Gastric cancer, HER2-positive

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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.
Last updated on 2024-07-23:15 regimens on this page
17 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.
==CAP/ASCP/ASCO==
*2017: Bartley et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers and NCCN Guidelines - Gastric Cancer.
=Metastatic or locally advanced disease, first-line=
==Capecitabine & Cisplatin (CX)==
CX: Cisplatin & Xeloda (Capecitabine)
XP: Xeloda (Capecitabine) & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bang et al. 2010 (ToGA)	2005-2008 	Phase 3 (C-RT)	1a. CF & Trastuzumab1b. CX & Trastuzumab	Shorter OSMedian OS: 11.1 vs 13.8 mo(HR 1.35, 95% CI 1.10-1.67)
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 2 hours once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01041404
==Capecitabine & Cisplatin (CX) & Trastuzumab==
CX & Trastuzumab: Cisplatin, Xeloda (Capecitabine), Trastuzumab
===Regimen variant #1, 80/1600===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shah et al. 2017 (HELOISE)	2011-2015 	Phase 3b (C)	CX & Trastuzumab; high-dose	Did not meet primary endpoint of OSMedian OS: 12.5 vs 10.6 mo(sHR 0.81, 95% CI 0.56-1.16)
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====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) as follows:
**Cycles 1 to 6: 800 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycles 2 to 6: 6 mg/kg IV once on day 1
**Cycle 7 onwards: 10 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, 80/2000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bang et al. 2010 (ToGA) 	2005-2008 	Phase 3 (E-RT-esc)	1a. CF1b. CX 	Longer OS (primary endpoint)Median OS: 13.8 vs 11.1 mo(HR 0.74, 95% CI 0.60-0.91)
Tabernero et al. 2018 (JACOB)	2013-2016 	Phase 3 (C) 	1a. CF, Pertuzumab, Trastuzumab1b. CX, Pertuzumab, Trastuzumab	Seems to have shorter OS1Median OS: 14.2 vs 18.1 mo(HR 1.18, 95% CI 1.01-1.39)
1Reported efficacy is based on the 2022 update.
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====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====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
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01041404
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01450696
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774786
##Update: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Siddiqui A, Heeson S, Kiermaier A, Macharia H, Restuccia E, Kang YK. Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial. Gastric Cancer. 2023 Jan;26(1):123-131. Epub 2022 Sep 6. link to original article link to PMC article EuroPMC
==Capecitabine & Cisplatin (CX), Pertuzumab, Trastuzumab==
CX, Pertuzumab, Trastuzumab: Cisplatin, Xeloda (Capecitabine), Pertuzumab, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tabernero et al. 2018 (JACOB)	2013-2016 	Phase 3 (E-esc)	1a. CF & Trastuzumab1b. CX & Trastuzumab	Seems to have longer OS1 (primary endpoint)Median OS: 18.1 vs 14.2 mo(HR 0.85, 95% CI 0.72-0.99)
1Reported efficacy is based on the 2022 update.
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Pertuzumab (Perjeta) 840 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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774786
##Update: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Siddiqui A, Heeson S, Kiermaier A, Macharia H, Restuccia E, Kang YK. Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial. Gastric Cancer. 2023 Jan;26(1):123-131. Epub 2022 Sep 6. link to original article link to PMC article EuroPMC
==Cisplatin & Fluorouracil (CF), Pertuzumab, Trastuzumab==
CF, Pertuzumab, Trastuzumab: Cisplatin, 5-FU, Pertuzumab, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tabernero et al. 2018 (JACOB)	2013-2016 	Phase 3 (E-esc)	1a. CF & Trastuzumab1b. CX & Trastuzumab	Seems to have longer OS1 (primary endpoint)Median OS: 18.1 vs 14.2 mo(HR 0.85, 95% CI 0.72-0.99)
1Reported efficacy is based on the 2022 update.
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Targeted therapy====
*Pertuzumab (Perjeta) 840 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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774786
##Update: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Siddiqui A, Heeson S, Kiermaier A, Macharia H, Restuccia E, Kang YK. Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial. Gastric Cancer. 2023 Jan;26(1):123-131. Epub 2022 Sep 6. link to original article link to PMC article EuroPMC
==CapeOx==
CapeOx: Capecitabine and Oxaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hecht et al. 2015 (LOGiC)	2008-2012 	Phase 3 (C)	CapeOx & Lapatinib	Did not meet primary endpoint of OSMedian OS: 10.5 vs 12.2 mo(HR 1.10, 95% CI 0.89-1.37)
100% adenocarcinoma histology (4% esophagus, 9% gastroesophageal junction, 87% gastric origin). 9% with ECOG PS of 2. 
