Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer

CancerVolume 125, Issue 23 p. 4139-4147 Review ArticleFree Access Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer Sorbarikor Piawah MD, MPH, Sorbarikor Piawah MD, MPH orcid.org/0000-0002-1655-6113 University of California San Francisco, San Francisco, CaliforniaSearch for more papers by this authorAlan P. Venook MD, Corresponding Author Alan P. Venook MD [email protected] University of California San Francisco, San Francisco, California Corresponding author: Alan P. Venook, MD, University of California San Francisco, 1450 Third Street, HD 376, San Francisco, CA 94158; [email protected]Search for more papers by this author Sorbarikor Piawah MD, MPH, Sorbarikor Piawah MD, MPH orcid.org/0000-0002-1655-6113 University of California San Francisco, San Francisco, CaliforniaSearch for more papers by this authorAlan P. Venook MD, Corresponding Author Alan P. Venook MD [email protected] University of California San Francisco, San Francisco, California Corresponding author: Alan P. Venook, MD, University of California San Francisco, 1450 Third Street, HD 376, San Francisco, CA 94158; [email protected]Search for more papers by this author First published: 21 August 2019 https://doi.org/10.1002/cncr.32163Citations: 187 The 2 authors contributed equally to this article. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific to cells within which these pathways, such as epidermal growth factor receptor (EGFR), are overactive; this is in contrast to the relatively indiscriminate mechanism by which cytotoxic chemotherapy tends to affect rapidly dividing cells, regardless of their role. Although factors unique to a given patient, such as the location of the primary tumor (sidedness) or the presence of mutations that confer resistance, may limit the utility of these agents, targeted therapies are now a part of the treatment paradigm for metastatic colorectal cancer, and survival outcomes have significantly improved. This review provides an overview of the role of targeted therapy in the management of patients with colorectal cancer metastases as well as a discussion of issues in patient selection, with a focus on inhibitors of angiogenesis, EGFR-targeted therapy, BRAF mutation–targeted therapies, and other novel strategies, including immunotherapy. Introduction Colorectal cancer remains the third most commonly diagnosed cancer in the United States and the third most common cause of cancer-related death.1 Survival is a function of the cancer stage at diagnosis, with approximately 35% of patients presenting with metastatic disease at diagnosis and as many as 50% of patients who present with nonmetastatic colorectal cancer ultimately manifesting metastatic disease.2 5-Fluorouracil (5-FU) was the first chemotherapy with demonstrable activity against colorectal cancer.3, 4 On the basis of in vitro evidence of a modulating effect on 5-FU, leucovorin was added, and 5-FU plus leucovorin became the standard for metastatic colorectal cancer (mCRC) with a median overall survival (mOS) of approximately 8 to 9 months.5 The availability of oxaliplatin and its favorable interaction with infusional fluorouracil led to the current standard combination of 5-FU and oxaliplatin (FOLFOX). Irinotecan was initially combined with bolus 5-FU (irinotecan, bolus 5-FU, and leucovorin [IFL]), which was then supplanted by infusional 5-FU (folinic acid (leucovirin), infusional 5-FU, irinotecan [FOLFIRI]). Each combination was found to be superior to 5-FU and leucovorin alone6, 7 and to have similar efficacy with a median survival of 18 to 20 months.8, 9 Targeted therapy is a term for agents directed at unique biological features of cancers rather than agents that kill cells as they replicate, including both cancer cells and others. In theory, turning off a dominant pathway with a precise antagonist should optimize the balance between tumor cell killing and off-target effects such as bone marrow and epithelial cell damage. Because patients with mCRC can sometimes be cured with combinations of systemic