Advances in immuno-oncology biomarkers for gastroesophageal cancer: Programmed death ligand 1, microsatellite instability, and beyond

Table 1 Phase I clinical trials of programmed cell death 1 inhibitors involving advanced gastroesophageal cancer

n	Primary tumor	Doses	Primary endpoint	Results	Ref.
2771	NSCLC, melanoma, cutaneous, mucosal, ocular, RCC, clear cell, non-clear cell, other (CRC, gastric, esophageal, HNSCC, sarcoma, ovarian, breast, pancreatic, uterine, pancreaticoduodenal)	Atezolizumab at escalating doses up to 20 mg/kg every 3 wk	Safety, tolerability, DLT, and RP2D	13% grade 3-4 TRAEs: 5 fatigue; 3 each of increased ALT, increased AST, hypoxia; 2 each of asthenia, dyspnea, myalgia, anemia, hyperglycemia, hyponatremia, cardiac tamponade, hypophosphatemia, tumor lysis syndrome; 1 each of nausea, headache, influenza-like illness, pain, vomiting	[49]
				ORR 18% overall; 21% of NSCLC, 26% of melanoma, 13% of RCC, and 13% of other malignancies (CRC, gastric, HNSCC)
151	Gastric or GEJ	Avelumab (MSB0010718C) 10 mg/kg every 2 wk until progression, toxicity, or withdrawal	Safety, efficacy	9.9% TRAEs grade ≥ 3: fatigue, asthenia, increased GGT, thrombocytopenia, anemia; 1 treat-ment-related death	JAVELIN [50]
				14 patients with unconfirmed response: 9.7% patients on 2nd line therapy (all PRs), 9.0% patients on 1st-line maintenance (2 CRs, 6 PRs); disease control rate 29% for 2nd line, 57.3% for 1st line maintenance
39	PD-L1+ Gastric (previously treated)	Pembrolizumab 10 mg/kg every 2 wk for 2 yr or PD	Safety, tolerability, ORR	13% grade 3-4 TRAEs: 2 grade 3 fatigue, 1 each of grade 3 pemphigoid, hypothyroidism, neuropathy, and 1 grade 4 pneumonitis	KEYNOTE 012 [51]
				ORR 22% (95%CI: 10-39)
23	PD-L1+ SCC or adenocarcinoma of esophagus or GEJ	Pembrolizumab 10 mg/kg every 2 wk up to 2 yr or until PD, intolerable toxicity, or investigator decision	Safety, ORR	17.4% grade 3-4 TRAEs: 2 with decreased lymphocytes, other 2 patients AE was not specified	KEYNOTE 028 [53]
				ORR 30.4% (95%CI: 13.2%-52.9%)

¹Note that 175 patients were “efficacy-evaluable”. PD: Progressive disease; SD: Stable disease; ORR: Overall response rate; TRAE: Treatment-related adverse effects; DCR: Disease control rate; DLT: Dose limiting toxicities; RP2D: Recommended phase 2 dose.

Table 2 Phase II and III clinical trials of programmed cell death 1 inhibitors in advanced gastroesophageal cancer

n (phase)	Experimental arm	Control or reference arm	Primary endpoint	Results	Ref.
160 (I/II)	N1 + I3: Nivolumab 1 mg/kg every 2 wk and ipilimumab 3 mg/kg every 3 wk	N3: Nivolumab 3 mg/kg every 2 wk	ORR	N3: ORR 12%, PD-L1 ≥ 1% ORR 19%, PD-L1< 1% ORR 12%	CheckMate 032 [54]
	N3 + I1: Nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 wk			N1+I3: ORR 24%, PD-L1≥ 1% ORR 40%, PD-L1< 1% ORR 22%
	Gastric, esophageal, or GEJ cancer			N3+I1: ORR 8%, PD-L1 ≥ 1% ORR 23%, PD-L1 < 1% ORR 0%
259 (II)	Cohort 1 (after ≥ 2 lines of therapy): Pembrolizumab 200 mg every 3 wk up to 2 yr, PD, decision to withdraw, or unacceptable toxicity in gastric cancer	N/A	ORR, safety, tolerability	Overall ORR 11.2% (95%CI: 7.6-15.7), CR 1.9% (95%CI: 0.6-4.4), PR 9.3% (95%CI: 6.0-13.5), SD 17% (95%CI: 12.6-22.1), PD 55.6% (95% CI 49.3-61.7)	KEYNOTE 059 [56]
				PD-L1+ ORR 15.5% (95% CI 10.1-22.4), PD-L1- ORR 5.5% (95% CI 2.0-11.6)
25 (II)	Cohort 2 (1st line): pembrolizumab 200 mg every 3 wk for up to 2 yr, cisplatin (80 mg/m2 day 1), and 5-FU (800 mg/m2 D1-5 Q3W) or capecitabine (1000 mg/ m2 bid)	N/A	Safety, ORR	Cohort 2: ORR 60% (39-79) overall, 73% (45-92) PD-L1+, 38% (9-76) PD-L1-. Median PFS 7 mo	KEYNOTE 059 [55]
31 (II)	Cohort 3 (PD-L1+, 1st line): pembrolizumab 200 mg every 3 wk for up to 2 yr	N/A	Safety, ORR	Cohort 3: ORR 26% (12-45). Median PFS 3 mo	KEYNOTE 059 [55]
	Gastric or GEJ cancer
41 (II)	Pembrolizumab 10 mg/kg every 2 wk	Cohort B: MMR-proficient CRC	ORR, PFS	MMR-deficient CRC: ORR 40%, PFS 78%; median PFS and OS not reached	Keynote-016 [58]
	Cohort A: Mismatch repair (MMR)-deficient colorectal cancers (CRC)			MMR-proficient CRC: ORR 0%, PFS 11%; median PFS 2.2 mo, OS 5.0 mo
	Cohort C: MMR-deficient non-CRC			MMR-deficient non-CRC: ORR 71%, PFS 67%
86 (II)	Pembrolizumab 10 mg/kg every 2 wk for MMR-deficient cancers (12 tumor types)	N/A	ORR, PFS	Objective radiographic response 53%, CR 21%; median PFS and OS not reached	[59]
493 (III)	Nivolumab 3 mg/kg every 2 wk until unacceptable toxicity or PD in gastric/GEJ cancers	Placebo	OS	Nivolumab: median OS 5.32 mo, 6-mo OS 46.4%, 12-mo OS 26.6%, ORR 11.2%, median PFS 1.61 mo	ATTRACTION-02 [57]
				Placebo: median OS 4.14 mo, 6-mo OS 34.7%, 12-mo OS 10.9%, ORR 0%, median PFS 1.45 mo

PD: Progressive disease; ORR: Overall response rate; CI: Confidence interval; OS: Overall survival.