Targeted Therapy in Metastatic Colorectal Cancer: Current Standards and Novel Agents in Review
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Purpose of Review
Treatment options for patients with metastatic colorectal cancer continue to advance as the therapeutic implications of the molecular subtypes of this disease are becoming better understood. DNA sequencing and mismatch repair assessment are now standard of care analyses for patients with metastatic colorectal cancer This review describes important aspects of the biology of the clinically relevant molecular subtypes of colorectal cancer based on the current standard of care testing. In addition, the clinical treatment strategies available now and potentially in the future for these colorectal cancer subtypes are discussed.
Currently, for metastatic colorectal cancer, standard of care molecular testing is done for mutations in exons 2, 3, and 4 of KRAS and NRAS, and BRAF V600E. Testing for mismatch repair (MMR) deficiency/microsatellite instability (MSI) status is also done. These aberrations are well known to change the clinical prognosis and guide patients’ treatment strategies. Additionally, three new subtypes have emerged: PIK3CAmut, HER2 amplified, and NTRK fusions. With the addition of these emerging subtypes, tumor heterogeneity further validates the need to examine mCRC as a heterogeneous disease. Here, we present recent exciting data from translational research and clinical trials exhibiting possible distinct treatment strategies for these different subtypes.
Altogether, these data show promising treatment strategies for many of these well-known and emerging subtypes of mCRC. In addition, these also give better clinical prognostic and predictive information. We believe that as molecular testing expands, PIK3CA mutation, HER2 amplification, and NTRK fusion molecular testing will be included in standard of care analyses. This incorporation of testing in clinical practice will generate further information regarding prognostic and therapeutic options for these and other CRC subtypes in the future.
KeywordsColon cancer Rectal cancer Targeted therapy Molecular subtypes Emerging subtypes chemotherapy
This project was supported by P30 CA014520 (Core Grant, University of Wisconsin Carbone Cancer Center).
Compliance with Ethical Standards
Conflict of Interest
Rebecca A. DeStefanis declares that she has no conflict of interest.
Jeremy D. Kratz declares that he has no conflict of interest.
Philip B. Emmerich declares that he has no conflict of interest.
Dustin A. Deming has received clinical trial funding from Merck, and has received compensation from Bristol-Myers Squibb, Genentech, Bayer, and Array Pharmaceuticals for service on advisory boards.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol. 2007;25(30):4779–86.CrossRefGoogle Scholar
- 5.Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.Google Scholar
- 6.Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30.Google Scholar
- 7.Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan Z-Z, Mitchell L, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist. 2013;18(9):1004–12.Google Scholar
- 11.Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1(11):1311–8.Google Scholar
- 15.Van Cutsem E, Kohne C-H, Láng I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.CrossRefGoogle Scholar
- 17.Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15(6):569–79.CrossRefGoogle Scholar
- 18.Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Fruth B, Meyerhardt JA, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317(23):2392–401.CrossRefGoogle Scholar
- 19.Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27(12):2091–6.CrossRefGoogle Scholar
- 20.Venook AP, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O’Neil BH et al. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). American Society of Clinical Oncology; 2016.Google Scholar
- 21.Segelov E, Earle C, Venook A, Saskin R, Mofid L, Singh S. 587PSurvival by sidedness of metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor antibodies (EGFR-Ab) in the refractory setting: A population-based study of 1509 patients. Ann Oncol. 2017;28(suppl_5)): v158–v208. https://doi.org/10.1093/annonc/mdx393.