====Biomarker eligibility criteria====
*HER2 positive
====Chemotherapy====
*Capecitabine (Xeloda) 850 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
===References===
#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 EuroPMC NCT00680901
#HERIZON-GEA-01: NCT05152147
==CapeOx, Pembrolizumab, Trastuzumab==
CapeOx, Pembrolizumab, Trastuzumab: Capecitabine, Oxaliplatin, Pembrolizumab, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (KEYNOTE-811)	2018-2020 	Phase 3 (E-RT-esc)	1a. CapeOx & Trastuzumab1b. CF & Trastuzumab	Longer PFS1 (co-primary endpoint)Median PFS: 10 vs 8.1 mo(HR 0.73, 95% CI 0.61-0.87)Longer OS2 (co-primary endpoint)Median OS: 20 vs 16.8 mo(HR 0.80, 95% CI 0.67-0.94)
1Reported efficacy is based on the 2023 update.
2Reported efficacy is based on the 2024 update.
====Biomarker eligibility criteria====
*HER2 positive
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
====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
21-day cycle for up to 35 cycles (2 years)
===References===
#KEYNOTE-811: Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. Epub 2021 Dec 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03615326
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY; KEYNOTE-811 Investigators. 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 Dec 9;402(10418):2197-2208. Epub 2023 Oct 20. link to original article EuroPMC
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yañez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin S, Van Cutsem E, Tabernero J, Luo S, Mahave M, Tang Y, Lowery M, Monteiro MMF, Xu L, Shih CS, Sharan KP, Bhagia P, Rha SY. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med. 2024 Oct 10;391(14):1360-1362. Epub 2024 Sep 14. link to original article EuroPMC
==CapeOx & Trastuzumab==
CapeOx & Trastuzumab: Capecitabine, Oxaliplatin, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (KEYNOTE-811)	2018-2020 	Phase 3 (C)	1a. CapeOx, Pembrolizumab, Trastuzumab1b. CF, Pembrolizumab, Trastuzumab	Shorter PFS1Median PFS: 8.1 vs 10 mo(HR 1.37, 95% CI 1.15-1.64)Shorter OS2Median OS: 16.8 vs 20 mo(HR 1.25, 95% CI 1.06-1.49)
1Reported efficacy is based on the 2023 update.
2Reported efficacy is based on the 2024 update.
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*HER2 positive
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 1
====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
21-day cycles
===References===
#KEYNOTE-811: Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. Epub 2021 Dec 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03615326
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY; KEYNOTE-811 Investigators. 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 Dec 9;402(10418):2197-2208. Epub 2023 Oct 20. link to original article EuroPMC
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yañez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin S, Van Cutsem E, Tabernero J, Luo S, Mahave M, Tang Y, Lowery M, Monteiro MMF, Xu L, Shih CS, Sharan KP, Bhagia P, Rha SY. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med. 2024 Oct 10;391(14):1360-1362. Epub 2024 Sep 14. link to original article EuroPMC
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin & Fluorouracil
FP: Fluorouracil & Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bang et al. 2010 (ToGA)	2005-2008 	Phase 3 (C)	1a. CF & Trastuzumab1b. CX & Trastuzumab	Shorter OSMedian OS: 11.1 vs 13.8 mo(HR 1.35, 95% CI 1.10-1.67)
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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01041404
==Cisplatin & Fluorouracil (CF) & Trastuzumab==
CF & Trastuzumab: Cisplatin, Fluorouracil, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bang et al. 2010 (ToGA) 	2005-2008 	Phase 3 (E-RT-esc)	1a. CF1b. CX 	Longer OS (primary endpoint)Median OS: 13.8 vs 11.1 mo(HR 0.74, 95% CI 0.60-0.91)
Tabernero et al. 2018 (JACOB) 	2013-2016 	Phase 3 (C) 	1a. CF, Pertuzumab, Trastuzumab1b. CX, Pertuzumab, Trastuzumab 	Seems to have shorter OS1Median OS: 14.2 vs 18.1 mo(HR 1.18, 95% CI 1.01-1.39)
Janjigian et al. 2021 (KEYNOTE-811)	2018-2020 	Phase 3 (C) 	1a. CapeOx, Pembrolizumab, Trastuzumab1b. CF, Pembrolizumab, Trastuzumab	Shorter PFS1Median PFS: 8.1 vs 10 mo(HR 1.37, 95% CI 1.15-1.64)Shorter OS2Median OS: 16.8 vs 20 mo(HR 1.25, 95% CI 1.06-1.49)
1Reported efficacy is based on the 2023 update.
2Reported efficacy is based on the 2024 update.
