Immunotherapy for advanced gastric cancer

Table 1 The Cancer Genome Atlas has presented a thorough depiction of the molecular basis of gastric cancer[25]

Subtypes	EBV-positive	MSI	GS	CIN
Frequency, %	8.8	21.7	19.7	449.8
Demographic	Male patients (81%)	Old age (median 72 yr)	Young age (median 59 yr)	Not specific
Histology	Not specific	Not specific	Diffuse	Intestinal
Main location	Fundus and body	Fundus, body, and antrum	Mostly diffuse subtype	Majority of tumors at the GEJ
Molecular	EBV-CIMP: (1) PD-L1/2, JAK2 overexpression; (2) Mutation in PIK3CA, ARID1A, and BCOR; (3) CDKN2A silencing; (4) Immune cell signaling; and (5) Rare TP53 mutations	Gastric-CIMP: (1) Hypermutation in TP53, PIK3CA, ERBB2/3, and ARID1A; (2) MLH1 silencing; (3) Mitotic pathways activation; and (4) Commune changes in the genes of CMH1	(1) CDH1 and RHOA mutation; (2) CLDN18-ARHGAP fusion; (3) Cell adhesion; (4) Angiogenesis pathways enriched; and (5) Rare TP53 mutations	(1) TP53 mutation; (2) RTK-RAS activation; and (3) Mutations of SMAD4 and APC
alterations
Potential therapeutic points	(1) PIK3CA; (2) JAK2; and (3) PD-L1/L2	(1) PIK3CA; (2) ERBB2/3; (3) EGFR; (4) PD-L1; and (5) MLH1 silencing	(1) RHOA; and (2) CLDN18	(1) RTKs; (2) EGFR; (3) VEGFA; (4) CCNE1; (5) CCND1; and (6) CDK6

APC: Adenomatous polyposis coli; ARHGAP: Rho GTPase activating protein; ARID1A: AT-rich interactive domain-containing protein 1A; BCOR: B-cell lymphoma 6 corepressor; CCND1: Cyclin-D1; CCNE1: Cyclin-E1; CDH1: Cadherin 1; CDK6: Cyclin-dependent kinase 6; CDKN2A: Cyclin-dependent kinase inhibitor 2A; CIMP: CpG island methylator phenotype; CIN: Chromosomal instability; CLDN18: Claudin-18; CMH1: Hypertrophic cardiomyopathy-1; GS: Genomically stable; GC: Gastric cancer; EBV: Epstein-Barr virus; EGFR: Epithelial growth factor receptor; ERBB2/3: Erb-b2 receptor tyrosine kinase 2/3; GEJ: Gastroesophageal junction; JAK2: Janus-associated kinase 2; MLH1: MutL protein homolog 1; MSI: Microsatellite instability; PD-L1/2: Programmed death ligand-1/2; PI3K: Phosphatidylinositol-3-kinase; RAS: Rat sarcoma virus; RHOA: Ras homolog family member A; RTKs: Receptor tyrosine kinases; SMAD4: Mothers against decapentaplegic homolog 4; TP53: Tumor protein 53; VEGFA: Vascular endothelial growth factor A.