treatment and surgery, added efficacy could make a major difference in outcomes. Unfortunately, although the RAS pathway is dominant in approximately 40% to 50% of patients with mCRC,10 there are numerous specific mutations within the RAS family that may drive cancer progression in a given patient. Therefore, even if, for example, the excitement recently engendered by new agents with an inhibitory effect on a K-RAS-12C–mutated preclinical mCRC model11 is affirmed in clinical trials, the impact will likely be limited to the 4% or so of patients whose tumors harbor that precise mutation.11 Arguably, until the mystery of RAS is solved, targeted therapies for biomarker-selected patients with mCRC may improve outcomes on the margins but are not likely to dramatically change treatment paradigms for the majority of patients. Targeting Angiogenesis Angiogenesis, the creation of networks of blood vessels, is a wondrous biological process that promotes the growth, proliferation, organization, and survival of normal cells. However, it also supports the growth and survival of cancer cells and facilitates the dissemination of metastases,12 and it is of variable importance in different cancers. For example, familial renal cell cancer is dependent on angiogenesis, but in mCRC and most other cancers, angiogenesis contributes to but is not determinant of cancer progression. It is mediated by a balance between pro-angiogenic and anti-angiogenic factors and receptors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and fibroblast growth factor.13 Bevacizumab (Avastin; Genentech, Inc, South San Francisco, California) is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) directed against VEGF-A, as depicted in Figure 1. Its potential mechanisms of action are believed to include the depletion of tumor vasculature as well as the temporary normalization of the crazy-quilt pattern of tumor vasculature to enhance chemotherapy delivery.14 Bevacizumab also appears to be a mediator of antigen presentation.14 Figure 1Open in figure viewerPowerPoint Schematic depiction of VEGFR and EGFR cascades and mechanism of targeted therapies. EGFR indicates epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Early studies of mCRC suggested that bevacizumab had modest activity, if any, as a single agent,14 and the first Food and Drug Administration (FDA) approval for bevacizumab, based on the phase 3 AVF2107g trial, was for its use in combination with a fluoropyrimidine for patients with mCRC.15 Presented in 2004, that study randomized 402 untreated patients with mCRC to receive irinotecan, IFL, and bevacizumab and 411 patients to receive IFL plus a placebo. The 4.7-month improvement in mOS (20.3 months with bevacizumab vs 15.6 months without it; hazard ratio [HR], 0.66; P < .001) and in progression-free survival (PFS; 10.6 vs 6.2 months; HR for disease progression, 0.54; P < .001)15 remains the high-water mark for bevacizumab in mCRC. Market research tells us that bevacizumab is most often used in the first line for patients with mCRC in combination with oxaliplatin-based chemotherapy, undoubtedly in light of the pivotal phase 3 NO16966 trial.16 That study had a 2 × 2 factorial design and randomized 1401 untreated patients with mCRC to receive FOLFOX4 or capecitabine and oxaliplatin (CAPEOX) and then to receive bevacizumab or a placebo. It showed an incremental PFS benefit with the addition of bevacizumab to either oxaliplatin-containing regimen: 9.4 months versus 8.0 months for the placebo group (HR, 0.83; P = .0023). However, differences in overall survival (OS) did not reach statistical significance: mOS was 21.3 months in the bevacizumab arms and 19.9 months in the placebo arm (HR, 0.89; confidence interval [CI], 0.76-1.03; P = .077).16 Although there are a number of possible explanations for the lack of a survival advantage, including disparate second-line treatment and the early stoppage of oxaliplatin due to neurotoxicity, the data do not support its universal use in the first line in comparison with other options. Second Line Bevacizumab also