shortly thereafter by approval of trifluridine-tipiracil by the FDA.287 With 800 patients with mCRC who progressed through at least 2 prior regimens randomized 2:1 to receive trifluridine-tipiracil or placebo, the primary endpoint of OS was met (5.3 vs 7.1 months; HR, 0.68; 95% CI, 0.58–0.81; P<.001).286 Improvement was also seen in the secondary endpoint of PFS (1.7 vs 2.0 months; HR, 0.48; 95% CI, 0.41–0.57; P<.001). The most common AEs associated with trifluridine-tipiracil in RECOURSE were neutropenia (38%), leukopenia (21%), and febrile neutropenia (4%); one drug-related death occurred.286 A postmarketing surveillance study did not reveal any unexpected safety signals,288 and a subgroup analysis of the RECOURSE trial reported similar efficacy and safety regardless of age, geographical origin, or KRAS mutation status.289

The combination of trifluridine-tipiracil and bevacizumab has also been studied in the non–first-line setting. The regimen was initially studied in the phase I/II C-TASK FORCE trial290 and a subsequent randomized phase II trial that compared trifluridine-tipiracil with and without bevacizumab.291 After positive results on these early trials, the phase III SUNLIGHT trial was conducted to compare trifluridine-tipiracil plus bevacizumab to trifluridine-tipiracil alone in 492 patients with previously treated mCRC.292 Nearly all patients on the trial had previously received a fluoropyrimidine, irinotecan, and oxaliplatin; 72% had received an anti-VEGF antibody; and 93.7% of those with RAS wild-type disease had received an anti-EGFR antibody. Median OS was longer for the bevacizumab combination compared with trifluridine-tipiracil alone (10.8 vs 7.5 months; HR, 0.61; 95% CI, 0.49–0.77; P<.001). Median PFS was also longer for the combination at 5.6 months versus 2.4 months for trifluridine-tipiracil alone (HR, 0.44; 95% CI, 0.36–0.54; P<.001). The most common AEs reported for both groups were neutropenia, nausea, and anemia, and no treatment-related deaths occurred in either group. A retrospective study of 57 patients with refractory mCRC showed similar results to the clinical trial data, with an improved median OS for trifluridine-tipiracil with bevacizumab versus without (14.4 vs 4.5 months; P<.001).293 Another retrospective study similarly reported improved OS and time to treatment discontinuation for trifluridine-tipiracil plus bevacizumab compared with either trifluridine-tipiracil alone or regorafenib.294

Based on these data, the panel added trifluridine-tipiracil, with or without bevacizumab, as a treatment option for patients whose disease has progressed through standard therapies. The bevacizumab combination is preferred over trifluridine-tipiracil alone. It can be given before or after regorafenib or fruquintinib; no data inform the best order of these therapies, although real-world data have shown that patients show better adherence to trifluridine-tipiracil compared with regorafenib.295 The 144 patients in RECOURSE who had prior exposure to regorafenib obtained similar OS benefit from trifluridine-tipiracil (HR, 0.69; 95% CI, 0.45–1.05) as the 656 patients who did not (HR, 0.69; 95% CI, 0.57–0.83).

The combination of trifluridine-tipiracil and bevacizumab has also been studied in the first-line setting in both the phase III SOLSTICE study296 and the phase II TASCO1 study.297,298 Both of these studies compared trifluridine-tipiracil plus bevacizumab to capecitabine plus bevacizumab in patients who were not candidates for intensive therapy and have shown similar OS and PFS results between the 2 treatment groups. Based on concerns about the hematologic and financial toxicities with trifluridine-tipiracil compared with capecitabine, the NCCN Panel does not currently recommend trifluridine-tipiracil, with or without bevacizumab, as first-line therapy for mCRC.

Fruquintinib

Fruquintinib is an orally administered kinase inhibitor that targets VEGFR 1, 2, and 3. Its efficacy and safety was evaluated in 2 randomized, double-blind, phase III clinical trials, FRESCO and FRESCO-2.299,300 FRESCO was conducted at 28 hospitals in China and randomized 416 patients with mCRC that had progressed after at least 2 lines of chemotherapy, but who had not received VEGFR inhibitor therapy, to either fruquintinib or placebo.300 Patients treated with fruquintinib had significantly longer median OS compared with those who received placebo (9.3 versus 6.6 months; HR, 0.65; P<.001). Median PFS was also longer with fruquintinib (3.7 versus 1.8 months; HR, 0.26; P<.001). FRESCO-2 was a larger study, conducted at 124 hospitals and cancer centers across 14 countries, and enrolled 691 patients with mCRC who had previously received all available cytotoxic and targeted therapies and had progressed on or were intolerant to trifluridine-tipiracil and/or regorafenib.299 Patients were randomized to receive fruquintinib or placebo, plus best supportive care. Patients in the FRESCO-2 study had received a median of 4 previous lines of systemic therapy for metastatic disease and 73% had received >3 lines of therapy. As opposed to FRESCO, 97% of patients had received prior VEGF inhibitor therapy and nearly half had experienced progression on both trifluridine-tipiracil and regorafenib. Patients received fruquintinib for a median of 3.1 months (compared with 1.8 months on placebo) and just 20% discontinued fruquintinib due to toxicities. Median OS was 7.4 months with fruquintinib compared with 4.8 months with placebo (HR, 0.66; 95% CI, 0.55–0.80; P<.0001). Grade ≥3 AEs occurred in 63% of patients who received fruquintinib compared with 50% who received placebo. The most common grade ≥3 AEs with fruquintinib were hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). Based on these data, the NCCN panel recommends fruquintinib as a treatment option for mCRC that has progressed through all other available regimens. It can be given before or after trifluridine-tipiracil, with or without bevacizumab, or regorafenib; no data inform the best order of these therapies.

Summary

Recommendations for patients with disseminated metastatic disease represent a continuum of care in which lines of treatment are blurred rather than discrete. Principles to consider at initiation of therapy include preplanned strategies for altering therapy for patients in both the presence and absence of disease progression, including plans for adjusting therapy for patients who experience certain toxicities. In addition to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapy regimens, immunotherapy and targeted therapy regimens are becoming an increasingly important part of the mCRC treatment landscape. Combination of a biologic agent (eg, bevacizumab, cetuximab, panitumumab) with some of the chemotherapy regimens is an option, depending on available data. Systemic therapy options for patients with progressive disease depend on the choice of initial therapy and biomarker status of the tumor.

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