1. Singh, Bhavana P. MD, MSC
  2. Marshall, John L. MD

Article Content

Colorectal cancer (CRC) is the third most common cancer worldwide, and approximately 1,361,000 new cases are diagnosed each year (Int J Cancer 2015;136:E359-386). Approximately 20 percent of patients will have metastatic disease at presentation and, of those with stage II/III disease that is surgically resected, the rate of recurrence at 5 years is 25-30 percent (J Clin Oncol 2016;34:843-853). Systemic chemotherapy remains a mainstay in the treatment of patients with metastatic CRC (mCRC), but additional information on biomarkers such as RAS and BRAF mutations, microsatellite instability (MSI) status, and left- versus right-sided colon cancer have helped oncologists to tailor systemic treatment regimens to individual patients. Although surgical resection and locoregional ablative therapies are an important aspect of oligometastatic disease treatment, most patients with disseminated disease require systemic therapy.

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Initial standard treatment of patients with mCRC typically consists of a fluoropyrimidine doublet (5-fluorouracil/leucovorin or capecitabine combined with oxaliplatin [FOLFOX or CAPOX] or irinotecan [FOLFIRI or CAPIRI]) combined with a monoclonal antibody targeting either angiogenesis (bevacizumab, ramucirumab, or ziv-aflibercept) or, in patients with RAS wild-type tumors (Ann Oncol 2016;27:1386-1422, (NCCN) Guide 2017. Version 1. doi:10.1016/B978-1-4557-4007-9.00045-5), the epidermal growth factor receptor (EGFR; cetuximab or panitumumab). Following a positive response to initial therapy, there is evidence that patients benefit from maintenance therapy with a fluoropyrimidine with or without bevacizumab.


A myriad of options exists for systemic therapy in the metastatic setting and it is often appropriate to draw upon different combinations of therapy. Tumor molecular profiling and administration of appropriately targeted therapy allows for a more personalized approach to the treatment of patients with mCRC. This was initially described by Guinney et al, who found that CRC is made up of distinct molecular subtypes, each driven by unique genomic and corresponding proteomic aberrations (Nat Med 2015;21:1350-1356). This finding led to studies exploring the role of RAS and BRAF mutations as predictive and prognostic markers.


More recently, the discovery of a disparate response of right- and left-sided primary tumors to anti-EGFR therapy has underscored the importance of subtyping mCRCs according to their primary anatomical location as well as their molecular profile. A better understanding of tumor heterogeneity has therefore led to improved therapy for patients with mCRC. This article focuses on mCRC and its variable response to treatment according to primary tumor location and molecular characteristics, recent advances in the development of novel targeted therapies, and the use of tumor molecular profiling to guide systemic therapy decisions in patients with this disease.


Current mCRC Treatment Strategies

In addition to first- or second-line therapy with any of FOLFOX, XELOX, FOLFIRI, or XELIRI, plus a monoclonal antibody against angiogenesis or EGFR, the current arsenal of agents against mCRC also includes TAS-102 and regorafenib, usually used in later lines of therapy. The order of administration of oxaliplatin and irinotecan in combination with a fluoropyrimidine does not appear to impact outcomes, and the decision regarding which to use first is usually based on toxicity profiles, patient comorbidities, and regional practice patterns (J Clin Oncol 2004;22:229-237, J Gastrointest Cancer 2014;45(2):154-160). Some patients who have a large disease burden or are candidates for metastasectomy may benefit from the use of concurrent fluoropyrimidine plus oxaliplatin plus irinotecan triplet therapy (FOLFIRINOX) plus bevacizumab (Lancet Oncol 2015;16(13):1306-1315).


Primary tumor location is an integral part of the initial treatment decision-making process. Patients with left-sided tumors are shown to have a better prognosis than those with right-sided tumors (J Natl Cancer Inst 2015;107(3)). This is thought to be due, in part, to the presence of specific molecular alterations including BRAF mutations and MSI, which are more commonly seen in right-sided tumors. These location-dependent molecular differences have strong implications for the use of anti-EGFR agents, which was seen in the CALGB 80405 study where patients with right-sided tumors generally responded poorly to anti-EGFR therapy. Hence, the median overall survival (mOS) of patients receiving the classic doublet plus cetuximab therapy was 39.3 months if they had left-sided CRC and only 13.7 months if they had right-sided CRC. When matched patients were treated with doublet plus bevacizumab therapy, the difference in response was not so extreme: 32.7 months versus 29.2 months, respectively. It has since been concluded that the anti-EGFR agents cetuximab and panitumumab are active in patients with left-sided mCRCs that are both RAS and BRAF wild-type. Otherwise, vascular endothelial growth factor (VEGF) inhibitors, typically bevacizumab, should be the biological agent of choice.


Refinement of RAS Testing

As genomic sequencing assays evolved, basic KRAS mutation testing was expanded to pan-RAS mutation testing, and active RAS mutations were found to be present in around 56 percent of mCRCs, as opposed to the 40 percent found on KRAS analysis using PCR-based assays (Eur J Cancer 2015;51:1704-1713). These PCR-based assays identified KRAS exon 2 mutations, which were shown to result in resistance to anti-EGFR therapy. However, a report published as part of the PRIME trial detailed that mutations in exon 2, 3, and 4 of both KRAS and NRAS lead to resistance to EGFR-directed therapy (Ann Oncol 2014;25:1346-1355).


The discovery of other RAS mutations using Sanger sequencing and, more recently, next-generation sequencing is important because it reveals a subset of patients that is unlikely to respond to, or may even be harmed by, anti-EGFR therapy. Studies are underway to determine if there is a way to target the RAS protein. The first direct RAS inhibitor is expected to enter clinical trials in 2019. There also has been recent development of ARS-1620, a covalent compound with high preclinical potency and selectivity for KRAS G12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression (Cell 2018;172(3):578-589 e17). These advances highlight the prospect of a future RAS target.


