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Cited by 11Colorectal Cancer Treatments and StudiesHER2/EGFR in Cancer ResearchLung Cancer Treatments and Mutations

Targeting HER2 in Metastatic Colorectal Cancer: Current Therapies, Biomarker Refinement, and Emerging Strategies

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Vaghi, Caterina, Tosi, Federica, Mauri, Gianluca, Bonazzina, Erica, Amatu, Alessio, Bencardino, Katia, Piscazzi, Daniele, Roazzi, Laura +11 more·2026·Drugs
DOI 10.1007/s40265-025-02253-2PMC PMC12799626
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Abstract

HER2 overexpression/amplification is a well-established oncogenic driver across several tumor types and has emerged as a therapeutically actionable biomarker in 3-5% of metastatic colon and rectal cancers (mCRCs). Based on increasing clinical evidence, several anti-HER2 therapeutic regimens have been incorporated into treatment guidelines. In this review, we provide a comprehensive overview of both established and emerging HER2-targeted strategies in mCRC, examining the mechanisms of action, toxicity profiles, and clinical efficacy of individual anti-HER2 drugs and their associations. As accurate and standardized HER2 testing remains critical, we also discuss current methodologies and challenges in HER2 screening for mCRC. In addition, we present an in-depth analysis of the relationship between HER2 amplification levels, co-occurring genomic alterations, and treatment outcomes across clinical trials, underscoring the importance of quantitative HER2 assessment and comprehensive tumor profiling. These data support the refinement of therapeutic strategies through more precise diagnostic approaches and improved patient selection, considering factors such as gene-dosage, toxicity, and coexisting mutations. Finally, the emerging role of anti-HER2 rechallenge strategies and the advent of novel HER2-directed therapies-including bispecific antibodies, novel tyrosine kinase inhibitors, antibody-drug conjugates, and immune-based therapies-are discussed as new opportunities to improve outcomes in this molecular subset of patients.

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  1. [1]Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A, Siegel RL. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73:233–54. 10.3322/CAAC.21772. 36856579 · DOI
  2. [2]Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:10–32. 10.1016/J.ANNONC.2022.10.003. 36307056 · DOI · Paper page
  3. [4]Siena S, Sartore-Bianchi A, Marsoni S, Hurwitz HI, McCall SJ, Penault-Llorca F, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29:1108–19. 10.1093/ANNONC/MDY100. 29659677 PMC5961091 · DOI
  4. [5]Tan RYC, Camat MD, Ng M, Lim TH, Lim AST, Lim KH, et al. HER2 positive rates are enriched amongst colorectal cancer brain metastases: a study amongst 1920 consecutive patients. Ann Oncol. 2018;29:1598–603. 10.1093/ANNONC/MDY156. 29868843 · DOI
  5. [6]Tosi F, Sartore-Bianchi A, Lonardi S, Amatu A, Leone F, Ghezzi S, et al. Long-term clinical outcome of trastuzumab and lapatinib for HER2-positive metastatic colorectal cancer. Clin Colorectal Cancer. 2020;19:256-262.e2. 10.1016/J.CLCC.2020.06.009. 32919890 · DOI · Paper page
