Colorectal cancer, HER2-positive

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Section editor
Travis Zack, MD, PhD
University of California San Francisco
San Francisco, CA, USA
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Note: the page has regimens specific to Her2-amplified colorectal cancer.

Last updated on 2024-09-06:
4 regimens on this page
5 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO


Japanese Society for Cancer of the Colon and Rectum


NCCN


SIOG


Advanced or metastatic disease, second or third-line therapy

Pertuzumab & Trastuzumab

Regimen

Study Dates of enrollment Evidence Efficacy
Meric-Bernstam et al. 2019 (MyPathwayCRC) 2014-2017 Phase 2a ORR: 32% (95% CI 20-45%)

Biomarker eligibility criteria

  • HER2 amplification

Patients enrolled in MyPathway had ECOG 0-2 Diagnostic criteria for Her2 positivity in MyPathway:

  • Patients with solid tumors that have HER2 overexpression, amplification, or HER2-activating mutation as identified by assays performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
    • Assays using in situ hybridization (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) must indicate the presence of gene amplification with a HER2/CEP17 ratio of at least 2 or HER2 gene copy number greater than 6.0.
    • Assays using IHC must indicate a score of 3 +.
    • Assays using next generation sequencing (NGS) of genes with known or potentially clinically relevant alterations or analysis by real-time polymerase chain reaction (RT-PCR) must identify clinically activating mutations (those with major coding disruptions resulting in an amino acid change that is likely to be detrimental to protein function, including premature stop codons or frameshift mutations early in the coding region) or copy number gain.
    • In cases where multiple assays are done, HER2 positivity by any of the testing methodologies would make the patient eligible as long as eligibility criteria are fulfilled.

Targeted therapy

  • Pertuzumab (Perjeta) as follows:
    • Cycle 1: 840 mg IV once on day 1
    • Cycle 2 onwards: 420 mg IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 1
    • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

  1. MyPathwayCRC: Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, Swanton C, Kurzrock R, Burris H, Sweeney C, Bose R, Spigel DR, Beattie MS, Blotner S, Stone A, Schulze K, Cuchelkar V, Hainsworth J. 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 Apr;20(4):518-530. Epub 2019 Mar 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02091141


Lapatinib & Trastuzumab

Regimen

Study Dates of enrollment Evidence Efficacy
Sartore-Bianchi et al. 2016 (HERACLES) 2012-2015 Phase 2 ORR: 30% (95% CI 14-50%)

Biomarker eligibility criteria

  • KRAS wild-type, HER2 amplification

Patients enrolled in HERACLES had ECOG 0-1 Diagnostic criteria for Her2 positivity in HERACLES:

  • Tumours with 3+ HER2 score in more than 50% of cells by immunohistochemistry

or

  • 2+ HER2 score and a HER2:CEP17 ratio higher than two in more than 50% of cells by FISH

Targeted therapy

7-day cycles

References

  1. HERACLES: Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassingena A, Lauricella C, Vanzulli A, Regge D, Veronese S, Comoglio PM, Bardelli A, Marsoni S, Siena S. 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 Jun;17(6):738-746. Epub 2016 Apr 20. link to original article PubMed EudraCT 2012-002128-33


Trastuzumab deruxtecan monotherapy

Regimen variant #1, 5.4 mg/kg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Raghav et al. 2024 (DESTINY-CRC02) 2021-03-05 to 2022-03-29 Randomized Phase 2 (E-RT-de-esc) T-DXd; 6.4 mg/kg Similar ORR1 (primary endpoint)

1DESTINY-CRC02 was not powered as an equivalence study.

Biomarker eligibility criteria

  • HER2 amplification

Antibody-drug conjugate therapy

21-day cycles


Regimen variant #2, 6.4 mg/kg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Siena et al. 2021 (DESTINY-CRC01) 2018-2019 Phase 2 ORR: 45% (95% CI 32-60%)
Raghav et al. 2024 (DESTINY-CRC02) 2021-03-05 to 2022-03-29 Randomized Phase 2 (C) T-DXd; 5.4 mg/kg Similar ORR1 (primary endpoint)

1DESTINY-CRC02 was not powered as an equivalence study.

Biomarker eligibility criteria

  • HER2 amplification

Diagnostic criteria for Her2 positivity in DESTINY-CRC01:

  • Three cohorts were based on the degree of Her2 positivity:
    • HER2-positive with immunohistochemistry (IHC) scoring 3+ or IHC 2+/in situ hybridization (ISH)+ (cohort A, n = 53)
    • HER2 IHC 2+/ISH– (cohort B, n = 7)
    • HER2 IHC 1+ (cohort C, n = 18).

Antibody-drug conjugate therapy

21-day cycles

References

  1. DESTINY-CRC01: Siena S, Di Bartolomeo M, Raghav K, Masuishi T, Loupakis F, Kawakami H, Yamaguchi K, Nishina T, Fakih M, Elez E, Rodriguez J, Ciardiello F, Komatsu Y, Esaki T, Chung K, Wainberg Z, Sartore-Bianchi A, Saxena K, Yamamoto E, Bako E, Okuda Y, Shahidi J, Grothey A, Yoshino T; DESTINY-CRC01 investigators. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):779-789. Epub 2021 May 4. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03384940
  2. DESTINY-CRC02: Raghav K, Siena S, Takashima A, Kato T, Van den Eynde M, Pietrantonio F, Komatsu Y, Kawakami H, Peeters M, Andre T, Lonardi S, Yamaguchi K, Tie J, Castro CG, Hsu HC, Strickler JH, Kim TY, Cha Y, Barrios D, Yan Q, Kamio T, Kobayashi K, Boran A, Koga M, Allard JD, Yoshino T. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol. 2024 Sep;25(9):1147-1162. Epub 2024 Aug 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT04744831


Tucatinib & Trastuzumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Strickler et al. 2023 (MOUNTAINEER) 2017-08-08 to 2021-09-22 Phase 2 (RT)

Biomarker eligibility criteria

  • HER2 amplification and KRAS wild-type

Targeted therapy

21-day cycles

References

  1. MOUNTAINEER: Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, Wu C, Paulson AS, Hubbard JM, Coveler AL, Fountzilas C, Kardosh A, Kasi PM, Lenz HJ, Ciombor KK, Elez E, Bajor DL, Cremolini C, Sanchez F, Stecher M, Feng W, Bekaii-Saab TS; MOUNTAINEER investigators. 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 May;24(5):496-508. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03043313


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