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====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====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
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01041404
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01774786
##Update: Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Siddiqui A, Heeson S, Kiermaier A, Macharia H, Restuccia E, Kang YK. Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial. Gastric Cancer. 2023 Jan;26(1):123-131. Epub 2022 Sep 6. link to original article link to PMC article EuroPMC
#KEYNOTE-811: Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. Epub 2021 Dec 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03615326
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY; KEYNOTE-811 Investigators. 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 Dec 9;402(10418):2197-2208. Epub 2023 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yañez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin S, Van Cutsem E, Tabernero J, Luo S, Mahave M, Tang Y, Lowery M, Monteiro MMF, Xu L, Shih CS, Sharan KP, Bhagia P, Rha SY. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med. 2024 Oct 10;391(14):1360-1362. Epub 2024 Sep 14. link to original article EuroPMC
#HERIZON-GEA-01: NCT05152147
==Cisplatin & Fluorouracil (CF), Pembrolizumab, Trastuzumab==
CF, Pembrolizumab, Trastuzumab: Cisplatin, Fluorouracil, Pembrolizumab, Trastuzumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Janjigian et al. 2021 (KEYNOTE-811)	2018-2020 	Phase 3 (E-RT-esc)	1a. CapeOx & Trastuzumab1b. CF & Trastuzumab	Longer PFS1 (co-primary endpoint)Median PFS: 10 vs 8.1 mo(HR 0.73, 95% CI 0.61-0.87)Longer OS2 (co-primary endpoint)Median OS: 20 vs 16.8 mo(HR 0.80, 95% CI 0.67-0.94)
1Reported efficacy is based on the 2023 update.
2Reported efficacy is based on the 2024 update.
====Biomarker eligibility criteria====
*HER2 positive
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
====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
21-day cycles
===References===
#KEYNOTE-811: Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. Epub 2021 Dec 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03615326
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY; KEYNOTE-811 Investigators. 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 Dec 9;402(10418):2197-2208. Epub 2023 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yañez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin S, Van Cutsem E, Tabernero J, Luo S, Mahave M, Tang Y, Lowery M, Monteiro MMF, Xu L, Shih CS, Sharan KP, Bhagia P, Rha SY. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med. 2024 Oct 10;391(14):1360-1362. Epub 2024 Sep 14. link to original article EuroPMC
=Metastatic or locally advanced disease, subsequent lines of therapy=
==Docetaxel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Thuss-Patience et al. 2017 (GATSBY)	2012-09-03 to 2013-10-14	Phase 2/3 (C)	T-DM1 	Did not meet primary endpoint of OSMedian OS: 8.6 vs 7.9 mo(HR 0.87, 95% CI 0.66-1.15)
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====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01641939
==Trastuzumab deruxtecan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2020 (DESTINY-Gastric01)	2017-2019 	Randomized Phase 2 (E-RT-switch-ooc)	Investigator's choice of:1a. Irinotecan1b. Paclitaxel	Longer OS (secondary endpoint)Median OS: 12.5 vs 8.4 mo(HR 0.59, 95% CI 0.39-0.88)Higher ORR (primary endpoint)
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
====Antibody-drug conjugate therapy====
*Trastuzumab deruxtecan (Enhertu) 6.4 mg/kg IV once on day 1
21-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03329690
==Irinotecan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shitara et al. 2020 (DESTINY-Gastric01)	2017-2019 	Randomized Phase 2 (C)	Trastuzumab deruxtecan	Shorter OSMedian OS: 8.4 vs 12.5 mo(HR 1.69, 95% CI 1.14-2.56)
====Biomarker eligibility criteria====
*DESTINY-Gastric01: HER2 over-expression
====Chemotherapy====
*Irinotecan (Camptosar) 150 mg/m2 IV once on day 1
14-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03329690
==Paclitaxel monotherapy==
===Regimen variant #1, 80 mg/m2 weekly===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Thuss-Patience et al. 2017 (GATSBY)	2012-09-03 to 2013-10-14	Phase 2/3 (C)	T-DM1 	Did not meet primary endpoint of OSMedian OS: 8.6 vs 7.9 mo(HR 0.87, 95% CI 0.66-1.15)
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====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
7-day cycles
===Regimen variant #2, 80 mg/m2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Satoh et al. 2014 (TyTAN) 	2007-2009 	Phase 3 (C) 	Lapatinib & Paclitaxel	Did not meet primary endpoint of OSMedian OS: 8.9 vs 11 mo(HR 1.19, 95% CI 0.90-1.56)
Shitara et al. 2020 (DESTINY-Gastric01)	2017-2019 	Randomized Phase 2 (C)	Trastuzumab deruxtecan	Shorter OSMedian OS: 8.4 vs 12.5 mo(HR 1.69, 95% CI 1.14-2.56)
====Biomarker eligibility criteria====
*HER2-positive disease
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00486954
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01641939
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03329690
==Paclitaxel & Ramucirumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (DESTINY-Gastric04)	2021-ongoing 	Phase 3 (C)	Trastuzumab deruxtecan	In progress
Note: Dosing information is from CT.gov.
====Targeted therapy====
*Ramucirumab (Cyramza) 8 mg/kg IV once per day on days 1 & 15
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
#DESTINY-Gastric04: NCT04704934
Category:Gastric cancer regimens
Category:Biomarker-specific pages
Category:Gastroesophageal cancers