  6. [7]Sartore-Bianchi A, Amatu A, Porcu L, Ghezzi S, Lonardi S, Leone F, et al. Her2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist. 2019;24:1395–402. 10.1634/THEONCOLOGIST.2018-0785. 30952821 PMC6795149 · DOI
  7. [8]Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54. 10.1038/NRC1609. 15864276 · DOI
  8. [10]Bartley K, Snider J, Cho-Phan C, Wang J, Martin P, Simon C, et al. The prognostic impact of human epidermal growth factor receptor 2 status in metastatic colorectal cancer. Future Sci OA. 2025. 10.1080/20565623.2025.2527482. 40631776 PMC12243896 · DOI
  9. [11]Yagisawa M, Sawada K, Nakamura Y, Fujii S, Yuki S, Komatsu Y, et al. Prognostic value and molecular landscape of HER2 low-expressing metastatic colorectal cancer. Clin Colorectal Cancer. 2021;20:113-120.e1. 10.1016/J.CLCC.2020.11.002. 33384243 · DOI
  10. [12]Germani MM, Borelli B, Hashimoto T, Nakamura Y, Oldani S, Battaglin F, et al. Impact of human epidermal growth factor receptor 2 in patients with metastatic colorectal cancer treated with chemotherapy plus bevacizumab or anti-EGFRs: exploratory analysis of eight randomized trials. J Clin Oncol. 2025. 10.1200/JCO-25-01003. 40906970 PMC12509457 · DOI
  11. [13]Battaglin F, Ou FS, Qu X, Hochster HS, Niedzwiecki D, Goldberg RM, et al. HER2 gene expression levels are predictive and prognostic in patients with metastatic colorectal cancer enrolled in CALGB/SWOG 80405. J Clin Oncol. 2024;42:1890–902. 10.1200/JCO.23.01507. 38457761 PMC11240881 · DOI
  12. [14]Sartore-Bianchi A, Marsoni S, Amatu A, Torri V, Bonoldi E, Bardelli A, et al. How to test HER2 for predicting resistance to anti-epidermal growth factor receptor therapy in metastatic colorectal cancer? evidence from the secondary analysis of biomarkers of CALGB/SWOG 80405. J Clin Oncol. 2024;42:3631–2. 10.1200/JCO.24.00805/ASSET/79D4B87C-2CC3-482A-B255-ED179587814E/ASSETS/JCO.24.00805.FP.PNG. 39079079 · DOI
  13. [16]Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3:99ra86. 10.1126/SCITRANSLMED.3002442. 21900593 PMC3268675 · DOI · Paper page
  14. [19]Cremolini C, Morano F, Moretto R, Berenato R, Tamborini E, Perrone F, et al. Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study. Ann Oncol. 2017;28:3009–14. 10.1093/ANNONC/MDX546. 29045518 · DOI
  15. [20]Ciardiello D, Bielo LB, Napolitano S, Latiano TP, De Stefano A, Tamburini E, et al. Comprehensive genomic profiling by liquid biopsy portrays metastatic colorectal cancer mutational landscape to predict antitumor efficacy of FOLFIRI plus cetuximab in the CAPRI-2 GOIM trial. ESMO Open. 2025. 10.1016/j.esmoop.2025.104511. 40107157 PMC11964631 · DOI
  16. [21]Germani MM, et al. The prognostic and predictive role of HER2 amplification/overexpression and HER2 mutations in metastatic colorectal cancer treated with first-line chemotherapy plus bevacizumab/anti-EGFRs: An individual patient data pooled analysis of eight randomized trials. J Clin Oncol. 2025;43:3537.
  17. [22]Raghav KPS, Guthrie KA, Tan B, Denlinger CS, Fakih M, Overman MJ, et al. Trastuzumab plus pertuzumab versus cetuximab plus irinotecan in patients with RAS/BRAF wild-type, HER2-positive, metastatic colorectal cancer (S1613): a randomized phase II trial. J Clin Oncol. 2025. 10.1200/JCO-24-01710/SUPPL_FILE/PROTOCOL_JCO-24-01710.PDF. 39761503 PMC11975499 · DOI
  18. [23]Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:738–46. 10.1016/S1470-2045(16)00150-9. 27108243 · DOI · Paper page
