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.