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Page 10 of 15 Kiyozumi et al. J Cancer Metastasis Treat 2018;4:31 I http://dx.doi.org/10.20517/2394-4722.2017.77

Immune checkpoint inhibitors
Nivolumab is a human IgG4 monoclonal antibody that acts against PD-1 and has been approved for monotherapy
and combination therapy for metastatic melanoma, NSCLC, renal cell carcinoma. Nivolumab works as a
checkpoint inhibitor blocking signal that prevents activated T cells from attacking cancer. In a phase I/II
trial, patients with nivolumab monotherapy received two or more prior regimens (CheckMate-032) . The
[41]
ORR was 14%, median PFS was 1.4 months, MST was 5.0 months and disease control rate was 32%. The
6-month survival rate was 49% and the 12-month survival rate was 36%. A phase III trial demonstrated
that nivolumab significantly prolonged OS in patients with AGC or GEJA who had failed two or more
standard chemotherapies (ONO-4538-12, ATTRACTION-2) . In this trial, MST was 5.32 months with
[7]
nivolumab vs. 4.14 months with placebo, and 12 months OS in the nivolumab group was 26.6% vs. 10.9%
in the placebo group. Therefore, these results strongly support establishing treatment with nivolumab as a
standard therapy for patients with GC. In practice, nivolumab was approved and started for treating AGC as
a third-line treatment or after treatment. In addition, in a phase III trial, nivolumab was added to cytotoxic
chemotherapy as first-line chemotherapy and evaluated (CheckMate649). This trial is expected to present
new clinical benefits in the near future.

Pembrolizumab is a selective, humanized, high-affinity IgG4κ monoclonal antibody designed to bind to PD-1
and block interactions between PD-1 and its ligands. In patients with recurrent or metastatic PD-L1-positive
GC enrolled in a phase Ib trial, pembrolizumab reportedly had a manageable toxicity profile and effective
antitumor activity (KEYNOTE-012) . In particular, 22% of patients with pembrolizumab had an overall
[42]
response and 13% patients had grade3 or 4 treatment-related adverse events. In addition, that trial suggested
a possible association between PD-L1 expression levels and pembrolizumab activity in GC. In a phase II
trial, as a first-line treatment for AGC or GEJA, pembrolizumab as a monotherapy has been combined
with cisplatin + 5-fluorouracil or capecitabine in subjects, with examinations ongoing (KEYNOTE-059,
NCT02335411). Furthermore, in two ongoing phase III trials, pembrolizumabis compared with paclitaxel as
second-line treatment for AGC or GEJA (KEYNOTE-061, NCT02370498), and pembrolizumab monotherapy
is compared with a combination therapy of 5-FU (or capecitabine) plus cisplatin plus pembrolizumab or
placebo as first-line treatment for patients who are PD-L1 positive and HER2 negative (KEYNOTE-062,
NCT02494583).

Ipilimumab is a human IgG1 monoclonal antibody that acts against cytotoxic T-lymphocyte antigen 4 (CTLA-4)/
B7 interaction to restore CD4 and CD8 effector activation. In a phase II trial, ipilimumab was compared with
BSC for patients who had received first-line chemotherapy that was not significantly superior in efficiency
as maintenance therapy . Comparing the efficiency of nivolumab as a single agent or in combination
[43]
with ipilimumab was performed in phase I/II trial (checkmate-032) . The nivolumab + ipilimumab group
[44]
showed a relatively higher ORR than the nivolumab monotherapy group (14% with nivolumab monotherapy
and 26% with nivolumab + ipilimumab). A phase III trial of nivolumab + ipilimumab in patients with AGC
is ongoing (NCT02872116).

Avelumab is an intravenously administered PD-L1 blocking human IgG1 lambda antibody for the treatment
of various tumors. Avelumab has now been approved by the Food and Drug Administration (FDA) for
the treatment of Merkel-cell carcinoma. In GC, the focus of a phase III study, avelumab is compared with
best supportive care after response or stability to oxaliplatin and fluoropyrimidine, with examination
ongoing (JAVELIN Gastric 100, NCT2625610). Avelumab is also now being verified to compare avelumab
and BSC vs. paclitaxel or irinotecan and BSC in third-line treatment of AGC (JAVELIN Gastric 300,
NCT02625623).

Durvalumab (MEDI4736) is a human IgG1κ monoclonal antibody that blocks the interaction of PD-L1
with PD-1 and CD80 molecules. This antibody has been approved for the treatment of patients with locally