Role of Nivolumab in the Management of First-Line Unresectable Advanced or Recurrent Gastric Cancer in Combination with Chemotherapy: Lessons from the Japanese Experience

Figures & data

Table 1 Summary of Pivotal Trials with Anti-PD1 Antibody Plus Chemotherapy for HER2-Negative AGC

		KEYNOTE062		CheckMate649			ATTRACTION-4	ORIENT16
Design	Phase	P3 / blinded		P3 / open			P3 / blinded	P3 / blinded
	Region	Global		Global			Asia (Japan, Korea, Taiwan)	China
	Eligibility	GC / GEJ, HER2-neg		GC / GEJ / EC, HER2-neg			GC / GEJ, HER2-neg	GC / GEJ, HER2-neg
	Chemo	XP / FP		CapeOX / FOLFOX			CapeOX / SOX	CapeOX
	Anti-PD1	Pembrolizumab		Nivolumab			Nivolumab	Sintilimab
	Primary endpoint	OS and PFS		OS and PFS			OS and PFS	OS and PFS
	Primary cohort	CPS≥1 and CPS ≥ 10		CPS ≥ 5			All	CPS ≥ 5 and all
Patients*	Age (median)	62		63			64	62
	Male	76%		70%			70%	77%
	PS 0/1	46% / 54%		41% / 59%			54% / 46%	27% / 73%
	Asia	25%		25%			100%	100%
Tumor status*	GC/EGJ/EC	67% / 33% / 0%		70% / 18% / 12%			65% / 8% / 0% (NA 27%)	81% / 19% / 0%
	Liver/ Peritoneal metastasis	NR		40% / 21%			36% / 48%	39% / NR
	TPS≥1	NR		23%			16%	NR
	MSI-H	6.60%		4%			NR	NR
Results	Cohort	CPS ≥ 1**	CPS ≥ 10**	CPS ≥ 5**	CPS < 5	All	All**	CPS ≥ 5**	All**
	mOS	12.5m vs 11.1m +1.4m HR 0.85 P = 0.05 Negative	12.3m vs 10.8m +1.5m HR 0.85 P = 0.16 Negative	14.4m vs 11.1m +3.3m HR 0.71 P < 0.0001 Positive	12.4m vs 12.3m +0.1m HR 0.94 P = 0.0001	13.8m vs 11.6m +2.2m HR 0.80	17.5m vs 17.2m +0.3m HR 0.90 P = 0.257 Negative	18.4m vs 12.9m +5.5m HR 0.66 P = 0.0023 Positive	15.2m vs 12.3m +2.9m HR 0.77 P = 0.0090 Positive
	mPFS	6.9m vs 6.4m +0.5m HR 0.84 P = 0.04 Negative	5.7m vs 6.1m - 0.4m HR 0.73 P = NA Negative	7.7m vs 6.0m +1.7m HR 0.68 P < 0.0001 Positive	NR	7.7m vs 6.9m +0.8m HR0.77	10.5m vs 8.3m +2.11m HR 0.68 P < 0.0001 Positive	7.7m vs 5.8m +1.9m HR 0.63 P = 0.0002 Positive	7.1m vs 5.7m +1.4m HR 0.64 P < 0.0001 Positive
	ORR	48.5% vs 37.2% +11.3%	52.5% vs 37.8% +14.7%	60% vs 45% +15%	55% vs 46% +9%	58% vs 46% +12%	57.5% vs 47.8% +9.7%	NR	58.2% vs 48.4% +9.8%
	Grade 3–4 AE	71% vs 68% +3%	NR	NR	NR	59% vs 45% +14%	69% vs 63% +6%	NR	59.8% vs 52.5% +7.3%
	Post treatment in control arm (Any / ICIs)	54% / 14%	NR	NR	NR	44% / 9%	73% / 25%	NR	NR

Notes: *Data in experimental cohort, **Primary cohort.

Abbreviations: AGC, advanced gastric cancer; XP, capecitabine plus cisplatin; FP, fluoropyrimidine plus cisplatin; PS, performance status; TPS, tumor proportion score; MSI-H, microsatellite instability-high; mOS, median overall survival; mPFS, median progression survival; m, months; AE, adverse event; ICIs, immune checkpoint inhibitors; NA, not available; NR, not released.