enhances the effects of second-line treatments, as demonstrated by the phase 3 trial E3200,17 which randomized 829 patients with mCRC who progressed on first-line FOLFIRI to receive FOLFOX4 with bevacizumab, FOLFOX4 alone, or bevacizumab alone. mOS was prolonged with FOLFOX4 and bevacizumab in comparison with FOLFOX4 alone (12.9 vs 10.8 months; HR, 0.75; P = .0011), and a shorter mOS of 10.2 months was found for bevacizumab alone. PFS was also prolonged with FOLFOX4 and bevacizumab in comparison with FOLFOX4 alone (7.3 vs 4.7 months; HR, 0.61; P < .001). The PFS of 2.7 months for bevacizumab alone argues against its use as a standalone treatment.17 The benefit of the continuation of bevacizumab beyond first-line progression was suggested in the Bevacizumab Regimens: Investigation of Treatment Effects and Safety (BRiTE) registry,18 a United States–based prospective, observational cohort study conducted from 2004 to 2005. The analysis suggested an mOS of 31.8 months in the bevacizumab-continuation group versus 19.9 months in the noncontinuation cohort with an HR of 0.48 (P < .001). The subsequent open-label, phase 3 trial ML18147,19 conducted mostly in Europe from 2006 to 2010, randomized 820 patients with disease progression after first-line bevacizumab and chemotherapy (oxaliplatin or irinotecan backbone) to receive second-line chemotherapy with or without bevacizumab. It corroborated the basic message of BRiTE while also serving as a reminder why we base decisions on clinical trials and not registries: an mOS of 11.2 months with bevacizumab plus chemotherapy versus an mOS of 9.8 months with chemotherapy alone (HR, 0.81; P = .0062), with more problematic toxicities in the bevacizumab arm.19 Other Anti-Angiogenesis Agents A number of other drugs targeting angiogenesis are available for second- and subsequent-line treatment of mCRC, although none are used nearly as commonly as bevacizumab. Ziv-aflibercept (Zaltrap; Sanofi-Genzyme, Cambridge, Massachusetts) is a fully humanized, soluble recombinant fusion protein that targets angiogenesis by blocking VEGF-A, VEGF-B, and placental growth factor and has a higher binding affinity for VEGF-A than bevacizumab.20 Its approval in the second line in combination with FOLFIRI is based on the double-blind phase 3 VELOUR trial,21 which randomized 1226 patients previously treated with oxaliplatin to receive FOLFIRI plus ziv-aflibercept or FOLFIRI plus a placebo. The addition of ziv-aflibercept significantly improved mOS to 13.5 months in contrast to 12.06 months in the placebo arm (P = .0032). The median progression-free survival (mPFS) and the objective response rate (ORR) also improved (6.90 vs 4.67 months and 19% vs 11.1%; P = .0001).21 Notably, ziv-aflibercept failed to improve outcomes in the first-line setting in combination with mFOLFOX6 in the randomized phase 2 AFFIRM trial,22 which found no difference in PFS but higher VEGF-related toxicity in comparison with mFOLFOX6 alone. There are no data supporting the use of ziv-aflibercept monotherapy. Ramucirumab (Cyramza; Eli Lilly, Indianapolis, Indiana) is a fully human IgG1 mAb targeting the vascular endothelial growth factor receptor 2 extracellular domain.23 It was evaluated in the second line in the phase 3 randomized RAISE 50 trial,23 in which 1072 patients who had progressed after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine received ramucirumab plus FOLFIRI or a placebo plus FOLFIRI. mOS was significantly longer in the ramucirumab arm (13.3 vs 11.7 months; P = .0219), as was mPFS (7 vs 4.5 months; P = .0005).23 As such, like ziv-aflibercept, ramucirumab is also approved for use in the second line in combination with FOLFIRI or irinotecan. There are no data to support the use of ramucirumab monotherapy for mCRC. Although bevacizumab, ziv-aflibercept, and ramucirumab have all demonstrated efficacy and are approved in the second line (in combination with FOLFIRI or irinotecan), bevacizumab remains more widely used and is a preferred agent largely because of the higher costs and toxicities associated with the latter