Gastric cancer, HER2-positive

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 Ivy Abraham, MD
University of Illinois at Chicago
Chicago, IL
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 Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL

Note: these are regimens tested in biomarker-specific populations and includes gastric and gastroesophageal cancers. Please see the main gastric cancer page or the main esophageal cancer page for other regimens.

14 regimens on this page
15 variants on this page


Guidelines

CAP/ASCP/ASCO

Metastatic or locally advanced disease, first-line

Capecitabine & Cisplatin (CX)

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CX: Cisplatin & Xeloda (Capecitabine)
XP: Xeloda (Capecitabine) & Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (C) CX & Trastuzumab Inferior OS

Patients:100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.

Biomarker eligibility criteria

  • Overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation

Chemotherapy

21-day cycles

References

  1. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed

Capecitabine & Cisplatin (CX) & Trastuzumab

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CX & Trastuzumab: Cisplatin, Xeloda (Capecitabine), Trastuzumab

Regimen variant #1, 80/1600

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shah et al. 2017 (HELOISE) 2011-2015 Phase IIIb (C) CX & Trastuzumab; high-dose Did not meet primary endpoint of OS

Patients: 79% gastric, 21% GE junction, and all patients had an ECOG of 2

Biomarker eligibility criteria

Patients had overexpression of HER2 protein by immunohistochemistry AND gene amplification by in-situ hybridization.

Chemotherapy

Targeted therapy

  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 1 (compared to HD-Trastuzumab at 10 mg/kg IV)
    • Subsequent cycles: 6 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Subsequent treatment

  • Trastuzumab maintenance

Regimen variant #2, 80/2000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (E-RT-esc) CX Superior OS
Tabernero et al. 2018 (JACOB) 2013-2016 Phase III (C) CX, Pertuzumab, Trastuzumab Might have inferior OS

ToGA patients: 81% gastric, 19% GE junction. 10% of patients with ECOG of 2.

Biomarker eligibility criteria

  • ToGA: overexpression of HER2 protein by immunohistochemistry OR gene amplification by fluorescence in-situ hybridization.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed NCT01041404
  2. HELOISE: Shah MA, Xu RH, Bang YJ, Hoff PM, Liu T, Herráez-Baranda LA, Xia F, Garg A, Shing M, Tabernero J. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2017 Aug 1;35(22):2558-2567. Epub 2017 Jun 2.link to original article contains verified protocol PubMed NCT01450696
  3. JACOB: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. Epub 2018 Sep 11. link to original article contains protocol PubMed NCT01774786

CapeOx

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CapeOx: Capecitabine and Oxaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hecht et al. 2015 (LOGiC) 2008-2012 Phase III (C) CapeOx & Lapatinib Did not meet primary endpoint of OS

100% adenocarcinoma histology (4% esophagus, 9% gastroesophageal junction, 87% gastric origin). 9% with ECOG PS of 2.

Biomarker eligibility criteria

  • HER2 positive

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. LOGiC: Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houé V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC--a randomized phase III trial. J Clin Oncol. 2016 Feb 10;34(5):443-51. Epub 2015 Nov 30. link to original article PubMed NCT00680901

Cisplatin & Fluorouracil (CF)

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CF: Cisplatin & Fluorouracil
FP: Fluorouracil & Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (C) CF & Trastuzumab Inferior OS

ToGA Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.

Biomarker eligibility criteria

  • Overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

Chemotherapy

  • Cisplatin (Platinol) 80 mg/m2 IV over 1 to 3 hours once on day 1, given first
  • Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)

21-day cycle for up to 6 cycles

References

  1. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed NCT01041404

Cisplatin & Fluorouracil (CF) & Trastuzumab

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CF & Trastuzumab: Cisplatin, Fluorouracil, Trastuzumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bang et al. 2010 (ToGA) 2005-2008 Phase III (E-esc) CF Superior OS

Patients: 100% adenocarcinoma (19% gastroesophageal junction, 81% gastric). 10% with ECOG of 2.

Biomarker eligibility criteria

  • Patients had overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. ToGA: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19. link to original article contains verified protocol PubMed NCT01041404

Metastatic or locally advanced disease, subsequent lines of therapy

Docetaxel monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Thuss-Patience et al. 2017 (GATSBY) 2012-2013 Phase II/III (C) T-DM1 Did not meet primary endpoint of OS

Note: study patients could only have been treated by one other regimen and could not have been exposed to anthracyclines

Patients: 68% gastric, 32% GEJ

Biomarker eligibility criteria

  • HER2-positive disease

Chemotherapy

21-day cycles

References

  1. GATSBY: Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. link to original article contains protocol PubMed NCT01641939

Fam-trastuzumab deruxtecan monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (E-RT-switch-ooc) Investigator's choice of:
1. Irinotecan
2. Paclitaxel 		Superior OS

Note: the dose is different from the FDA-approved dose for breast cancer.

Patients had received a median of two prior therapies for advanced or metastatic disease (17% had received at least four prior therapies, 72% had previously received ramucirumab and 86% had received taxanes).

The median time since the last administration of trastuzumab was 5.9 months in the trastuzumab deruxtecan group and 6.5 months among those in the investigator's choice group.

Biomarker eligibility criteria

  • HER2 over-expression

Chemotherapy

21-day cycles

References

  1. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690

Irinotecan monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (C) Trastuzumab deruxtecan Inferior OS

=Biomarker eligibility criteria

  • DESTINY-Gastric01: HER2 over-expression

Chemotherapy

14-day cycles

References

  1. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690

Paclitaxel monotherapy

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Regimen variant #1, 80 mg/m2 weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Thuss-Patience et al. 2017 (GATSBY) 2012-2013 Phase II/III (C) T-DM1 Did not meet primary endpoint of OS

GATSBY included patients with GE junction malignancy (68% gastric, 32% GE junction)

Biomarker eligibility criteria

  • Overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation

Chemotherapy

21-day cycles

Regimen variant #2, 80 mg/m2, 3 out of 4 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Satoh et al. 2014 (TyTAN) 2007-2009 Phase III (C) Lapatinib & Paclitaxel Did not meet primary endpoint of OS
Shitara et al. 2020 (DESTINY-Gastric01) 2017-2019 Randomized Phase II (C) Trastuzumab deruxtecan Inferior OS

Biomarker eligibility criteria

  • HER2-positive disease

Chemotherapy

28-day cycles

References

  1. TyTAN: Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol. 2014 Jul 1;32(19):2039-49. Epub 2014 May 27. link to original article contains verified protocol PubMed NCT00486954
  2. GATSBY: Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017 May;18(5):640-653. Epub 2017 Mar 23. link to original article contains protocol PubMed NCT01641939
  3. DESTINY-Gastric01: Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. Epub 2020 May 29. link to original article contains verified protocol PubMed NCT03329690
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