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

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 PubMed

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 & Trastuzumab 1b. 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

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 PubMed 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 OS Median 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. CF 1b. CX	Superior 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, Trastuzumab 1b. CX, Pertuzumab, Trastuzumab	Seems to have inferior OS¹ Median 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 PubMed 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 PubMed 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 PubMed NCT01774786
1. 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 PubMed

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 & Trastuzumab 1b. CX & Trastuzumab	Seems to have superior 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 PubMed NCT01774786
1. 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 PubMed

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 & Trastuzumab 1b. CX & Trastuzumab	Seems to have superior 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 PubMed NCT01774786
1. 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 PubMed

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 OS Median 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 PubMed 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 & Trastuzumab 1b. CF & Trastuzumab	Superior PFS¹ (co-primary endpoint) Median PFS: 10 vs 8.1 mo (HR 0.73, 95% CI 0.61-0.87) Superior 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 PubMed NCT03615326
1. 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 PubMed
2. 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 PubMed

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, Trastuzumab 1b. CF, Pembrolizumab, Trastuzumab	Inferior PFS¹ Inferior OS²

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 PubMed NCT03615326
1. 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 PubMed
2. 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 PubMed

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 & Trastuzumab 1b. CX & 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

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 PubMed 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. CF 1b. CX	Superior 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, Trastuzumab 1b. CX, Pertuzumab, Trastuzumab	Seems to have inferior OS¹ Median 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, Trastuzumab 1b. CF, Pembrolizumab, Trastuzumab	Inferior PFS¹ Inferior OS²

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 PubMed 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 PubMed NCT01774786
1. 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 PubMed
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 PubMed NCT03615326
1. 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 PubMed
2. 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 PubMed
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 & Trastuzumab 1b. CF & Trastuzumab	Superior PFS¹ (co-primary endpoint) Median PFS: 10 vs 8.1 mo (HR 0.73, 95% CI 0.61-0.87) Superior 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 PubMed NCT03615326
1. 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 PubMed
2. 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 PubMed

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 OS Median 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 PubMed 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. Irinotecan 1b. Paclitaxel	Superior OS (secondary endpoint) Median OS: 12.5 vs 8.4 mo (HR 0.59, 95% CI 0.39-0.88) Superior 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 PubMed 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	Inferior OS

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 PubMed 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 OS Median 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 OS Median 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	Inferior OS

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 PubMed 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 PubMed 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 PubMed 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

Gastric cancer, HER2-positive

Guidelines

CAP/ASCP/ASCO

NCCN

Metastatic or locally advanced disease, first-line

Capecitabine & Cisplatin (CX)

Regimen

Biomarker eligibility criteria

Chemotherapy

References

Capecitabine & Cisplatin (CX) & Trastuzumab

Regimen variant #1, 80/1600

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

Regimen variant #2, 80/2000

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

Capecitabine & Cisplatin (CX), Pertuzumab, Trastuzumab

Regimen

Chemotherapy

Targeted therapy

References

Cisplatin & Fluorouracil (CF), Pertuzumab, Trastuzumab

Regimen

Chemotherapy

Targeted therapy

References

CapeOx

Regimen

Biomarker eligibility criteria

Chemotherapy

References

CapeOx, Pembrolizumab, Trastuzumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Immunotherapy

Targeted therapy

References

CapeOx & Trastuzumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

Cisplatin & Fluorouracil (CF)

Regimen

Biomarker eligibility criteria

Chemotherapy

References

Cisplatin & Fluorouracil (CF) & Trastuzumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

References

Cisplatin & Fluorouracil (CF), Pembrolizumab, Trastuzumab

Regimen

Biomarker eligibility criteria

Chemotherapy

Immunotherapy

Targeted therapy

References

Metastatic or locally advanced disease, subsequent lines of therapy

Docetaxel monotherapy

Regimen

Biomarker eligibility criteria

Chemotherapy

References

Trastuzumab deruxtecan monotherapy

Regimen

Biomarker eligibility criteria

Antibody-drug conjugate therapy

References

Irinotecan monotherapy

Regimen

Biomarker eligibility criteria

Regimen variant #1, 80 mg/m² weekly

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