two. As described in Table 1, toxicities of VEGF inhibition include hypertension, proteinuria, wound healing complications, mucosal bleeding, arterial thrombosis, and gastrointestinal perforation.13 Table 1. Toxicities of Targeted Therapies Class Most Common Adverse Effects VEGF inhibition13 Bleeding GI perforation Arterial thromboembolism Impaired wound healing Proteinuria Hypertension Regorafenib24 Hand-foot syndrome Rash Fatigue Diarrhea VEGF-related adverse effects EGFR inhibition25 Acneiform rash Paronychial infections, skin fissuring Infusion-related hypersensitivity/allergic reaction Mucositis Hypomagnesemia Immune checkpoint inhibitors26 Immune-mediated inflammation of any organ (most commonly endocrine glands, skin, liver, and GI tract) Fatal pneumonitis BRAF inhibition27,a Fatigue Rash/skin toxicity Diarrhea Abbreviations: EGFR, epidermal growth factor receptor; GI, gastrointestinal; VEGF, vascular endothelial growth factor. a With MEK inhibition, there are rare cases of pneumonitis and ophthalmologic changes. Lastly, regorafenib (Stivarga; Bayer HealthCare Pharmaceuticals, Inc, Berlin, Germany) is a tyrosine kinase inhibitor with inhibitory activity across a wide range of targets, including KIT and RET, in addition to those involved in the development of angiogenesis.24 Its use in refractory mCRC is based on the phase 3 CORRECT trial,28 which randomized 760 patients who had progressed on all other lines of standard therapy to receive best supportive care plus regorafenib or a placebo. mOS was significantly prolonged with regorafenib (6.4 vs 5.0 months; P = .0052). PFS was also improved in comparison with a placebo (HR, 0.49; CI, 0.42-0.58; P < .0001).28 Non–VEGF-related adverse effects of regorafenib include rash and diarrhea, as shown in Table 1. Targeting Epidermal Growth Factor Receptor Epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases,29 and as shown in Figure 1, ligand binding to its extracellular domain leads to phosphorylation of the tyrosine kinase domain, which activates signaling pathways for cell proliferation, angiogenesis, migration, survival, and adhesion.30 EGFR serves as a meaningful target in the treatment of colorectal cancer metastases because cancer cells depend on these pathways. Cetuximab and panitumumab are both FDA-approved for mCRC. Cetuximab (Erbitux; Bristol-Myers Squibb, New York, New York) is a chimeric murine human IgG1 mAb31 that binds to the extracellular domain of EGFR, and this results in downregulation of pro-oncogenic signaling. The binding of cetuximab to natural killer cells may also trigger an immune-mediated antitumor response leading to antibody-dependent cell-mediated cytotoxicity.31 Panitumumab (Vectibix; Amgen, South San Francisco, California) is a human IgG2 mAb that binds to the extracellular domain of EGFR. Unlike cetuximab, it does not activate antibody-dependent cell-mediated cytotoxicity.31 Cetuximab first demonstrated activity in mCRC in the so-called BOND study32 (nicknamed after the study number, ImClone 007), in which 329 patients with disease progression after irinotecan received cetuximab and irinotecan or cetuximab monotherapy. The cetuximab/irinotecan and monotherapy results (ORR, 22.9% vs 10.8%; P = .007; mPFS, 4.1 vs 1.5 months; P < .001) suggest that the EGFR pathway may be important in chemotherapy resistance. Cetuximab was approved in the first line in combination with FOLFIRI on the basis of the phase 3 CRYSTAL trial,33 in which previously untreated patients with mCRC (599 in each arm) received FOLFIRI with or without cetuximab. A primary analysis showed that cetuximab reduced the risk of progression (adjusted HR, 0.85; CI, 0.72-0.99; P = .48), although we later learned that this benefit was limited to those patients with KRAS wild-type tumors. For example, mOS in the FOLFIRI/cetuximab and FOLFIRI groups was 24.9 and 21.0 months, respectively, in the KRAS wild-type population and 17.5 and 17.7 months, respectively, in the KRAS-mutant population.33 Cetuximab may also be combined with oxaliplatin in the first line for KRAS-selected