Application and challenge of immunotherapy in perioperative therapy of gastric cancer

doi:10.19401/j.cnki.1007-3639.2024.03.003

Abstract

Abstract:

Gastric cancer is one of the common malignant tumors of digestive system in our country. The proportion of patients in advanced and late stage is large, and the choice of perioperative treatment program is always difficult in clinic. For most locally advanced gastric cancer, compared with standard radical surgery combined with postoperative adjuvant chemotherapy, perioperative treatment mode may further improve the survival of patients. However, the efficacy of conventional chemotherapy regimen has reached a plateau, while the progress of traditional molecular targeted therapy is relatively slow. In recent years, with the increasing role of immunotherapy in the treatment of advanced gastric cancer, more and more clinical studies have shown that immunotherapy can also achieve better efficacy in perioperative gastric cancer patients. This article reviewed the research progress of immunotherapy in perioperative gastric cancer in recent years.

Key words: Gastric cancer, Immunotherapy, Clinical trials, Neoadjuvant therapy, Conversion therapy

CLC Number:

R735.2

XUE Chi, GAO Peng, ZHU Zhi, WANG Zhenning. Application and challenge of immunotherapy in perioperative therapy of gastric cancer[J]. China Oncology, 2024, 34(3): 259-267.

Figures/Tables 2

Tab. 1

Tab. 2

References 33

[1]	KANG Y K, BOKU N, SATOH T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2017, 390(10111): 2461-2471. doi: 10.1016/S0140-6736(17)31827-5
[2]	JANJIGIAN Y Y, BENDELL J, CALVO E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer[J]. J Clin Oncol, 2018, 36(28): 2836-2844. doi: 10.1200/JCO.2017.76.6212 pmid: 30110194
[3]	SHITARA K, AJANI J A, MOEHLER M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer[J]. Nature, 2022, 603(7903): 942-948. doi: 10.1038/s41586-022-04508-4
[4]	KANG Y K, CHEN L T, RYU M H, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2022, 23(2): 234-247. doi: 10.1016/S1470-2045(21)00692-6
[5]	JANJIGIAN Y Y, SHITARA K, MOEHLER M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial[J]. Lancet, 2021, 398(10294): 27-40. doi: 10.1016/S0140-6736(21)00797-2 pmid: 34102137
[6]	SHITARA K, VAN CUTSEM E, BANG Y J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial[J]. JAMA Oncol, 2020, 6(10): 1571-1580. doi: 10.1001/jamaoncol.2020.3370
[7]	HUANG J, MO H N, ZHANG W L, et al. Promising efficacy of SHR-1210, a novel anti-programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China[J]. Cancer, 2019, 125(5): 742-749. doi: 10.1002/cncr.31855 pmid: 30508306
[8]	XU J M, JIANG H P, PAN Y Y, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial[J]. JAMA, 2023, 330(21): 2064-2074. doi: 10.1001/jama.2023.19918 pmid: 38051328
[9]	MURO K, VAN CUTSEM E, NARITA Y, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS[J]. Ann Oncol, 2019, 30(1): 19-33. doi: S0923-7534(19)31003-8 pmid: 30475956
[10]	WANG F H, ZHANG X T, LI Y F, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2021[J]. Cancer Commun, 2021, 41(8): 747-795. doi: 10.1002/cac2.v41.8
[11]	MOEHLER M H, KATO K, ARKENAU H T, et al. Rationale 305: phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment (1L) of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC)[J]. 2023, 41(4_suppl): 286.
[12]	HASEGAWA H, SHITARA K, TAKIGUCHI S, et al. A multicenter, open-label, single-arm phase Ⅰ trial of neoadjuvant nivolumab monotherapy for resectable gastric cancer[J]. Gastric Cancer, 2022, 25(3): 619-628. doi: 10.1007/s10120-022-01286-w
[13]	ANDRÉ T, TOUGERON D, PIESSEN G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase Ⅱ study[J]. J Clin Oncol, 2023, 41(2): 255-265.
[14]	VERSCHOOR Y L, VAN DE HAAR J, VAN DEN BERG J G, et al. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial[J]. Nat Med, 2024, 30(2): 519-530. doi: 10.1038/s41591-023-02758-x pmid: 38191613
[15]	PIETRANTONIO F, RAIMONDI A, LONARDI S, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase Ⅱ trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC)[J]. J Clin Oncol, 2023, 41(4_suppl): 358.
