Colorectal cancer, HER2-positive

Section editor
	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

Note: the page has regimens specific to Her2-amplified colorectal cancer.

• See the main colorectal cancer page for general regimens.

3 regimens on this page 2 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. PubMed

• 2013: Labianca et al. Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
• 2013: Balmaña et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PubMed

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 PubMed

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 PubMed

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. MyPathway_CRC: 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 contains dosing details in manuscript 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

• 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

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

Study	Dates of enrollment	Evidence	Efficacy
Siena et al. 2021 (DESTINY-CRC01)	2018-2019	Phase 2	ORR: 45% (95% CI 32-60%)

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

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 contains dosing details in abstract PubMed NCT03384940

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

• 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

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 contains dosing details in abstract PubMed NCT03043313