Targeted therapies in gastric cancer and future perspectives

Table 1 Completed randomized Phase II and Phase III trials

Target	Agents	Name of trial and setting	Phase	Number of patients	PFS (mo)	P value	OS (mo)	P value	Results
HER-2	Fluoropyrimide/cisplain + Trastuzumab vs Fluoropyrimide/cisplain	ToGA, First line	III	594	6.7 vs 5·5	< 0.001	13.8 vs 11.1	0.004	PFS and OS was improved
HER-2	Lapatinib plus once-per-week paclitaxel vs paclitaxel	TYTAN, Second line	III	261	5.4 vs 4.4	0.850	11.0 vs 8.9	0.104	No effect on PFS and OS
HER-2	Cap/Ox plus lapatinib or Cap/Ox plus placebo	LOGiC, First line	III	545	6.0 vs 5.4	0.100	12.2 vs 10.5	0.350	No effect on PFS and OS
EGFR	Cisplatin and capecitabine + cetuximab vs cisplatin and capecitabine	EXPAND, First line	III	904	4.4 vs 5.6	0.320	9·4 vs 10.7	0.950	No effect on PFS and OS
EGFR	mEOC plus panitumumab vs EOC	REAL, First line	III	553	6.0 vs 7.4	0.068	8·8 vs 11.3	0.013	No effect on PFS and OS
VEGF	Bevacizumab plus cisp/cape/fluorouracil vs plc plus cisplatin/capecitabine/fluorouracil	AVAGAST, First line	III	774	6.7 vs 5.3	0.003	12.1 vs 10.1	0.100	PFS was improved, No effect on OS
VEGF	Ramucirumab vs placebo	REGARD, Second line	III	355	2.1 vs 1.3	< 0.001	5.2 vs 3.8	0.047	PFS and OS was improved
VEGF	Ramucirumab plus paclitaxel vs placebo plus paclitaxel	RAINBOW, Second line	III	665	4.4 vs 2.9	< 0.001	9.6 vs 7·4	0.017	PFS and OS was improved
VEGF	Apatinib 850 mg vs apatinib 425 vs placebo	NN, Third line	II	144	3.67 vs 3.20 vs 1.40	< 0.001	4.83 vs 4.27 vs 2.50	< 0.001	PFS and OS was improved
MET	Rilotumumab 15 mg/kg per rilotumumab 7.5 mg/kg, or placebo plus ECX	NN, First line	II	121	5.1 vs 6.8 vs 4.2	0.016	9.7 vs 11.1 vs 8.9	0.100	PFS and OS was improved
m-TOR	Everolimus 10 mg vs placebo	GRANITE, ≥ Second line	III	656	1.7 vs 1.4	0.780	5.4 vs 4.3	0.124	No effect on PFS and OS

Plc: Placebo; mEOC: Modified epirubicin, oxaliplatin and capecitabine; DCF: Docetaxel, cisplatin, 5-fluorouracil; ECF/ECX: Epirubicin, cisplatin, fluorouracil/capecitabine; EGFR: Epidermal Growth Factor Receptor; VEGF: Vascular Endothelial Growth Factor; ECX: Epirubicin, cisplatin, capecitabine; NN: No specific study name was defined; OS: Overal survival; PFS: Progression free survival.

Table 2 Finished Phase II studies

Target	Agents	Name of Trial and Setting	Phase	Number of patients	PFS (mo)	OS (mo)	Results
HER-2	Lapatinib	S0413, First line	II	47	1.9	4.8	Positive
HER-2	Lapatinib plus ECF or ECX vs placebo plus ECF or ECX	EORTC 40071, First line	II	28	7.1 vs 5.9	13.8 vs 10.1	Negative1
HER-2	MK-2206 (AKT inhibitor)	S1005, Second line	II	70	1.8	5.1	Negative
Pan-HER	Saracatinib (Src inhibitor)	NN, ≥ Second line	II	21	1.8	7.8	Negative
Pan-HER	Dacomitinib	NN, ≥ Second line	II	27	2.1	7.1	Positive
EGFR	Cetuximab plus mFOLFOX6	NN, First line	II	40	5.5	9.9	Positive
EGFR	Cetuximab plus FOLFIRI	NN, First line	II	49	9.0	16.5	Positive
EGFR	Panitumumab with dose dense DCF	NN, First line	II	52	4.8	9.4	Positive
VEGF	Bevacizumab plus irinotecan and cisplatin	NN, First line	II	47	8.3	12.3	Positive
VEGF	Bevacizumab plus docetaxel/oxaliplatin	NN, First line	II	38	6.6	11.1	Positive
m-TOR	Everolimus 10 mg	NN, ≥ Second line	II	53	2.7	10.1	Positive

¹Early terminated. VEGF: Vascular endothelial growth factor; m-TOR: Mammalian target of rapamycin; NN: No specific study name was defined.

Table 3 Ongoing Phase II and III studies

Target	Agents	Trial number	Setting	Phase	Primary end point	Status
HER-2	Arm A: pertuzumab + trastuzumab + cisplatin + fluoropyrimidine vs Arm B: placebo + trastuzumab + cisplatin + fluoropyrimidine	NCT01774786	First line	III	OS	Recruiting
HER-2	Arm A: Docetaxel or paclitaxel	NCT01641939	First line	II/III	Phase II: Dose of TDM-1	Recruiting
	Arm B: T-DM1 3.6 mg/kg every 3 wk
	Arm C: T-DM1 2.4 mg/kg once a week				Phase III: OS
HER-3	Arm A: MM-111 + Paclitaxel + Trastuzumab	NCT01774851	≥ Second line	II	PFS	Active, not recruiting
	Arm B: Paclitaxel + Trastuzumab
MET	Arm A: Rilotumumab 15 mg/kg plus ECX	NCT01697072	First line	III	OS	Active, not recruiting
	Arm B: Placebo plus ECX
MET	Arm A: onartuzumab plus mFOLFOX6	NCT01662869	First line	III	OS	Active, not recruiting
	Aram B: placebo plus mFOLFOX6
CTLA4	Arm A: Ipilimumab	NCT01585987	Maintanence	II	PFS	Active, not recruiting
	Arm B: Best Supportive Care
PD-1	Arm A: Nivolumab (ONO-4538)	NCT02267343	≥ Second line	III	OS	Recruiting
	Arm B: Placebo

CTLA4: Cytotoxic T lymphocyte antigen; PD-1: Programmed cell death.