ToGA Trial: Efficacy and Safety of Trastuzumab Added to Chemotherapy for First-line Treatment of Advanced Gastric or Gastro-oesophageal Junction Cancers with Overexpression of HER2

23 Apr, 21

Introduction

Trastuzumab is a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity, inhibits HER2-mediated signalling, and prevents cleavage of the extracellular domain of HER2.

ToGA (Trastuzumab for Gastric Cancer) trial assessed the clinical efficacy and safety of trastuzumab added to chemotherapy for first-line treatment of advanced gastric or gastro-oesophageal junction cancers with overexpression of HER2.

Patient Profile

Patients with gastric or gastro-oesophageal junction cancer

Methods

Open-label, international, phase 3, randomised controlled Trial

Chemotherapy was given every 3 weeks for six cycles. Capecitabine 1000 mg/m2 was given orally twice a day for 14 days followed by a 1-week rest, or fluorouracil 800 mg/m² per day was given by continuous intravenous infusion on days 1–5 of each cycle. Cisplatin 80 mg/m² on day 1 was given by intravenous infusion.
Trastuzumab was given by intravenous infusion at a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent

Endpoint

The primary endpoint was overall survival, defined as time from randomisation until death from any cause
Secondary endpoints included progression-free survival, time to progression, overall tumour response rate, duration of response, and safety

Results

Efficacy Outcomes

Median follow-up was 18.6 months in the trastuzumab plus chemotherapy group and 17.1 months in the chemotherapy alone group

Median overall survival was 13.8 months in patients assigned to trastuzumab plus chemotherapy compared with 11.1 months in those assigned to chemotherapy alone (figure 1)
26% reduction in the death rate

Figure 1: Median overall Survival Outcomes with Trastuzumab plus chemotherapy vs Chemotherapy Alone

Table 1: Secondary endpoints

	Trastuzumab plus chemotherapy (n=294)	Chemotherapy alone (n=290)	Non-stratified eï¬€ect size		Stratified eï¬€ect size*		Odds ratio	p value
			Hazard ratio	p value	Hazard ratio	p value
Progression-free survival (months)	6·7 (6–8)	5·5 (5–6)	0·71	0·0002	0·71	0·0004	··	··
Time to progression (months)	7·1 (6–8)	5·6 (5–6)	0·70	0·0003	0·69	0·0003	··	··
Duration of response (months)	6·9 (6–8) †	4·8 (4–6) ‡	0·54	<0·0001	0·53	<0·0001	··	··
Tumour response
Overall tumour response rate	139 (47%)	100 (35%)	··	··	··	··	1·70	0·0017§
Complete response	16 (5%)	7 (2%)	··	··	··	··	2·33	0·0599§
Partial response	123 (42%)	93 (32%)	··		··	··	1·52	0·0145§
Stable disease	93 (32%)	101(35%)	··	··	··	··	··	··
Progressive disease	35 (12%)	53 (18%)	··	··	··	··	··	··
Missing	27 (9%)	36 (12%)	··	··	··	··	··	··

Data are median (95% CI) or number (%). *Stratified by extent of disease (local vs metastatic), primary tumour site (stomach vs gastro-oesophageal junction), measurability (measurable vs non-measurable), Eastern Cooperative Oncology Group performance status (0–1 vs 2), and fluoropyrimidine regimen (fluorouracil vs capecitabine). †n=139. ‡n=100. §χ2 test.

Exploratory, post-hoc analysis showed that trastuzumab plus chemotherapy substantially improved overall survival in patients with high expression of HER2 protein (immunohistochemistry 2+ and FISH positive or immunohistochemistry 3+) compared with patients with low expression of HER2 protein (immunohistochemistry 0 or 1+ and FISH positive)

Safety

The most common adverse events in both groups were
- Nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%])
- Vomiting (147 [50%] vs 134 [46%])
- Neutropenia (157 [53%] vs 165 [57%])
Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups

Conclusion

The study demonstrated that addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone
The findings suggested trastuzumab can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer when combined with a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin.

Reference

Lancet 2010; 376: 687–97