Table 1. Phase I clinical trials of PD-1 inhibitors in advanced gastroesophageal cancer.
| n | Primary tumor | Doses | Primary endpoint | Results | Ref. |
|---|---|---|---|---|---|
| 39 | Gastric (KEYNOTE-012) | Pembrolizumab 10 mg/kg every 2 weeks for 2 years or PD | Safety, tolerability, ORR | 13% grade ≥3 AEs: grade 3 fatigue (n=2), grade 3 pemphigoid, hypothyroidism, neuropathy (n=1), grade 4 pneumonitis (n=1); ORR 22% (95% CI, 10–39) | (30) |
| 277 | Multiple cancer types | MPDL-3280A 20 mg/kg every 3 weeks | Safety and tolerability | 13% grade ≥3 AEs: fatigue (n=5); increased ALT, increased AST, hypoxia (n=1 per AE); asthenia, dyspnea, myalgia, anemia, hyperglycemia, hyponatremia, cardiac tamponade, hypophosphatemia, tumor lysis syndrome (n=2 per AE); nausea, headache, influenza-like illness, pain, vomiting (n=1 per AE); ORR 18% overall; 26% of melanoma, 21% of NSCLC, 13% of RCC, 13% other |
(31) |
| 55 | GEA | BGB-A317 at 2 mg/kg or 5 mg/kg every 2 or 3 weeks | Safety, tolerability, and efficacy | 46% grade ≥3 AEs however none were treatment related; DCR of 32% with 6% PR | (32) |
| 151 | Multiple cancer types | MEDI4736 10 mg/kg IV every 2 weeks for 12 months | Safety and efficacy | 7% grade 3≥ AEs with 13% fatigue, 8% nausea, 6% rash, 5% vomiting, and 5% pyrexia | (33) |
| 83 | Esophageal (KEYNOTE-028) | Pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until disease progression | Safety and ORR | ORR 30% (95% CI, 13–53%) | (34) |
| 28 | GEA | Ramucirumab 8 mg/kg on days 1 & 8 with pembrolizumab 200 mg on day 1 every 3 weeks | Safety and tolerability | 61% grade ≥3 adverse events with 14% hypotension, 11% diarrhea, and 7% liver function abnormalities; DCR 68%; median PFS 5.3 months (95% CI, 3.2–11) | (35) |
| 29 | GEA | Ramucirumab 8 mg/kg and durvalumab 750 mg every 2 weeks | Safety and tolerability | 35% grade 3≥ AEs with 34% hypertension, 31% fatigue, 24% headache, 21% diarrhea, 10% pyrexia, and 10% decreased appetite; 5/29 patients (17%) PR; median PFS 2.6 months (95% CI, 1.45–6.28) | (36) |
| 30 | Gastroesophageal | SHR-1210 60 mg with escalations to 200 and 400 mg | Safety, activity, and pharmacokinetics | 6.7% grade 3≥ AEs; 3.3% interstitial lung disease, 3.3% pruritus; ORR 23.3% (95% CI, 9.9–42.3%); median PFS 8.0 weeks (95% CI, 7.9–8.1 weeks) |
(37) |
| 43 | GEA, hepatocellular | SHR-1210 200 mg every 2 weeks and apatinib 125–500 mg once daily until unacceptable toxicity or disease progression | Safety and efficacy | 60.6% grade ≥3 AE; 15.2% hypertension, 15.2% increased aspartate aminotransferase; ORR 30.8% overall (95% CI, 17.0–47.6%); 5/25 gastroesophageal patients (20%) with PR, median PFS 2.9 months (95% CI, 2.5–4.2 months) | (38) |
| 57 | GEA (JAVELIN) | Avelumab 10 mg/kg every 2 weeks | Safety and efficacy | 3/40 patients (7.5%) grade ≥3 AE including alanine aminotransferase increase, anemia, and hyponatremia; ORR 10.0% (95% CI, 2.8–23.7%); median OS 9.1 months (95% CI, 7.2–11.2 months) | (39) |
| 150 | GEA (JAVELIN) | Avelumab 10 mg/kg every 2 weeks | Safety and efficacy | 8.7% grade ≥3 AE with 1 treatment-related death (hepatic failure/autoimmune hepatitis); 1st line cohort: ORR 6.7% (95% CI 2.5–13.9) with CR 2.2%; 2nd line cohort: ORR 6.7% (95% CI, 1.8–16.2), DCR 28.3%, median PFS 1.4 months (95% CI, 1.3–1.5), median OS 6.8 months (95% CI, 5.4–9.5) | (40) |
| 92 | GEA | Pembrolizumab 200mg day 1 every 3 weeks with ramucirumab 10 mg/kg on day 1 or 8 mg/kg days 1 and 8 every 3 weeks | Safety and efficacy | ORR and OS in PD-L1 positive vs. negative patients (9% vs. 6%, 14.9 vs. 5.2 months) | (41) |
| 56 | Esophageal | JS001 3 mg/kg every 2 weeks | Safety and efficacy | No grade ≥3 AE; ORR 23.5% with 8 PR | (42) |
| 16 | GEA | Induction nivolumab every 2 weeks prior to carboplatin + paclitaxel/radiation plus 3 additional cycles of nivolumab on weeks 1, 3 and 5 of chemoradiation followed by Ivor-Lewis esophagectomy | Safety and feasibility | Grade ≥3 AEs include dermatitis (1/16) and hepatitis (1/16); pathological complete response 40% | (43) |
| 6 | Esophageal | Durvalumab 1.5 g + Tremelimumab 75 mg on day 1 every 4 weeks plus chemotherapy | Safety and tolerability | 3/6 patients with grade ≥3 neutropenia attributed to chemotherapy; 2/6 patients with PR |
(44) |
| 18 | Gastric | Cohort 1 (n=8): Andecaliximab (GS-5745) 800 mg IV every 2 weeks; Cohort 4 (n=10): Nivolumab plus Andecaliximab |
Safety and tolerability, pharmacokinetics | Cohort 1: Grade ≥ 3 AEs with anemia (25%), fatigue (13%), hydronephrosis (13%); Cohort 4: Grade ≥3 AEs were anemia (20%), DIC (10%), fatigue (10%), anorexia (10%); ORR 40% |
(45) |
| 23 | GEA | GLS-010 (anti-PD-1) 240 mg every 2 weeks | Efficacy | 4 patients with PR; Grade ≥3 AEs include multiple organ dysfunction (n=1), interstitial lung disease (n=1), increased bilirubin (n=1) | (46) |
GEA, gastroesophageal adenocarcinoma; PD, progressive disease; ORR, overall response rate; CI, confidence interval; AE, adverse event; DCR, disease-control rate; CR, complete response; PR, partial response.