patients. The phase 2 OPUS34 trial showed an increased response rate (58% vs 29%; P = .0084) and increased PFS (8.3 vs 7.2 months; P = .0064) with cetuximab and FOLFOX4 in comparison with FOLFOX4 alone for KRAS exon 2 wild-type patients and a detrimental effect of cetuximab and FOLFOX4 for those with KRAS exon 2 mutations (HR for progression, 1.72; HR for death, 1.29). The phase 3 MRC COIN trial35 also showed an increased response rate with the addition of cetuximab to FOLFOX or CAPEOX in patients with wild-type KRAS. An exploratory analysis subsequently showed improvements in PFS only for those KRAS wild-type patients treated with FOLFOX and cetuximab (HR, 0.72; P = .037) and not capecitabine, oxaliplatin, and cetuximab.35 Panitumumab's initial approval in the first line was in combination with FOLFOX and was based on the phase 3 PRIME study,36 which showed benefits in PFS (10 vs 8.6 months; P = .01) and OS (HR, 0.83; P = .03) with the combination of FOLFOX and panitumumab in comparison with FOLFOX alone. Second Line and Beyond Several phase 2 and 3 trials have also demonstrated the efficacy of panitumumab and cetuximab for KRAS wild-type patients in the second-line setting37-39 and beyond. Van Cutsem et al40 demonstrated the efficacy of panitumumab as monotherapy for chemorefractory mCRC with prolonged PFS (8.0 vs 7.3 weeks; P < .001) and a better ORR (10% vs 0%; P < .0001) in comparison with best supportive care, and a similar result was seen with cetuximab monotherapy.41 Panitumumab or Cetuximab? Cetuximab and panitumumab both target EGFR, but their differences are not limited to the antibody structure (cetUXImab is a chimeric antibody, whereas panitUMUmab is a fully human antibody). According to the ASPECCT trial42 of patients with refractory, wild-type KRAS mCRC, panitumumab was noninferior to cetuximab with respect to mOS, mPFS, and ORR, and this suggests that antibody-dependent cell-mediated cytotoxicity is not an important mechanism with these drugs. An economic analysis of these data, however, found panitumumab to be superior to cetuximab in projected drug acquisition costs and to have better outcomes in terms of quality-adjusted life-years.42 At standard doses, it is said that panitumumab leads to a more intense acneiform skin rash than cetuximab. Rash intensity is a pharmacodynamic marker for efficacy in this class of drugs,25 and panitumumab was developed after this had been established, so the dose chosen (6 mg/kg) was based somewhat on the rash intensity. A dose escalation to maximal rash strategy was used with cetuximab in the EVEREST trial,43 and dosing to worsening acne did increase the overall response rate but did not affect OS. Another distinction between the 2 drugs is the markedly greater risk of hypersensitivity reactions seen with cetuximab (3.5%-7.5%)25 in comparison with panitumumab (0.6%-3%),25 particularly in patients from the southeastern United States.44 This clinical observation is explained by the presence of an immunoglobulin E specific for galactose-α-1,3-galactose that may be present in patients from the southeastern United States before exposure to cetuximab45; it is believed to be a cross-reacting antibody from an early life exposure, probably to a plant in the region. Other common toxicities of EGFR-targeted therapy are summarized in Table 1. Other Considerations Sidedness The side of the primary tumor in patients with mCRC matters.46 Although Cancer and Leukemia Group B/Southwest Oncology Group (SWOG) 80405 found no difference with the addition of bevacizumab or cetuximab to first-line FOLFIRI or FOLFOX in patients with all RAS wild-type mCRC,47 a subgroup analysis demonstrated the primary tumor location as an independent prognostic factor with an mOS of 32.9 months in the left-sided tumor group and an mOS of 19.6 months in the right-sided tumor group (P < .0001). Is the liver a unique organ? The liver is the most common metastatic site in colorectal cancer,48 and for carefully selected patients, OS may be improved and a cure may be possible if surgical resection is feasible. However, phase 