[16]	TERASHIMA M, IWASAKI Y, MIZUSAWA J, et al. Randomized phase Ⅲ trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501)[J]. Gastric Cancer, 2019, 22(5): 1044-1052. doi: 10.1007/s10120-019-00941-z
[17]	CUNNINGHAM D, ALLUM W H, STENNING S P, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer[J]. N Engl J Med, 2006, 355(1): 11-20. doi: 10.1056/NEJMoa055531
[18]	YCHOU M, BOIGE V, PIGNON J P, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase Ⅲ trial[J]. J Clin Oncol, 2011, 29(13): 1715-1721.
[19]	KANG Y K, YOOK J H, PARK Y K, et al. Phase Ⅲ randomized study of neoadjuvant chemotherapy (CT) with docetaxel(D), oxaliplatin(O) and S-1(S) (DOS) followed by surgery and adjuvant S-1, vs surgery and adjuvant S-1, for resectable advanced gastric cancer (GC) (PRODIGY)[J]. Ann Oncol, 2019, 30: v876-v877.
[20]	AL-BATRAN S E, HOMANN N, PAULIGK C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial[J]. Lancet, 2019, 393(10184): 1948-1957. doi: 10.1016/S0140-6736(18)32557-1
[21]	WANG X X, LI S, XIE T Y, et al. Early results of the randomized, multicenter, controlled evaluation of S-1 and oxaliplatin as neoadjuvant chemotherapy for Chinese advanced gastric cancer patients (RESONANCE trial)[J]. J Clin Oncol, 2020, 38(4_suppl): 280.
[22]	YUAN S Q, NIE R C, JIN Y, et al. Author correction: perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial[J]. Nat Med, 2024, 30(2): 605.
[23]	AL-BATRAN S E, LORENZEN S, THUSS-PATIENCE P C, et al. Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: interim results from DANTE, a randomized, multicenter, phase Ⅱb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK[J]. J Clin Oncol, 2022, 40(16_suppl): 4003.
[24]	SHITARA K, RHA S Y, WYRWICZ L S, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study[J]. Lancet Oncol, 2024, 25(2): 212-224. doi: 10.1016/S1470-2045(23)00541-7 pmid: 38134948
[25]	RHA S Y, OH D Y, YAÑEZ P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial[J]. Lancet Oncol, 2023, 24(11): 1181-1195. doi: 10.1016/S1470-2045(23)00515-6
[26]	ZHANG X, WANG J, WANG G, et al. LBA79 GEMSTONE-303: prespecified progression-free survival (PFS) and overall survival (OS) final analyses of a phase Ⅲ study of sugemalimab plus chemotherapy vs placebo plus chemotherapy in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma[J]. Ann Oncol, 2023, 34: S1319. doi: 10.1016/j.annonc.2023.10.080
[27]	JANJIGIAN Y Y, KAWAZOE A, YAÑEZ P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer[J]. Nature, 2021, 600(7890): 727-730. doi: 10.1038/s41586-021-04161-3
[28]	SATOH T, KANG Y K, CHAO Y E, et al. Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase Ⅲ clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer[J]. Gastric Cancer, 2020, 23(1): 143-153. doi: 10.1007/s10120-019-00970-8
[29]	JANJIGIAN Y Y, KAWAZOE A, BAI Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial[J]. Lancet, 2023, 402(10418): 2197-2208. doi: 10.1016/S0140-6736(23)02033-0 pmid: 37871604
[30]	LEE K W, BAI L Y, JUNG M, et al. 1518P Zanidatamab (zani) plus chemotherapy (chemo) and tislelizumab (tis) as first-line (1l) therapy for patients (pts) with advanced HER2-positive (+) gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): updated results from a phase Ⅰb/Ⅱ study[J]. Ann Oncol, 2023, 34: S855-S856.
[31]	ZHU L J, LI S, BAO J, et al. First-line of camrelizumab plus pyrotinib and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: a dose escalation and expansion phase Ⅰ study[J]. J Clin Oncol, 2023, 41(4_suppl): 356.
[32]	KAWAKAMI H, HIRONAKA S, ESAKI T, et al. An investigator-initiated phase 2 study of nivolumab plus low-dose ipilimumab as first-line therapy for microsatellite instability-high advanced gastric or esophagogastric junction cancer (NO LIMIT, WJOG13320G/CA209-7W7)[J]. Cancers, 2021, 13(4): 805.
[33]	KIM S T, CRISTESCU R, BASS A J, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer[J]. Nat Med, 2018, 24(9): 1449-1458. doi: 10.1038/s41591-018-0101-z pmid: 30013197