- 22.Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194–201.CrossRefGoogle Scholar
- 25.Wasan H, Meade AM, Adams R, Wilson R, Pugh C, Fisher D, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol. 2014;15(6):631–9.CrossRefGoogle Scholar
- 27.Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64.CrossRefGoogle Scholar
- 30.Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53(1):57–64. https://doi.org/10.1007/DCR.0b013e3181c703a4.CrossRefGoogle Scholar
- 35.Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 1990;50(3 Suppl):814s–9s.Google Scholar
- 38.Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C et al. A molecularly annotated platform of patient-derived xenografts (‘xenopatients’) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508–23.Google Scholar
- 40.De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753–62.CrossRefGoogle Scholar
- 45.Khan KH, Cunningham D, Werner B, Vlachogiannis G, Spiteri I, Heide T, et al. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial. Cancer Discov. 2018;8(10):1270–85.CrossRefGoogle Scholar
- 47.Parseghian CM, Loree JM, Morris VK, Liu X, Clifton K, Napolitano S, et al. Anti-EGFR resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol. 2018; (in press).Google Scholar
- 48.Sievers CK, Kratz JD, Zurbriggen LD, LoConte NK, Lubner SJ, Uboha N, et al. The multidisciplinary management of colorectal cancer: present and future paradigms. Clin Colon Rectal Surg. 2016;29(03):232–8.Google Scholar
- 51.Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti–epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67(6):2643–8.CrossRefGoogle Scholar
- 55.• Bendell J, Ciardiello F, Tabernero J, Tebbutt N, Eng C, Di Bartolomeo M, et al. LBA-004Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol. 2018;29(suppl_5):mdy208.003-mdy208.003. https://doi.org/10.1093/annonc/mdy208.003 Important clinical trial highlighting the need for more work to better understand the clinical significance of RAS mutations in mCRC. CrossRefGoogle Scholar
- 56.Oberst MD, Fuhrmann S, Mulgrew K, Amann M, Cheng L, Lutterbuese P et al. CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas. MAbs; Taylor & Francis; 2014.Google Scholar
- 60.Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature. 2017;552(7683):116–20.Google Scholar
- 64.Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.Google Scholar
- 65.Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.CrossRefGoogle Scholar
- 66.•• Overman MJ, Lonardi S, Wong KYM, Lenz H-J, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9 The largest single group assignment immunotherapy combination study done in dMMR/MSI-H mCRC with encouranging overall response rates.Google Scholar
- 67.Overman MJ, Kopetz S, McDermott RS, Leach J, Lonardi S, Lenz H-J, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. 2016;34(15_suppl):3501. https://doi.org/10.1200/JCO.2016.34.15_suppl.3501.
- 68.Overman MJ, Bergamo F, McDermott RS, Aglietta M, Chen F, Gelsomino F, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142. 2018;36(4_suppl):554. https://doi.org/10.1200/JCO.2018.36.4_suppl.554.
- 71.Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–75.CrossRefGoogle Scholar
- 74.Kopetz S, McDonough SL, Morris VK, Lenz H-J, Magliocco AM, Atreya CE, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). 2017;35(4_suppl):520. https://doi.org/10.1200/JCO.2017.35.4_suppl.520.
- 75.• Cutsem EV, Cuyle P-J, Huijberts S, Yaeger R, Schellens JHM, Elez E, et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): Efficacy and tumor markers. 2018;36(4_suppl):627. https://doi.org/10.1200/JCO.2018.36.4_suppl.627 An exciting ongoing clinical trial for patients with a BRAF V600E mutation which promises to be a new clinical practice for this subset of patients.
- 76.Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY, et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35(23):2624–30.Google Scholar
- 78.Fricke SL, Payne SN, Favreau PF, Kratz JD, Pasch CA, Foley TM et al. MTORC1/2 inhibition as a therapeutic strategy for PIK3CA mutant cancers. Mol Cancer Ther. 2018:18(2):346–55.Google Scholar
- 81.Marsoni S, Bertotti A, Sartore-Bianchi A, Leone F, Lonardi S, Ciardiello F, et al. Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: the HERACLES trial (HER2 amplification for Colo-rectaL cancer enhanced stratification). J Clin Oncol. 2013;31, no. 15_suppl.Google Scholar
- 82.• Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol. 2018;36(6):536–42 An important basket trial which found significant objective response rates among HER2 receptor amplified mCRC patients.Google Scholar
- 84.Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019;32(1):147–53.Google Scholar
- 85.Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A, et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst. 2017;109(12).Google Scholar
- 88.Khan KH, Cunningham D, Werner B, Vlachogiannis G, Spiteri I, Heide T, et al. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial. Cancer Discov. 2018;8(10):1270–85.CrossRefGoogle Scholar