3 data do not support a role of targeted therapy in patients with resectable liver-only metastases. The phase 3 new EPOC trial49 evaluated the benefit of the addition of cetuximab to chemotherapy in the preoperative setting for patients with resectable liver metastases, but it was closed prematurely after an interim analysis showed significantly decreased PFS for patients who received cetuximab with FOLFOX, CAPEOX, or FOLFIRI in comparison with those patients who received chemotherapy only (14.1 vs 20.5 months; HR, 1.48; P = .030).49 Likewise, studies of bevacizumab in combination with FOLFOX have demonstrated only modest responses in patients with resectable liver metastases, and this must be counterbalanced by treatment-related toxicity. Immune Checkpoint Inhibitors Self-tolerance is maintained by the immune system through checkpoints such as programmed cell death protein 1 (PD-1), which is expressed on T cells. The binding of ligands (programmed death ligand 1 [PD-L1] and PD-L2) to PD-1 leads to downregulation of effector functions.50 One mechanism by which cancer cells remain hidden from the immune response is upregulation of PD-1/PD-L1,50 which is the basis for the advances seen in the use of immunotherapy in cancer. Despite recent successes with immune checkpoint inhibition in the treatment of many cancers, its benefits in mCRC are restricted to the 3% to 7% of patients with defective mismatch repair (dMMR) proteins/microsatellite instability (microsatellite instability–high [MSI-H]).51 These patients generally present with poorly differentiated proximal tumors with abundant tumor-infiltrating lymphocytes, and survival is better with early (stage II) disease.52 Pembrolizumab (Keytruda; Merck, Kenilworth, New Jersey) and nivolumab (Opdivo; Bristol-Myers Squibb, New York, New York) are IgG4 mAbs that bind to PD-1 (Fig. 2). Their FDA approval for subsequent-line treatment of mismatch repair (MMR)–deficient or MSI-H mCRC is based on 2 trials. KEYNOTE-16453 evaluated pembrolizumab in 11 patients with dMMR mCRC and in 21 patients with MMR-proficient mCRC who had progressed through 2 to 4 prior therapies. It demonstrated an ORR of 40% and a 20-week immune-related PFS rate of 78% in the dMMR arm and an ORR of 0% and a PFS rate of 67% in the MMR-proficient arm. mPFS and mOS were not reached in the dMMR group and were 2.2 and 5.0 months, respectively, in the MMR-proficient group (P < .001). Checkmate 142 studied nivolumab in the subsequent line in 74 patients with dMMR mCRC and demonstrated an ORR of 31.1%, a PFS rate of 50%, and an OS rate of 73% at 1 year.54 A second cohort in Checkmate 142 also included patients with dMMR mCRC who were treated with a combination of nivolumab and ipilimumab in the subsequent line, and they demonstrated a higher ORR of 55% and higher PFS and OS rates of 71% and 85%, respectively, at 1 year.54 As such, this combination is also approved and is a reasonable option, though with higher potential toxicities. Figure 2Open in figure viewerPowerPoint Depiction of PD-1 inhibition by pembrolizumab and nivolumab. PD-1 indicates programmed cell death protein 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor. Because MSI-H colorectal cancer represents a very small minority of cases, many active clinical trials are exploring the potential synergistic immune effects of the combination of chemotherapy or targeted therapy with immunotherapy in patients with microsatellite-stable disease. Other studies seek to evaluate the role of immunotherapy in the first line. The toxicities of immune checkpoint inhibitors, as summarized in Table 1, are largely due to T-cell activity against any host tissue with subsequent autoimmune inflammation. The most commonly affected organs include the skin (rash), gastrointestinal tract (colitis), and endocrine axis (eg, diabetes, thyroid dysfunction, and hypophysitis).26 BRAF-Targeted Therapies BRAF mutations are found in 8% to 12% of mCRC cases, and the V600E mutation in particular confers a worse prognosis for mCRC.55 Although single-agent vemurafenib, an oral