  19. [24]Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol. 2015;28:1481–91. 10.1038/MODPATHOL.2015.98. 26449765 · DOI
  20. [25]Sawada K, Nakamura Y, Yamanaka T, Kuboki Y, Yamaguchi D, Yuki S, et al. Prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2018;17:198–205. 10.1016/J.CLCC.2018.05.006. 29866615 · DOI
  21. [26]Lee WS, Park YH, Lee JN, Baek JH, Lee TH, Ha SY. Comparison of HER2 expression between primary colorectal cancer and their corresponding metastases. Cancer Med. 2014;3:674. 10.1002/CAM4.228. 24668895 PMC4101759 · DOI
  22. [27]Shan L, Lv Y, Bai B, Huang X, Zhu H. Variability in HER2 expression between primary colorectal cancer and corresponding metastases. J Cancer Res Clin Oncol. 2018;144:2275–81. 10.1007/S00432-018-2744-Z. 30203148 PMC11813305 · DOI
  23. [28]DiPeri TP, Kong K, Varadarajan K, Karp DD, Ajani JA, Pant S, et al. Discordance of HER2 expression and/or amplification on repeat testing. Mol Cancer Ther. 2023;22:976–84. 10.1158/1535-7163.MCT-22-0630/727379/AM/DISCORDANCE-OF-HER2-EXPRESSION-AND-OR. 37339271 PMC10751575 · DOI
  24. [29]D’Angelo F, Monnien F, Overs A, Pem I, Dor F, Abad M, et al. Temporal and spatial heterogeneity of HER2 status in metastatic colorectal cancer. Diagn Pathol. 2024;19:88. 10.1186/S13000-024-01508-Y. 38909265 PMC11193188 · DOI
  25. [30]Lorenzini D, Salvatori R, Volpi CC, Trupia DV, Niger M, Nichetti F, et al. Validating HER2 copy number variation assessment by NGS: a comparative analysis with immunohistochemistry and in situ hybridization. Tumori J. 2025;111(4):322–30. 10.1177/03008916251345409. 40629669 · DOI
  26. [31]Shimada Y, Yagi R, Kameyama H, Nagahashi M, Ichikawa H, Tajima Y, et al. Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer. Hum Pathol. 2017;66:1–9. 10.1016/J.HUMPATH.2017.02.004. 28235632 · DOI
  27. [32]Cenaj O, Ligon AH, Hornick JL, Sholl LM. Detection of ERBB2 amplification by next-generation sequencing predicts HER2 expression in colorectal carcinoma. Am J Clin Pathol. 2019;152:97–108. 10.1093/AJCP/AQZ031. 31115453 · DOI
  28. [33]Fujii S, Magliocco AM, Kim J, Okamoto W, Kim JE, Sawada K, et al. International harmonization of provisional diagnostic criteria for ERBB2-amplified metastatic colorectal cancer allowing for screening by next-generation sequencing Panel. JCO Precis Oncol. 2020;4:6–19. 10.1200/PO.19.00154. 35050726 · DOI
  29. [34]Siravegna G, Sartore-Bianchi A, Nagy RJ, Raghav K, Odegaard JI, Lanman RB, et al. Plasma HER2 (ERBB2) copy number predicts response to HER2-targeted therapy in metastatic colorectal cancer. Clin Cancer Res. 2019;25:3046–53. 10.1158/1078-0432.CCR-18-3389. 30808777 · DOI
  30. [35]Siravegna G, Lazzari L, Crisafulli G, Sartore-Bianchi A, Mussolin B, Cassingena A, et al. Radiologic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer. Cancer Cell. 2018;34:148-162.e7. 10.1016/J.CCELL.2018.06.004. 29990497 · DOI
  31. [36]Nakamura Y, Okamoto W, Kato T, Esaki T, Kato K, Komatsu Y, et al. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nat Med. 2021;27:1899–903. 10.1038/S41591-021-01553-W. 34764486 PMC8604726 · DOI · Paper page
  32. [37]Strickler JH, Cercek A, Ng K, Siena S, Andre T, Van Cutsem E, et al. HER2 testing in the MOUNTAINEER trial: analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS. J Clin Oncol. 2023;41:3528–3528. 10.1200/JCO.2023.41.16_SUPPL.3528. · DOI