Table 2 Regulatory Approval and Recommendation of Each Region About First-Line Chemotherapy Plus Nivolumab.^2,28,29

		US/FDA	EU/EMA	Japan
1st line nivolumab indication		All comer	CPS ≥ 5	All comer
Guideline		NCCN guideline 2022 ver2	ESMO-MCBS ver1.1 (ESMO guideline)	JGCA
Recommendation	CPS ≥ 5	Preferred (Category 1)	ESMO-MCBS: 4	Recommended
	CPS < 5	Useful in certain circumstance (Category 2B)	ESMO-MCBS: 3	Need to carefully select chemotherapy or nivolumab plus chemotherapy
	All	–	ESMO-MCBS: 2	–
Other G/GEJ AC indication		Pembrolizumab: 1st line HER2+ ≥ 2nd line MSI-H ≥ 2nd line TMB-H	None	Nivolumab: ≥3rd line all comer Pembrolizumab: ≥ 2nd line MSI-H

Notes: Category 1, there is uniform NCCN consensus that the intervention is appropriate based upon high-level evidence; Category 2B, there is uniform NCCN consensus that intervention is appropriate based upon lower-level evidence; ESMO-MCBS, ESMO-magnitude of Clinical Benefit Scale of ≥4 indicate a substance magnitude of clinical benefit.

Abbreviations: CPS, PD-L1 combined positive score; G, gastric; GEJ, gastroesophageal junctional; AC, adenocarcinoma; FDA, US Food and Drug Administration; EMA, European Medicines Agency; JGCA, Japanese gastric Cancer Association.

Table 3 Viewpoints of Each Stance About the Adaptation of Chemotherapy Plus Nivolumab as a First-Line Treatment

Viewpoint	Conflicting Stance
	Limit Use in CPS ≥ 5 (and MSI-H)	Use Regardless of CPS
Efficacy	Limited survival benefits in CPS < 5	OS benefit shown in all comers
Adverse event	Increased toxicities	Manageable toxicities
Post ICI treatment	Availability in later line (Subgroup in Japan)	Not all can receive later-line or not available
Others	Cost performance	Limitations of CPS evaluation (Heterogeneity, sample quality, inter-pathologist variability, difference in antibodies, etc)
Japanese subgroup	No survival benefit in overall all patients in ATTRACTION4 and Japanese subgroup.	–

Abbreviation: CPS, PD-L1 combined positive score.

Figure 1 Patients’ flow after the first visit from November 2021 to June 2022 in National Cancer Center Hospital East.

Abbreviations: CT, computed tomography; MDT, multidisciplinary team; chemo, chemotherapy; HER2, human epidermal growth factor receptor 2; PD-L1, programmed cell death 1 ligand 1; CPS, combined positive score; MMR, mismatch repair; EBV, Epstein-Barr virus; FGFR2, fibroblast growth factor receptor 2; CLDN18.2, claudin 18 isoform 2; EGFR, epidermal growth factor receptor; MSI-H, microsatellite instability-high; Tras, trastuzumab.

Figure 2 CT scan in case 1. (A) Before the start of nivolumab plus SOX. (B) After the third course of nivolumab plus SOX. Explanations: Arrows in upper pictures show liver metastasis; Arrows in lower pictures show bilateral ovarian metastasis.

Abbreviations: CT, computed tomography; SOX, S-1+oxaliplatin.

Figure 3 Upper gastrointestinal endoscopy and CT in case 2. (A) Upper gastrointestinal endoscopy before chemotherapy. (B and C) CT revealed interstitial pneumonia and lymph node and lung metastases before chemotherapy. (D–F) CT showed mediastinal and subcutaneous emphysema after two courses of pembrolizumab, while interstitial pneumonia was almost stable and the metastatic lesions had maintained shrinkage. Explanations: Yellow arrows in (C and F) show lymph node metastasis; White arrows in (C and F) shows liver metastasis.

Abbreviation: CT, computed tomography.

Table 4 Overview of Ongoing Pivotal Clinical Trials, Including ICI as a First-Line Treatment in HER2-Negative AGC

Trial	Phase	Patients	Target Structure	Arm
KEYNOTE-859 (NCT03675737)	III	All comer	PD-1	CapeOX/ FP + Pembrolizumab
				CapeOX / FP
BGB-A317-305 (NCT03777657)	III	All comer	PD-1	CapeOX + Tislelizumab
				CapeOX
ATTRACTION-6 (NCT02999295)	III	All comer	PD-1 + CTLA4	SOX / CapeOX + Nivolumab + Ipilimumab
				SOX / CapeOX
LEAP-15 (NCT04662710)	III	All comer	PD-1 + VEGF, etc	CapeOX / FOLFOX + Lenvatinib + Pembrolizumab
				CapeOX / FOLFOX
SHR-1210 (NCT03813784)	III	All comer	PD-1 + VEGF, etc	CapeOX + SHR-1210 (Anti-PD1) Maintenance: SHR-1210 ± Apatinib
				CapeOX

Abbreviation: FP, fluoropyrimidine + platinum.

Ajani JA, D’Amico TA, Bentrem DJ, et al. Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(2):167–192.

 PubMed Web of Science ®Google Scholar

Lordick F, Carneiro F, Cascinu S; on behalf of the ESMO Guidelines Committee, Gastric cancer, et al. ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022. doi:10.1016/j.annonc.2022.07.004

 Google Scholar

Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines. 6th ed. Tokyo, Japan: Kanehara Shuppan; 2021.

 Google Scholar