Current and emerging therapies in unresectable and recurrent gastric cancer

Table 1 First line chemotherapy completed trials

Ref.	Arms	n	TTP/PFS (mo)	OS (mo)
Van Cutsem et al[7]	DCF vs CF	445	TTP: 5.6 vs 3.7	9.2 vs 8.6
			P < 0.001	P = 0.02
Al-Batran et al[8]	FLO vs FLP	220	PFS: 5.8 vs 3.9	10.7 vs 8.8
			P = 0.077
REAL-2[9]	ECF vs ECX vs EOF vs EOX	1002	PFS: 6.2 vs 6.7 vs 6.5 vs 7.0	9.9 vs 9.9 vs 9.3 vs 11.2
Kang et al[10]	XP vs FP	316	PFS: 5.6 vs 5.0	10.5 vs 9.3
SPIRITS[11]	CS vs S-1	298	PFS: 6.0 vs 4.0	13.0 vs 11.0
			P < 0.0001	P = 0.04
FLAGS[12]	CS vs CF	1053	PFS: 4.8 vs 5.5	8.6 vs 7.9
			P = 0.920	P = 0.20
Dank et al[13]	IF vs CF	333	TTP: 5.0 vs 4.2	9.0 vs 8.7
			P = 0.088
Guimbaud et al[14]	FOLFIRI vs ECX	416	PFS: 5.3 vs 5.8	9.5 vs 9.7
			P = 0.960	P = 0.95

DCF: Docetaxel/cisplatin/fluorouracil; CF: Cisplatin/fluorouracil; FLO: Fluorouracil/leucovorin/oxaliplatin; FLP: Fluorouracil/leucovorin/cisplatin; ECF: Epirubicin/cisplatin/fluorouracil; ECX: Epirubicin/cisplatin/capecitabine; EOF: Epirubicin/oxaliplatin/fluorouracil; EOX: Epirubicin/oxaliplatin/capecitabine; XP: Cisplatin/capecitabine; FP: Cisplatin/fluorouracil; CS: Cisplatin/S-1; SOX: S-1/oxaliplatin; IF: Irinotecan/fluorouracil; FOLFIRI: Fluorouracil/leucovorin/irinotecan.

Table 2 Targeted therapy completed trials

Ref.	Name	Indication	Line	Arms	n	PFS (mo)	OS (mo)
	Phase
HER2
[28]	ToGA	HER2(+) Adv/Met GC and GEJ	1st	Fluoropyrimidine/cisplatin ± trastuzumab	594	6.7 vs 5.5	13.8 vs 11.1
	Phase III					P = 0.0002	P = 0.0050
[29]	LOGiC	HER2(+) Adv/Met GC and GEJ	1st	CapeOx ± lapatinib	545	6.4 vs 5.4	12.2 vs 10.5
	Phase III					p = 0.1000	P = 0.3492
[30]	TyTAN	HER2(+) Adv/Met GC and GEJ	2nd	Paclitaxel ± lapatinib	261	5.4 vs 4.4	11.0 vs 8.9
	Phase III					P = 0.2441	P = 0.2088
EGFR
[36]	EXPAND	Adv/Met GC and GEJ	1st	Capecitabine/cisplatin ± cetuximab	904	4.4 vs 5.9	9.4 vs 10.7
	Phase III					P = 0.3200	P = 0.9500
[37]	REAL3	Adv/Met GC and GEJ	1st	EOX vs modified EOX + panitumumab	553	6.0 vs 7.4	8.8 vs 11.3
	Phase III					P = 0.0680	P = 0.013
VEGFR
[48]	Sunitinib	Adv GC and GEJ	2nd	Sunitinib	78	2.3	6.8
	Phase II
[49]	Sunitinib	Adv GC and GEJ	2nd or 3rd	FOLFIRI ± sunitinib	91	3.6 vs 3.3	10.5 vs 9.0
	Phase II					P = 0.6600	P = 0.2100
[50]	Sorafenib	Adv/Met GC and GEJ	1st	Docetaxel/cisplatin + sorafenib	44	5.8	13.6
	Phase II
[51]	Sorafenib	Adv GC and GEJ	2nd	Oxaliplatin + sorafenib	40	3	6.5
	Phase II
[53]	Regorafenib	Adv GC and GEJ	2nd or 3rd	Regorafenib vs placebo	152	11.1 wk vs 3.9 wk	25 wk vs 19.4 wk
	Phase II					P < 0.0001	P = 0.1100
[41]	AVAGAST	Adv GC and GEJ	1st	Capecitabine/cisplatin ± bevacizumab	774	6.7 vs 5.3	12.1 vs 10.1
	Phase III					P = 0.0037	P = 0.1002
[43]	REGARD	Met GC and GEJ	2nd	BSC ± ramucirumab	355	2.1 vs 1.3	5.2 vs 3.8
	Phase III					P < 0.0001	P = 0.0473
[44,45]	RAINBOW	Met GC and GEJ	2nd	Paclitaxel ± ramucirumab	665	4.4 vs 2.86	9.63 vs 7.36
	Phase III					P < 0.0001	P = 0.0169
[47]	Apatinib	Adv GC and GEJ	3rd	Apatinib vs placebo	270	78 d vs 53 d	195 d vs 140 d
	Phase III					P < 0.0001	P < 0.016
mTOR
[58]	GRANITE-1	Adv GC and GEJ	2nd or 3rd	BSC ± everolimus	656	1.7 vs 1.4	5.4 vs 4.3
	Phase III					P = 0.0010	P = 0.124