  33. [38]Roazzi L, Patelli G, Bencardino KB, Amatu A, Bonazzina E, Tosi F, et al. Ongoing clinical trials and future research scenarios of circulating tumor DNA for the treatment of metastatic colorectal cancer. Clin Colorectal Cancer. 2024;23:295–308. 10.1016/J.CLCC.2024.02.001. 38519391 · DOI
  34. [39]Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20:518–30. 10.1016/S1470-2045(18)30904-5. 30857956 PMC6781620 · DOI · Paper page
  35. [40]Gupta R, Meric-Bernstam F, Rothe M, Garrett-Mayer E, Mangat PK, D’Andre S, et al. Pertuzumab plus trastuzumab in patients with colorectal cancer with ERBB2 amplification or ERBB2/3 mutations: results from the TAPUR study. JCO Precis Oncol. 2022. 10.1200/PO.22.00306. 36315917 · DOI
  36. [41]Sweeney CJ, Hainsworth JD, Bose R, Burris HA, Kurzrock R, Swanton C, et al. Mypathway human epidermal growth factor receptor 2 basket study: pertuzumab 1 trastuzumab treatment of a tissue-agnostic cohort of patients with human epidermal growth factor receptor 2–altered advanced solid tumors. J Clin Oncol. 2024;42:258–65. 10.1200/JCO.22.02636/SUPPL_FILE/PROTOCOL_JCO.22.02636.PDF. 37793085 PMC10824375 · DOI
  37. [42]Narita Y, Yoshimoto T, Namai T, Asakawa T, Kawakami S, Gower-Page C, et al. Pertuzumab plus trastuzumab for treatment-refractory HER2-amplified metastatic colorectal cancer: comparison of the MyPathway trial with a real-world external control arm. JCO Clin Cancer Inform. 2022. 10.1200/CCI.22.00022. 35649212 PMC9225680 · DOI
  38. [43]Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, ras wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24:496–508. 10.1016/S1470-2045(23)00150-X. 37142372 · DOI · Paper page
  39. [44]Spiekman IAC, Zeverijn LJ, Geurts BS, Verkerk K, Mohammad SFH, van der Noort V, et al. Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer: results from the drug rediscovery protocol (DRUP). Eur J Cancer. 2024;202:113988. 10.1016/J.EJCA.2024.113988. 38471288 · DOI
  40. [45]Amatu A, Ghezzi S, Vaghi C, Mauri G, Bencardino K, Tosi F, et al. 446P bayesian monitoring of lapatinib (L) plus trastuzumab (T) treatment of HER2 positive metastatic colorectal cancer (MCRC): an observational cohort study. Ann Oncol. 2021;32:S557. 10.1016/j.annonc.2021.08.967. · DOI
  41. [46]Sartore-Bianchi A, Lonardi S, Martino C, Fenocchio E, Tosi F, Ghezzi S, et al. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial. ESMO Open. 2020. 10.1136/ESMOOPEN-2020-000911. 32988996 PMC7523198 · DOI
  42. [47]Yoshino T, Di Bartolomeo M, Raghav K, Masuishi T, Loupakis F, Kawakami H, et al. Final Results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun. 2023;14(1):1–13. 10.1038/s41467-023-38032-4. 37286557 PMC10247780 · DOI · Paper page
  43. [48]Raghav K, Siena S, Takashima A, Kato T, Van den Eynde M, Pietrantonio F, et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25:1147–62. 10.1016/S1470-2045(24)00380-2. 39116902 · DOI
  44. [49]Yoshino T, Bartolomeo MD, Raghav KPS, Masuishi T, Kawakami H, Yamaguchi K, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (Pts) with HER2-expressing metastatic colorectal cancer (MCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40:119–119. 10.1200/JCO.2022.40.4_SUPPL.119. · DOI
