Clinical trialPhase 3Stomach cancer

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 · 2010594 patients randomised (298 trastuzumab + chemotherapy and 296 chemotherapy); 584 patients in the primary analysis

Bang YJ, Van Cutsem E, Feyereislova A, et al. Lancet. 2010. 376:687-697

Study type: Clinical trial
Study name: ToGA
Phase: Phase 3
Design: Randomised controlled, open-label, international trial at 122 centres in 24 countries (1:1 randomisation)
Sample size: 594 patients randomised (298 trastuzumab + chemotherapy and 296 chemotherapy); 584 patients in the primary analysis
Source: Lancet · 2010
Trial registration: NCT01041404

In plain words

In some patients with advanced stomach cancer (about 14% in a large multinational study cited in the NCCN guideline), the tumour cells carry large amounts of the protein HER2 (the same target known from breast cancer). ToGA was the first study to show that adding the targeted drug trastuzumab to chemotherapy in these patients helps them live longer (a median of 13.8 versus 11.1 months), without a notable increase in severe side effects or heart problems. For this reason, HER2 testing is now done for all patients with advanced stomach cancer.

Key results

13.8 vs 11.1 months

Median overall survival

HR 0.74 (95% CI 0.60 to 0.91); p=0.0046

68% vs 68%

Grade 3 or 4 adverse events

201 vs 198 patients

6% vs 6%

Cardiac adverse events

17 vs 18 patients

Drugs in this study:Capecitabine (Xeloda)Cisplatin (Platinol)Fluorouracil (5-FU)Pembrolizumab (Keytruda)Trastuzumab (Herceptin)

Dose and schedule cards

Trastuzumab + cisplatin + fluoropyrimidine (ToGA trial)

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-positive (IHC 3+ or gene amplification on FISH), with adequate cardiac function (in the trial, LVEF above 50%)Cycle length: Every 21 daysOn the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-positive

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-positive (IHC 3+ or gene amplification on FISH), with adequate cardiac function (in the trial, LVEF above 50%)

Drug	Dose	Route	Schedule
Trastuzumab	First dose 8 mg/kg (90-min infusion), then 6 mg/kg (30 to 90 min)	IV	Day 1
Cisplatin	80 mg/m²	IV (2-h infusion)	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14
Or fluorouracil (instead of capecitabine)	800 mg/m² per day	IV, continuous infusion	Days 1–5

Cycle length: Every 21 days
Duration: Chemotherapy for 6 cycles; trastuzumab until disease progression

Doses from the FDA label for trastuzumab (description of the ToGA trial). In tumours with PD-L1 CPS ≥1, adding pembrolizumab (next regimen) is recommended.

On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-positive

HER2-positive adenocarcinoma: trastuzumab + cisplatin + fluoropyrimidine, ± pembrolizumab (ToGA and KEYNOTE-811)

Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumours; add pembrolizumab if PD-L1 CPS ≥1Cycle length: Every 21 daysOn the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumours; add pembrolizumab if PD-L1 CPS ≥1

Drug	Dose	Route	Schedule
Trastuzumab	First dose 8 mg/kg (90 minutes), then 6 mg/kg (30–90 minutes)	IV	Day 1
Cisplatin	80 mg/m²	IV	Day 1 (6 cycles)
Capecitabine or fluorouracil	Capecitabine 1000 mg/m² twice daily (Days 1–14) or fluorouracil 800 mg/m²/day continuous infusion (Days 1–5)	Oral / IV	Days 1–14 or 1–5
Pembrolizumab (if CPS ≥1)	200 mg (or 400 mg every 6 weeks)	IV, before trastuzumab and chemotherapy	Day 1

Cycle length: Every 21 days
Duration: Chemotherapy for 6 cycles; trastuzumab until disease progression; pembrolizumab for up to 24 months

Doses from the FDA labels for trastuzumab (ToGA) and pembrolizumab (KEYNOTE-811; CAPOX was also permitted in this trial: oxaliplatin 130 mg/m² on Day 1 for 6 to 8 cycles + capecitabine). Monitor LVEF before starting and every 3 months; withhold trastuzumab for an absolute decrease of 16% or more, or for an LVEF below the lower limit of normal with a decrease of 10% or more.