Table 2 Immunotherapies for advanced gastric cancer patients

Ref.	Drug(s)	Number of patients	Study phase	ORR (%)	Median OS (months)	Median PFS (months)	Results
Muro et al[52]	Pembrolizumab	39	1b	33	11.4	1.8	Pembrolizumab demonstrated a reasonable safety profile and potential antitumor efficacy in metastatic PD-L1-positive GC, warranting further exploration in phase 2 and 3 studies
Fuchs et al[53]	Pembrolizumab	259	2	15.5	5.6	2.0	Pembrolizumab is a potential new therapy option for AGC or AGEJC that has progressed following second-line treatment, demonstrating high and persistent responses. Pembrolizumab has a mechanism of action, duration of response, and toxicity profile that differs from and does not overlap with conventional treatment for gastroesophageal adenocarcinoma
Shitara et al[54]	Pembrolizumab vs Paclitaxel	395	3	-	9.1/8.3 (Pem/Pac)	1.5/4.1 (Pem/Pac)	When compared to Paclitaxel, Pembrolizumab did not significantly improve overall survival when administered as a second-line therapy for AGC or AGEJC with PD-L1 CPS of 1 or higher
Bang et al[55]	Pembrolizumab vs Pembrolizumab plus chemotherapy	56	2	25.8/60.0 (Pem/Pem+Chem)	13.8/20.7 (Pem/Pem+Chem)	3.3/6.6 (Pem/Pem+Chem)	Pembrolizumab combined chemotherapy showed acceptable tolerability and potential anticancer efficacy in AGC or AGEJC, independent of PD-L1 expression. In patients with PD-L1 CPS ≥ 1, pembrolizumab monotherapy revealed good antitumor efficacy and acceptable safety
Kawazoe et al[56]	Pembrolizumab plus chemotherapy	54	2b	72.2	Not reached	9.4	For the first-line treatment of AGC or AGEJC patients, chemotherapy with Pembrolizumab shown good effectiveness and a tolerable toxicity profile
Kawazoe et al[57]	Pembrolizumab plus Lenvatinib	29	2	69.0	Not reached	7.1	In patients with AGC, the combination of Lenvatinib and Pembrolizumab demonstrated promising anti-tumor effectiveness while maintaining a tolerable safety profile
Shitara et al[58]	Pembrolizumab vs Pembrolizumab plus chemotherapy vs chemotherapy	763	3	-	10.6/11.1 (Pem/chem) CPS ≥ 1; 17.0/10.8 CPS ≥ 10	6.9/6.4 (Pem/chem)	In individuals with untreated AGC or AGEJC, Pembrolizumab was shown to be noninferior to chemotherapy, with less adverse effects. Pembrolizumab alone or in combination with chemotherapy did not outperform treatment in terms of OS and PFS
Kwon et al[60]	Pembrolizumab	18	2	55.6	-	-	A subset of MSI-H GC patients with certain immunological responses at baseline, such as stronger TMB, abundant T cell infiltration, more TCR clonal diversity, and less stem-like exhausted T cells, may not require anything more than anti-PD-1 monotherapy
Yamaguchi et al[63]	Pembrolizumab plus SOX vs Pembrolizumab plus SP	100	2b	72.2/80.4	16.9/17.1	9.4/8.3	In Japanese patients with PD-L1 positive, HER-2 negative AGC or AGEJC, the combination of Pembrolizumab plus SOX or SP as first-line treatment indicated high efficacy and reasonable tolerability
Lee et al[64]	Pembrolizumab plus Trastuzumab plus Capecitabine plus Cisplatin	43	1b/2	76.7	19.3	8.6	The use of a quadruplet combination as first-line therapy (Pembrolizumab plus Trastuzumab plus Capecitabine plus Cisplatin) resulted in tumor decrease in HER-2-positive AGC
Satake et al[65]	Pembrolizumab vs Pembrolizumab plus chemotherapy vs chemotherapy	187	3	22.6/37.7 (Pem/chem); 26.9/31.8 (PD-L1 CPS ≥ 10)	22.7/13.8 (Pem/chem); 28.5/14.8 (PD-L1 CPS ≥ 10)	4.1/6.5 (Pem/chem); 7.2/6.9 (PD-L1 CPS ≥ 10)	Pembrolizumab monotherapy was related with statistically better OS results in patients with AGC or AGEJC with PD-L1 CPS ≥ 1 and CPS ≥ 10 tumors as compared to chemotherapy alone. When compared to chemotherapy, Pembrolizumab monotherapy had a better tolerability profile
Janjigian et al[66]	Nivolumab plus Ipilimumab vs Nivolumab	160	1/2	24/12 (Niv+Ipi/Niv)	6.9/6.2 (Niv+Ipi/Niv)	1.6/1.4 (Niv+Ipi/Niv)	Nivolumab and Nivolumab in combination with Ipilimumab provide a viable treatment option for individuals with AGEJC
Kang et al[67]	Nivolumab vs placebo	493	3	11.2/0.0	5.32/4.14	1.61/1.45	Nivolumab might be a potential therapy option for people with AGC or AGEJC who have been highly pretreated
Boku et al[69]	Nivolumab plus SOX vs Nivolumab plus CapeOX	77	2	57.1/76.5	Not reached	9.7/10.6	In these individuals, Nivolumab in conjunction with SOX or CapeOX was well tolerated and showed potential efficacy
Nakajima et al[71]	Nivolumab plus Paclitaxel plus Ramucirumab	43	1/2	37.2	13.1	5.1	As a second-line treatment for AGC, Nivolumab in combination with Paclitaxel and Ramucirumab shown promising antitumor activity with tolerable tolerability
Janjigian et al[72]	Nivolumab plus chemotherapy vs chemotherapy	1,581	3	51/41	14.4/11.1	7.7/6.1	Nivolumab in conjunction with chemotherapy is being considered as a new standard first-line treatment for these individuals
Shah et al[73]	Andecaliximab plus Nivolumab vs Nivolumab	141	2	10/7	7.1/5.9	-	When compared to Nivolumab alone, the combination of Andecaliximab and Nivolumab exhibited a favorable safety profile but did not boost efficacy in these people
Kang et al[74]	Nivolumab plus oxaliplatin-based chemotherapy vs placebo plus oxaliplatin-based chemotherapy	724	2/3	-	17.45/17.15	10.45/8.34	In these patients, Nivolumab in conjunction with oxaliplatin-based chemotherapy improved PFS but not OS
Bang et al[76]	Avelumab vs chemotherapy	371	3	2.2/4.3	4.6/5.0	1.4/2.7	As compared to chemotherapy, treating these patients in the third-line setting with single-agent Avelumab did not improve OS or PFS. Avelumab, on the other hand, had a more manageable toxicity profile than chemotherapy
Moehler et al[77]	Avelumab vs chemotherapy	499	3	-	10.4/10.9	-	In patients with AGC or AGEJC in general, or in a specified PD-L1-positive population, Avelumab maintenance therapy did not give a superior OS when compared to continuing chemotherapy

AGC: Advanced gastric cancer; AGEJC: Advanced gastroesophageal junction cancer; CapeOX: Capecitabine plus oxaliplatin C; Chem: Chemotherapy; CPS: Combined positive score; HER-2: Human epidermal growth factor receptor 2; MIS-H: High microsatellite instability; Niv: Nivolumab; Niv+Ipi: Nivolumab plus Ipilimumab; ORR: Objective response rate; OS: Overall survival; Pac: Paclitaxel; Pem: Pembrolizumab; PD-L1: Program cell death ligand 1; PFS: Progression-free survival; SOX: S-1 plus oxaliplatin; SP: S-1 and cisplatin; TCR: T-cell receptor; TMB: Tumor mutational burden.