  45. [50]Conte P, Ascierto PA, Patelli G, Danesi R, Vanzulli A, Sandomenico F, et al. Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment. ESMO Open. 2022. 10.1016/J.ESMOOP.2022.100404. 35219244 PMC8881716 · DOI
  46. [51]Chang J, Xu M, Wang C, Huang D, Zhang Z, Chen Z, et al. Dual HER2 targeted therapy with pyrotinib and trastuzumab in refractory HER2 positive metastatic colorectal cancer: a result from HER2-FUSCC-G study. Clin Colorectal Cancer. 2022;21:347–53. 10.1016/J.CLCC.2022.07.003. 35941028 · DOI
  47. [52]Fu X, Ying J, Yang L, Fang W, Han W, Hu H, et al. Dual targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: a phase 2 trial. Cancer Sci. 2023;114:1067–74. 10.1111/CAS.15660. 36382603 PMC9986078 · DOI
  48. [53]Zhou H, Lv M, Li W, Wang Y, Wu J, Liu Q, et al. Efficacy of pyrotinib with/without trastuzumab in treatment-refractory, HER2-positive metastatic colorectal cancer: result from a prospective observational study. Clin Colorectal Cancer. 2024;23:58–66. 10.1016/J.CLCC.2023.10.008. 38177002 · DOI
  49. [54]Weisser NE, Sanches M, Escobar-Cabrera E, O’Toole J, Whalen E, Chan PWY, et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity. Nat Commun. 2023;14(1):1–22. 10.1038/s41467-023-37029-3. 36914633 PMC10011572 · DOI
  50. [55]Meric-Bernstam F, Hanna D, Beeram M, Lee K-W, Kang Y-K, Chaves J, et al. Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours. Ann Oncol. 2019;30:v167–8. 10.1093/annonc/mdz244.015. · DOI
  51. [56]Meric-Bernstam F, Beeram M, Hamilton E, Oh DY, Hanna DL, Kang YK, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022;23:1558–70. 10.1016/S1470-2045(22)00621-0. 36400106 · DOI
  52. [57]Rha SY, Lee K-W, Lee S, Kang Y-K, Chandana S, Escalante A, et al. 516MO Zanidatamab (Zani) + chemotherapy (CT) in first-line (1L) human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic colorectal cancer (MCRC). Ann Oncol. 2024;35:S436–7. 10.1016/J.ANNONC.2024.08.585. · DOI
  53. [58]Li J, Luo S, Liu T, Dong L, Yuan X, Feng J, et al. 684p phase I trial of SHR-A1811 in HER2-expressing advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) and colorectal cancer (CRC). Ann Oncol. 2023;34:S478. 10.1016/j.annonc.2023.09.1870. · DOI
  54. [59]Yao H, Yan M, Tong Z, Wu X, Ryu M-H, Park JJ, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2–directed antibody-drug conjugate, in human epidermal growth factor receptor 2–expressing or mutated advanced solid tumors: a global phase I trial. J Clin Oncol. 2024. 10.1200/JCO.23.02044. 38900984 · DOI
  55. [60]Rossini D, Germani MM, Lonardi S, Pietrantonio F, Dell’Aquila E, Borelli B, et al. Treatments after second progression in metastatic colorectal cancer: a pooled analysis of the TRIBE and TRIBE2 studies. Eur J Cancer. 2022;170:64–72. 10.1016/J.EJCA.2022.04.019. 35594613 · DOI
  56. [61]Strickler JH, Cercek A, Ng K, Siena S, André T, Van Cutsem E, et al. 551o impact of baseline molecular alterations on the efficacy of tucatinib (TUC) plus trastuzumab (Tras) for HER2+, RAS WT metastatic CRC (MCRC) in MOUNTAINEER. Ann Oncol. 2023;34:S411–2. 10.1016/J.ANNONC.2023.09.1742. · DOI
  57. [62]Xu T, Wang X, Xin Y, Wang Z, Gong J, Zhang X, et al. Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: a phase ii single-arm study and exploratory biomarker analysis. Cancer Res Treat. 2023;55:626–35. 10.4143/CRT.2022.1058. 36550683 PMC10101806 · DOI