On the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Metastatic gastric or GEJ cancer (ToGA)

HER2-positive, no previous treatment for metastatic diseaseCycle length: Every 3 weeksOn the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

HER2-positive, no previous treatment for metastatic disease

Drug	Dose	Route	Schedule
Trastuzumab	Initial dose 8 mg/kg, then 6 mg/kg	IV infusion; initial 90 minutes, then 30 to 90 minutes	Every 3 weeks
6 cycles
Cisplatin	80 mg/m²	IV infusion over 2 hours	Day 1
Capecitabine or fluorouracil	1000 mg/m² twice a day, or 800 mg/m²/day	Oral / continuous IV infusion	Days 1 to 14 / days 1 to 5

Cycle length: Every 3 weeks
Duration: Trastuzumab until disease progression

With PD-L1 CPS 1 or more: add pembrolizumab 200 mg before trastuzumab and chemotherapy (KEYNOTE-811; pembrolizumab label).

On the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Trastuzumab + chemotherapy

Trastuzumab IV at an initial dose of 8 mg/kg, then 6 mg/kg every 3 weeks until disease progression; with cisplatin 80 mg/m² IV (over 2 hours) on day 1 and a fluoropyrimidine: capecitabine 1000 mg/m² orally twice daily for 14 days of each 21-day cycle, or fluorouracil 800 mg/m²/day as a continuous IV infusion on days 1 to 5; chemotherapy every 3 weeks for 6 cycles.

2Chemotherapy alone (control group)

Cisplatin with capecitabine or fluorouracil at the same doses, every 3 weeks for 6 cycles.

Source of the regimen details: FDA label for Herceptin (section 14, description of the ToGA trial) and ClinicalTrials.gov NCT01041404; note: ClinicalTrials.gov gives capecitabine on days 1 to 15, but the FDA label reports 14 days of each 21-day cycle (the FDA label was followed here)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with advanced gastric or gastro-oesophageal junction cancer (per the FDA label: previously untreated metastatic adenocarcinoma) with HER2 protein overexpression on immunohistochemistry (IHC ‎3+‎) or gene amplification on FISH, and adequate cardiac function.

Endpoints

Primary outcome: overall survival (OS) in all randomised patients who received at least one dose of study drug.

Secondary outcomes: including progression-free survival, objective response and safety (details in the full text).

Safety and side effects

The most common adverse events in both groups were nausea (67% with trastuzumab + chemotherapy versus 63% with chemotherapy), vomiting (50% versus 46%) and neutropenia (53% versus 57%). The overall rate of grade 3 or 4 adverse events (68% versus 68%) and cardiac adverse events (6% versus 6%) did not differ. The FDA label requires assessment of left ventricular ejection fraction before starting and periodically during trastuzumab treatment.

Clinical significance and place in guidelines

ToGA was the basis for the FDA's 2010 approval of trastuzumab with cisplatin and capecitabine or fluorouracil for HER2-overexpressing metastatic gastric or gastro-oesophageal junction adenocarcinoma, and made HER2 testing part of the standard work-up of advanced gastric cancer. The 2022 ESMO guideline recommends trastuzumab-chemotherapy for HER2-positive tumours with level of evidence [I, A], and NCCN (version 2.2025) recommends adding trastuzumab to first-line chemotherapy (category 1 with cisplatin, category 2A with oxaliplatin). Today, in HER2-positive patients with PD-L1 CPS ≥1, adding pembrolizumab to this combination based on KEYNOTE-811 is also a preferred option.

Limitations

The trial was open-label. According to a post-hoc subgroup analysis summarised in the NCCN guideline, the benefit was seen mainly in IHC ‎3+‎ or IHC ‎2+‎ with FISH-positive tumours, and no benefit was observed in IHC 0 or ‎1+‎ FISH-positive tumours (overall survival HR 0.65 versus 1.07). The backbone regimen was cisplatin-based; today oxaliplatin is used more often because of lower toxicity.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.