Microsatellite Instability

Microsatellite instability (MSI) is present in approximately 15 percent of all CRCs, with 4 percent occurring due to inheritance of germline mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM. MSI testing is important in the identification of patients who are candidates for immune checkpoint inhibitor therapy. Le et al, found that patients with microsatellite stable tumors did not respond to pembrolizumab (a PD-1 inhibitor), whereas those with MSI tumors had a 40 percent response rate (N Engl J Med 2015;372:2509-2520). These differential outcomes are thought to be due to the elevated mutational burden of MSI tumors and corresponding presence of neoepitopes that may be targets for an activated immune system (Clin Cancer Res 2016;22(4):813-820, Science 2015;348(6230):124-128).


As part of National Comprehensive Cancer Center (NCCN) guidelines, MSI testing is recommended for mCRC and, if tumors are found to be MSI-high (MSI-H), immunotherapy is recommended as second- or third-line therapy (NCCN Guide 2017. Version 1. doi:10.1016/B978-1-4557-4007-9.00045-5). Both single-agent nivolumab (a PD-1 inhibitor) and pembrolizumab are now FDA-approved for mCRC patients after disease progression on oxaliplatin- and irinotecan-based regimens. This approval was based on data from CheckMate-142 and KEYNOTE-164, both of which showed an improvement in overall response rate (ORR) in this subset of patients receiving nivolumab (Lancet Oncol 2017;18(9):1182-1191) or pembrolizumab (J Clin Oncol 2016;34:TPS787-TPS).


Given the success of single-agent immunotherapy in MSI-H mCRC, immunotherapy combinations are also being explored in MSI-H mCRC patients. In CheckMate-142, the combination of nivolumab and ipilimumab showed an ORR of 55 percent, disease control rate (DCR) of 80 percent, and a median PFS and OS that had not been reached after 13.8 months of follow-up (J Clin Oncol 2018;36(8):773-779).


In a study by Hochster et al, the combination of atezolizumab (a PD-L1 inhibitor) and bevacizumab demonstrated an ORR of 30 percent with a DCR of 90 percent (J Clin Oncol 2017;35:S673). The mOS after 11 months of follow-up had not been reached. More recently, data on the combination durvalumab (a PD-L1 inhibitor) and tremelimumab (a CTLA-4 inhibitor) was shown to improve survival outcomes in patients with advanced refractory CRC (J Clin Oncol 2017;35:TPS3621-TPS). When compared to best supportive care, combination therapy increased mOS by 2.5 months in this patient population. More immunotherapy combination trials are underway.



HER2 amplifications occur in 3-5 percent of colorectal tumors (PLoS One 2014;9(5):e98528). In preclinical studies, HER2-amplified xenografts were not inhibited by single-agent trastuzumab (a HER2 inhibitor) or single-agent lapatinib (a dual HER2 and EGFR inhibitor). The combination, however, appears to overcome single-agent tumor resistance, which led to the initiation of multiple trials under the direction of the HERACLES group. In the phase II HERACLES study, researchers found that when patients with HER2 amplified tumors (determined using IHC and FISH) were treated with lapatinib (1,000 mg daily) and trastuzumab (2 mg/kg weekly), the DCR was 74 percent and the ORR was 30 percent (Lancet Oncol 2016;17(6):738-746). Phase III trials using EGFR-family targeted agents are still underway.



Tropomyosin receptor kinases (TRKA,B,C) are encoded by the neurotrophic receptor tyrosine kinase genes (NTRK1,2,3). Recurrent TRK fusions with different upstream partner proteins create oncogene addicted cancers across diverse sites; these mutations are found in 0.2-2.4 percent of mCRC patients. Inhibition of tumors expressing these fusion proteins with selective small molecule inhibitors such as larotrectinib has become an area of interest due to remarkable responses seen with monotherapy.


Results from 55 patients with a range of solid tumors and 17 NGS-confirmed unique TRK fusions between them were treated with larotrectinib (N Engl J Med 2018;378:731-739). Over the entire cohort, ORR was 75 percent and DCR was 88 percent; 13 percent of patients had a complete response and 62 percent had a partial response. Four of the 55 patients had CRC and three of these four CRC patients experienced an anti-tumor effect: two achieved a partial response while one achieved stable disease. Results of this trial led to the FDA approval of larotrectinib for adult and pediatric patients with solid tumors that are metastatic and have an NTRK gene fusion without a known acquired resistance mutation. This was the second tumor-agnostic FDA approval for the treatment of cancer.



The past decade of research has led to the approval of many new therapies for mCRC patients. Beyond adding to existing combination backbones of systemic therapy, subsets of mCRC patients have been identified that may benefit from novel treatments that inhibit mutant RAS signaling pathways, block immune checkpoint pathways, inhibit HER2 activity, and inhibit TRK fusions, the latter being linked to the continuing identification of novel NTRK fusions. Where these novel therapies fit into the framework of existing treatment remains to be elucidated. The world of molecular profiling is evolving at a rapid rate and the clinical world must evolve with it if patients are to fully reap the benefit of our innovations.


BHAVANA P. SINGH, MD, MSC, is a Fellow of Hematology/Oncology at MedStar Georgetown University Hospital. JOHN L. MARSHALL, MD, is Chief of the Division of Oncology at Lombardi Comprehensive Cancer Center, Georgetown University; and Director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer. The authors would like to thank Marion Hartley for her contribution in editing this article.


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