Colorectal cancer, HER2-positive

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Note: the page has regimens specific to Her2-amplified colorectal cancer. 
*See the main colorectal cancer page for general regimens.
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==
*2016: Van Cutsem et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. EuroPMC
*2013: Labianca et al. Early Colon Cancer: ESMO Clinical Practice Guidelines EuroPMC
*2013: Balmaña et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. EuroPMC
==Japanese Society for Cancer of the Colon and Rectum==
*2016: Watanabe et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer link to PMC article EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Colon Cancer.
==SIOG==
*2014: Papamichael et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013 EuroPMC
=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===
#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 EuroPMC 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====
*Lapatinib (Tykerb) 1000 mg PO once per day on days 1 to 7
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 4 mg/kg IV once on day 1
**Cycle 2 onwards: 2 mg/kg IV once on day 1
7-day cycles
===References===
#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 EuroPMC 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====
*Trastuzumab deruxtecan (Enhertu) 5.4 mg/kg IV once on day 1
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====
*Trastuzumab deruxtecan (Enhertu) 6.4 mg/kg IV once on day 1
21-day cycles
===References===
#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 EuroPMC NCT03384940
#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 EuroPMC NCT04744831
==Tucatinib & Trastuzumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Efficacy
Strickler et al. 2023 (MOUNTAINEER)	2017-08-08 to 2021-09-22	Phase 2 (RT)	ORR: 38.1%, 95% CI 27.7-49.3
====Biomarker eligibility criteria====
*HER2 amplification and KRAS wild-type
====Targeted therapy====
*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
*Tucatinib (Tukysa) 300 mg PO twice per day on days 1 to 21
21-day cycles
===References===
#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 manuscript have been reviewed by our editors EuroPMC NCT03043313
Category:Colon cancer regimens
Category:Biomarker-specific pages
Category:Colorectal cancers