Adv: Advanced; Met: Metastatic; GC: Gastric cancer; GEJ: Gastroesophageal junction; CapeOx: Capecitabine/oxaliplatin; EOX: Epirubicin/oxaliplatin/capecitabine; FOLFIRI: Fluorouracil/leucovorin/irinotecan; BSC: Best supportive care; HER2: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; VEGFR: Vascular endothelial growth factor receptor; mTOR: Mammalian target of rapamyin.

Table 3 Ongoing trials

Name	Indication	Line	Agent	ClinicalTrials.gov Identifier
Phase
HER2
HELOISE	HER2(+) Met GC and GEJ	1st	Trastuzumab	NCT01450696
Phase III
JACOB	HER2(+) Met GC and GEJ	1st	Pertuzumab	NCT01774786
Phase III
VEGFR
RAINFALL	HER2(-) Met GC and GEJ	1st	Ramucirumab	NCT02314117
Phase III
PARP
Olaparib	Adv GC and GEJ	2nd	Olaparib	NCT01924533
Phase III
Immune checkpoints
KEYNOTE-059	Adv GC and GEJ		Pembrolizumab	NCT02335411
Phase II
KEYNOTE-061	Adv GC and GEJ	2nd	Pembrolizumab	NCT02370498
Phase III
KEYNOTE-062	Adv GC and GEJ	1st	Pembrolizumab	NCT02494583
Phase III
MEDI4736	Advanced solid tumors		MEDI4736	NCT01693562
Phase I/II
JAVELIN Gastric 100	Adv/Met GC and GEJ	1st	Avelumab	NCT02625610
Phase III
JAVELIN Gastric 300	Met/recurrent GC and GEJ	3rd	Avelumab	NCT02625623
Phase III
Phase I/II	Met/recurrent GC and GEJ		MEDI4736 + Tremelimumab vs MEDI4736 vs Tremelimumab	NCT02340975
Phase I/II	Advanced solid tumors		Nivolumab +/- Ipilimumab	NCT01928394

Adv: Advanced; Met: Metastatic; GC: Gastric cancer; GEJ: Gastroesophageal junction; HER2: Human epidermal growth factor receptor 2; VEGFR: Vascular endothelial growth factor receptor; PARP: Poly ADP-ribose polymerase.