  58. [64]Randon G, Nakamura Y, Yaeger R, Lonardi S, Cremolini C, Elez E, et al. Negative hyperselection of patients with HER2+ and RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade: the PRESSING-HER2 study. Clin Cancer Res. 2024;30:436–43. 10.1158/1078-0432.CCR-23-1379. 37610454 PMC10792357 · DOI
  59. [65]Imai M, Nakamura Y, Shin S, Okamoto W, Kato T, Esaki T, et al. Artificial intelligence-powered human epidermal growth factor receptor 2 and tumor microenvironment analysis in human epidermal growth factor receptor 2-amplified metastatic colorectal cancer: exploratory analysis of phase II TRIUMPH trial. JCO Precis Oncol. 2025. 10.1200/PO-24-00385. 39823559 PMC11753463 · DOI
  60. [66]Lazzari L, Corti G, Picco G, Isella C, Montone M, Arcela P, et al. Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer. Clin Cancer Res. 2019;25:6243–59. 10.1158/1078-0432.CCR-18-3440/74915/AM/PATIENT-DERIVED-XENOGRAFTS-AND-MATCHED-CELL-LINES. 31375513 PMC7611232 · DOI
  61. [67]Hoyek C, Zheng-Lin B, Pirozzi A, Abidoye O, Eslinger C, Iida N, et al. Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (MCRC). J Clin Oncol. 2025;43:277–277. 10.1200/JCO.2025.43.4_SUPPL.277. · DOI
  62. [68]Sartore Bianchi A, Lonardi S, Amatu A, Bergamo F, Mauri G, Martino C, et al. 370p trastuzumab-emtansine (T-DM1) in HER2-amplified metastatic colorectal cancer patients progressing to trastuzumab-lapatinib: the HERACLES RESCUE phase II trial. Ann Oncol. 2022;33:S705–6. 10.1016/j.annonc.2022.07.508. · DOI
  63. [69]Bianchi AS, Mauri G, Troiani T, Bergamo F, Gori V, Ghezzi S, et al. 44P rechallenge with anti-HER2 regimens in metastatic colorectal cancer: the retrospective RHEA study. Ann Oncol. 2025;36:S27. 10.1016/J.ANNONC.2025.05.056. · DOI
  64. [70]Martinelli E, Troiani T, Sforza V, Martini G, Cardone C, Vitiello PP, et al. Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case. ESMO Open. 2018;3:299. 10.1136/esmoopen-2017-000299. PMC5786925 29387480 · DOI
  65. [71]Song N, Teng Y, Shi J, Teng Z, Jin B, Qu J, et al. A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive heavily pretreated solid tumors: results from a phase Ia/Ib first-in-human, open-label, single center study. Front Immunol. 2024;15:1481326. 10.3389/FIMMU.2024.1481326. 39676868 PMC11637859 · DOI
  66. [72]Bekaii-Saab TS, Cutsem EV, Tabernero J, Siena S, Yoshino T, Nakamura Y, et al. Mountaineer-03: phase 3 study of tucatinib, trastuzumab, and MFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—trial in progress. J Clin Oncol. 2023;41:TPS261–TPS261. 10.1200/JCO.2023.41.4_SUPPL.TPS261. · DOI
  67. [73]Wilding B, Woelflingseder L, Baum A, Chylinski K, Vainorius G, Gibson N, et al. Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers. Cancer Discov. 2025. 10.1158/2159-8290.CD-24-0306. 39248702 PMC11726021 · DOI
  68. [74]Heymach JV, Opdam F, Barve M, Tu HY, Wu YL, Berz D, et al. HER2-selective tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with advanced/metastatic solid tumors with HER2 alterations: a phase Ia dose-escalation study. J Clin Oncol. 2025;43:1337. 10.1200/JCO-24-01727. 40030100 PMC11974636 · DOI
  69. [75]Schram AM, Clay TD, Prenen H, Park JJ, Lunger L, Hussain J, et al. Beamion PANTUMOR-1: a phase II, multicenter, multicohort, open-label trial to evaluate the efficacy and safety of the oral HER2-selective tyrosine kinase inhibitor zongertinib for the treatment of HER2 -mutated or overexpressed/amplified solid tumors. J Clin Oncol. 2025. 10.1200/JCO.2025.43.16_SUPPL.TPS3187. · DOI