Treatment	Clinical trial	Medication regimen	Cycle	Stage	Content
ICI monotherapy	JapicCTI-183895	Nivolumab	2 cycles	Ⅰ	pCR: 1 (3.2%); MPR: 5 (16.1%)
The combination of neoadjuvant chemotherapy and ICI	GERCOR NEONIPIGA	Nivolumab+ipilimumab pre-operative; Nivolumab post-operative	6 cycles pre-operative; 9 cycles post-operative	Ⅱ	pCR rate: 58.6% (17/32); TRG 0-1: 73% (21/32)
	PANDA	Atezolizumab; Atezolizumab+docetaxel	1 cycles Atezolizumab; 4 cycles atezolizumab+docetaxel	Ⅱ	MPR rate: 70% (14/20); pCR rate: 45% (9/20)
	INFINITY	Tremelimumab+durvalumab	3 cycles tremelimumab (300 mg)+durvalumab (1500 mg), q4w	Ⅱ	pCR rate: 60% (9/15); MPR rate: 80% (12/15)
The combination of perioperative treatment and ICI	NEOSUMMIT-01	Toripalimab +SOX/XELOX	3 cycles pre-operative; 5 cycles post-operative	Ⅱ	TRG 0-1: 44.4%
	DANTE	Atezolizumab+FLOT	4 cycles atezolizumab +FLOT pre-operative and post-operative; 4 cycles atezolizumab vs FLOT post-operative	Ⅱ/Ⅲ	TRG 0-1: 24.0%
	KEYNOTE-585	Pembrolizumab+XP/FP/FLOT vs placebo+XP/FP/FLOT	4 cycles pre-operative; 3+11 cycles post-operative	Ⅲ	pCR rate: 12.9% vs 2.0%; mOS: 60.7 months vs 58.0 months; mPFS: 44.4 months vs 25.3 months

Patient classification	Clinical trial	Patient population	Medication regimens	Stage	Content
PD-L1 CPS≥5	CheckMate-649	Advanced or metastatic HER2- gastric or gastro-oesophageal junction adenocarcinoma	Nivolumab+XELOX/FOLFOX vs XELOX/FOLFOX	Ⅲ	mOS: 14.4 months vs 11.1 months; mPFS: 7.7 months vs 6.05 months; ORR: 60% vs 45%
	ORIENT-16	Unresectable gastric or gastroesophageal Junction cancer	Sintilimab+XELOX vs Placebo+XELOX	Ⅲ	mOS: 18.4 months vs 12.9 months; mPFS: 7.7 months vs 5.8 months; ORR: 63.6% vs 49.4%
PD-L1 CPS≥1 vs PD-L1 CPS≥10	KEYNOTE-061	Previously treated, advanced gastric or gastro-oesophageal junction cancer	Pembrolizumab vs paclitaxel	Ⅲ	PD-L1 CPS≥1 mOS: 9.1 months vs 8.3 months, P=0.042 1*; mPFS: 1.5 months vs 4.1 months; ORR: 16% vs 14% PD-L1 CPS≥10 mOS: 10.4 months vs 8.0 months, P<0.000 1; ORR: 24.5% vs 9.1%
	KEYNOTE-859	Advanced or metastatic HER2- gastric or gastro-esophageal junction adenocarcinoma	Pembrolizumab+FP/XELOX vs placebo+P/XELOX	Ⅲ	PD-L1 CPS≥1 mOS: 13.0 months vs 11.4 months, P<0.000 1; ORR: 61% vs 43% PD-L1 CPS≥10 mOS: 15.7 months vs 11.8 months, P<0.000 1; ORR: 52% vs 43%
	KEYNOTE-062	Untreated, advanced gastric/gastroesophageal junction cancer	Pembrolizumab+ cisplatin/fluorouracil vs placebo+cisplatin/fluorouracil	Ⅲ	PD-L1 CPS≥1 mOS: 12.5 months vs 11.1 months, P=0.05*; ORR: 49% vs 37% PD-L1 CPS≥10 mOS: 12.3 months vs 10.8 months, P=0.16; ORR: 53% vs 37.8%
PD-L1 CPS≥5 vs PD-L1 CPS≥10	GEMSTONE-303	Untreated, advanced gastric/gastroesophageal junction cancer	Sugemalimab+XELOX vs Placebo+XELOX	Ⅲ	PD-L1 CPS≥5 mOS: 15.64 months vs 12.65 months; mPFS: 7.62 months vs 6.08 months PD-L1 CPS≥10 mOS: 17.81 months vs 12.45 months; mPFS: 7.79 months vs 5.52 months