Background
Phase III RCT (ToGA). 594 patients with HER2-positive (IHC 3+ or IHC 2+/FISH+) advanced gastric or gastroesophageal junction adenocarcinoma, no prior treatment for advanced disease, at 122 centers in 24 countries. Randomized 1:1 to trastuzumab + chemotherapy vs chemotherapy alone. HER2 positivity was present in ~22% of screened patients (1,646 screened for 594 enrolled).
Interventions and follow up
Arm A: Trastuzumab 8 mg/kg loading → 6 mg/kg q3wks + chemotherapy (cisplatin 80 mg/m² d1 + capecitabine 1000 mg/m² BID d1–14 or 5-FU 800 mg/m²/day d1–5, q3wks × 6 cycles)
Arm B: Chemotherapy alone (cisplatin + capecitabine or 5-FU × 6 cycles)
Primary endpoint: Overall survival
Median follow-up: 18.6 months
Arm B: Chemotherapy alone (cisplatin + capecitabine or 5-FU × 6 cycles)
Primary endpoint: Overall survival
Median follow-up: 18.6 months
Results
OS (ITT): 13.8 vs 11.1 months, HR 0.74 (95% CI 0.60–0.91), P=.0046
OS (HER2 IHC 3+ or IHC 2+/FISH+): 16.0 vs 11.8 months
PFS: 6.7 vs 5.5 months, HR 0.71, P=.0002
ORR: 47% vs 35%, P=.0017
OS (HER2 IHC 3+ or IHC 2+/FISH+): 16.0 vs 11.8 months
PFS: 6.7 vs 5.5 months, HR 0.71, P=.0002
ORR: 47% vs 35%, P=.0017
Adverse events
Overall: Grade 3/4 AEs 68% vs 68%; no treatment-related deaths.
Most common (trastuzumab+chemo vs chemo): Nausea 67% vs 63%, vomiting 50% vs 46%, neutropenia 53% vs 57%.
Cardiac: Cardiac AEs 6% vs 6% — no increase with trastuzumab.
Most common (trastuzumab+chemo vs chemo): Nausea 67% vs 63%, vomiting 50% vs 46%, neutropenia 53% vs 57%.
Cardiac: Cardiac AEs 6% vs 6% — no increase with trastuzumab.
Conclusions
Trastuzumab plus chemotherapy significantly improved OS, PFS, and ORR in HER2-positive advanced gastric/GEJ cancer, with greatest benefit in IHC 3+ or IHC 2+/FISH+ tumors, establishing trastuzumab-based chemotherapy as the standard first-line therapy for HER2-positive advanced gastric cancer.
Key Limitations
Key Limitations: Modest OS benefit (2.7 months median) — no OS benefit observed in IHC 0 or IHC 1+ patients, emphasizing the need for accurate HER2 testing. Trastuzumab added beyond 6 cycles was not studied; optimal duration is unknown. HER2 heterogeneity in gastric cancer may reduce response durability. Two chemotherapy backbones were allowed (capecitabine vs 5-FU), adding heterogeneity. Subsequent HER2 targeting with trastuzumab deruxtecan (DESTINY-Gastric01) has now established a later-line option.
Clinical Context
ToGA established HER2 testing as mandatory in all advanced gastric and GEJ cancers and defined trastuzumab + platinum/fluoropyrimidine as first-line standard for HER2-positive (~15–22%) tumors. More recently, pembrolizumab + trastuzumab + chemotherapy (KEYNOTE-811) shows further OS improvement in HER2-positive disease. Trastuzumab deruxtecan (T-DXd) is now a preferred later-line option in HER2-positive gastric cancer (DESTINY-Gastric01). These positions are reflected in ASCO and ESMO guidelines.
References
References: Bang YJ et al, Lancet 2010 (ToGA)