  70. [76]Jhaveri K, Han H, Dotan E, Oh D-Y, Ferrario C, Tolcher A, et al. 460MO preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers. Ann Oncol. 2022;33:S749–50. 10.1016/J.ANNONC.2022.07.589. · DOI
  71. [77]Oh D-Y, Bedard PL, Lee K-W, Han HS, Kang Y-K, Miller WH, et al. Abstract B130: phase 1 study of zanidatamab zovodotin (ZW49): safety profile and recommended dose (RD) in patients with human epidermal growth factor 2 (HER2)-positive solid cancers. Mol Cancer Ther. 2023;22:B130–B130. 10.1158/1535-7163.TARG-23-B130. · DOI
  72. [78]Hardaker EL, Sanseviero E, Karmokar A, Taylor D, Milo M, Michaloglou C, et al. The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment. Nat Commun. 2024;15(1):1–20. 10.1038/s41467-024-45996-4. 38402224 PMC10894296 · DOI
  73. [79]Xu Y, Wang Y, Gong J, Zhang X, Peng Z, Sheng X, et al. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer. 2021;24:913–25. 10.1007/S10120-021-01168-7/TABLES/4. 33945049 PMC8205919 · DOI
  74. [80]Xu H, Peng J, Wu H, Yang L, Wang W, Wang Y, et al. Disitamab vedotin combined with fruquintinib in patients with HER2-expressing or HER2 mutation/amplified metastatic colorectal cancer refractory to at least two standard regimens: a prospective, exploratory, single-arm study. J Clin Oncol. 2024;42:e15003–e15003. 10.1200/JCO.2024.42.16_SUPPL.E15003. · DOI
  75. [81]Wang Y, Gong J, Wang A, Wei J, Peng Z, Wang X, et al. Disitamab vedotin (RC48) plus toripalimab for HER2-expressing advanced gastric or gastroesophageal junction and other solid tumours: a multicentre, open label, dose escalation and expansion phase 1 trial. EClinicalMedicine. 2024;68:102415. 10.1016/j.eclinm.2023.102415. 38235421 PMC10789637 · DOI
  76. [82]Liu H, Zhou D, Liu D, Xu X, Zhang K, Hu R, et al. Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer. Cell Death Dis. 2024;15(3):1–13. 10.1038/s41419-024-06572-2. 38443386 PMC10914798 · DOI
  77. [83]Chen J, Wang J, Zheng Q. Disitamab vedotin combined with pyrotinib as salvage treatment in Her-2-amplified treatment refractory metastatic colorectal cancer: a case report. Front Pharmacol. 2025. 10.3389/FPHAR.2025.1431422. 40051563 PMC11883190 · DOI
  78. [85]Wu S, Zhang Q, Zhang F, Meng F, Liu S, Zhou R, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat Cell Biol. 2019;21(8):1027–40. 10.1038/s41556-019-0352-z. 31332347 · DOI
  79. [86]Gall VA, Philips AV, Qiao N, Clise-Dwyer K, Perakis AA, Zhang M, et al. Trastuzumab increases HER2 uptake and cross-presentation by dendritic cells. Cancer Res. 2017;77:5374–83. 10.1158/0008-5472.CAN-16-2774/652776/AM/TRASTUZUMAB-INCREASES-HER2-UPTAKE-AND-CROSS. 28819024 PMC5626640 · DOI
  80. [87]Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402:2197–208. 10.1016/S0140-6736(23)02033-0. 37871604 · DOI
  81. [88]Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab in HER2-positive gastric cancer. N Engl J Med. 2024;391:1360–2. 10.1056/NEJMC2408121. 39282917 PMC11620791 · DOI
  82. [89]Rohaan MW, Borch TH, van den Berg JH, Met Ö, Kessels R, Geukes Foppen MH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022;387(23):2113–25. 10.1056/NEJMOA2210233. 36477031 · DOI