inhibitor of BRAF V600 kinase, is efficacious in melanoma, it has minimal impact in mCRC as monotherapy. Preclinical trials have shown that BRAF inhibition may induce EGFR overactivation and that anti-EGFR therapy may render previously resistant cell lines sensitive to a BRAF inhibitor.56 Other studies have identified other mechanisms of resistance such as activation of the PI3K/AKT pathway.57 As such, current treatment strategies for BRAF V600E–mutated mCRC use combinations of targeted inhibition. The phase 2 SWOG S1406 trial58 established the combination of vemurafenib, irinotecan, and cetuximab or panitumumab as a subsequent-line therapy for BRAF V600E–mutated mCRC. One hundred six patients with BRAF V600E–mutated, RAS wild-type tumors (who had received 1 or 2 prior lines of chemotherapy without an EGFR mAb) received irinotecan and cetuximab with or without vemurafenib. Vemurafenib prolonged mPFS (4.4 vs 2.0 months; P < .001) and improved disease control rates (67% vs 22%; P = .001).58 In August 2018, the FDA granted a breakthrough designation for the combination of binimetinib, encorafenib, and cetuximab per the ongoing phase 3 BEACON CRC trial on the basis of robust safety lead-in results: an overall response rate of 48%, a 1-year OS rate of 62%, and an mPFS of 8 months for patients who received the combination after 1 or 2 prior lines of chemotherapy.59 Although the randomized portion of the trial is ongoing, it may very well supplant the SWOG regimen in the treatment of BRAF-mutated mCRC. The most common toxicities associated with BRAF inhibition include rash, arthralgia, fatigue, and diarrhea, whereas pulmonary toxicities and ophthalmic changes have been observed with the use of MEK inhibitors in combination.27 HER2-Targeted Therapy Amplification of Her2 is observed in 2% to 11% of mCRC cases, is more common in left-sided colon and rectal tumors, and is thought to impart resistance to EGFR-targeted therapy.60 Although the clinical benefit of Her2 inhibition in refractory mCRC has been seen, its role in the overall treatment paradigm remains to be determined. The phase 2 HERACLES study61 evaluated the efficacy of trastuzumab and lapatinib in 27 Her2-positive/KRAS exon 2 wild-type patients with mCRC who had progressed on all other therapies, including cetuximab, and it showed an ORR of 30%. MyPathway,62 a phase 2a basket study of solid tumors with Her2 amplification, included a trastuzumab and pertuzumab arm and demonstrated an even more promising ORR of 52% in Her2-amplified/KRAS wild-type patients and no response in KRAS-mutated patients. Ongoing clinical trials such as RESCUE continue to explore the potential role of HER2-targeted therapy in mCRC.63 Conclusions: Targeted Therapies in mCRC Thousands of patients with mCRC have been treated in clinical trials with targeted therapies, and subsets of patients clearly benefit, but the relative paucity of biomarkers in mCRC has slowed our progress in this area. Recent studies have added more confusion with the recognition of other potential factors, including sidedness, and with burgeoning research on the human gut microbiome. As of today, we can find encouragement in the fact that patients with mCRC are living longer, but we realize that if we could only understand the complex biology of colorectal cancer, we could do much more. Funding Support Sorbarikor Piawah receives funding from the Maisin Foundation. Conflict of Interest Disclosures Alan P. Venook reports data safety monitoring for Halozyme; personal fees from AstraZeneca, Eisai, and Taiho Pharmaceutical; and grants and personal fees from Genentech and Roche outside the submitted work. The other author made no disclosures. Author Contributions Sorbarikor Piawah: Writing and editing. Alan P. Venook: Writing and editing. References 1Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68: 7- 30. 2Zacharakis M, Xynos ID, Lazaris A, et al. Predictors of survival in stage IV metastatic colorectal cancer. Anticancer Res. 2010; 30: 653- 660. 3Duschinsky R, Pleven E, Heidelberger C. The synthesis of 5-fluoropyrimidi