  83. [90]Hu L, Fan C, Bross P, Das A, Cho ES, Knudson KM, et al. FDA approval summary: lifileucel for unresectable or metastatic melanoma previously treated with an anti-PD-1-based immunotherapy. Clin Cancer Res. 2025. 10.1158/1078-0432.CCR-25-0880. 40699950 PMC12313226 · DOI
  84. [91]Xu J, Meng Q, Sun H, Zhang X, Yun J, Li B, et al. HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. Cell Death Dis. 2021;12(12):1–11. 10.1038/s41419-021-04100-0. 34839348 PMC8627513 · DOI
  85. [92]Makawita S, Gibbs JM, McFadden DR, Porter C, Shaw AR, Robertson C, et al. Binary oncolytic adenovirus in combination with HER2-specific autologous CAR VST for treatment of advanced HER2-positive solid tumors (VISTA). J Clin Oncol. 2024;42:TPS2679–TPS2679. 10.1200/JCO.2024.42.16_SUPPL.TPS2679. · DOI
  86. [93]Reiss KA, Angelos MG, Dees EC, Yuan Y, Ueno NT, Pohlmann PR, et al. CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial. Nat Med. 2025. 10.1038/s41591-025-03495-z. 39920391 · DOI
  87. [94]Mishima Y, Isoda F, Matsumoto N, Hiranuka K, Yamada T, Fujinami N, Shimomura M, Suzuki T, Nakatsura T, Nakamura N, et al. 1006P ACE1702, a first-in-class, off-the-shelf, selected natural killer cell [ONK] product using antibody cell conjugation technology [ACC], with pre-clinical and early clinical activity in HER2 < 3+ tumors. 2021. 10.1016/j.annonc.2021.08.1389. · DOI
  88. [95]Janku F, Han SW, Doi T, Amatu A, Ajani JA, Kuboki Y, et al. Preclinical characterization and phase I study of an anti-HER2-TLR7 immune-stimulator antibody conjugate in patients with HER2+ malignancies. Cancer Immunol Res. 2022;10:1441–61. 10.1158/2326-6066.CIR-21-0722. 36129967 · DOI
  89. [96]Li BT, Pegram MD, Lee K-W, Sharma M, Lee J, Spira AI, et al. A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors. J Clin Oncol. 2023;41:2538–2538. 10.1200/JCO.2023.41.16_SUPPL.2538. · DOI

Cited by

Sorted by citations

Authors
Vaghi, C., Tosi, F., Mauri, G., Bonazzina, E., Amatu, A., Bencardino, K., Piscazzi, D., Roazzi, L., Villa, F., Maggi, M., Monti, L., Bombelli, A., Marrapese, G., Ghezzi, S., Patelli, G., Ros, J., Elez, E., Sartore-Bianchi, A., & Siena, S.
Affiliations
  • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
  • University of Milan (IT)
  • Universitat Autònoma de Barcelona (ES)
Corresponding author
Siena, Salvatore
ORCID
Venue
Drugs
Publisher
Springer Science and Business Media LLC
Published
2025-11-17
Volume
86
Issue
1
Pages
37-57
ISSN
  • 0012-6667 (ISSN-L)
  • 1179-1950
DOI
10.1007/s40265-025-02253-2
PMC
PMC12799626
OpenAlex
W4416297791
Cited by
11
References
6
Citations by year
2026: 11
FWCI
1.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Drugs (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • Fondazione Oncologia Niguarda Onlus
  • Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
HER2, metastatic colorectal cancer, HER2-targeted therapy, HER2 amplification, HER2 testing, bispecific antibodies, antibody-drug conjugates, tyrosine kinase inhibitors, immune checkpoint inhibitors, patient selection, drug toxicity
MeSH terms
Antineoplastic Agents, Humans, Neoplasm Metastasis, Biomarkers, Tumor, Colorectal Neoplasms, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Protein Kinase Inhibitors, Molecular Targeted Therapy

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