58
agents targeting at the HCF/MET pathway have no role in the
management of metastatic gastric or esophagogastric junction
adenocarcinoma.Immune surveillance is a crucial process in which cancer cells are
identified and eventually eliminated from the body. However, fail-
ure of the immune system to function properly will lead to immune
escape of the cancer cells and development of cancer [ 43 ]. PD-1 is
a negative co-stimulatory receptor expressed mainly on activated T
cells, which naturally serves to down-regulated unwanted immune
responses by binding to its ligands PD-L1 and PD-L2 [ 44 , 45 ].
PD-L1 expression on tumor tissues, including gastric and esopha-
gogastric junction adenocarcinoma, can result in suppression of
the antitumor immune response. Pembrolizumab and nivolumab
are examples of monoclonal antibody against the PD-1 molecule.
These drugs have shown promising results in various cancers
including melanoma [ 46 , 47 ], renal cell carcinoma [ 48 ], and non-
small cell lung carcinoma [ 49 – 51 ]. There is emerging evidence to
suggest their efficacy in gastric and esophagogastric junction ade-
nocarcinoma. Muro et al. reported the result of a phase 1b study
on pembrolizumab in PD-L1-positive advanced gastric carcinoma
[ 52 ]. PD-L1 positivity was defined as membrane staining in at least
1% of scorable cells or the presence of a distinctive interface pat-
tern. Forty percent of the screened patients were positive and 39
were enrolled. Majority of patients (67%) had received two or
more lines of treatment for metastatic disease. Of the 36 evaluable
patients, response was seen in 22% with the median time-to-
response and duration of response of 8 weeks and 40 weeks,
respectively. The median progression-free survival was rather short
(1.9 months) but the median OS (11.4 months) was encouraging
in this group of heavily pretreated patients. Clinically significant
treatment-related adverse events were noted in 13% of patients,
which include one case of grade 4 pneumonitis. Similar result of
nivolumab was reported in a phase III randomized study that
enrolled 493 patients irrespective of their PD-L1 status [ 53 ].
Compared to placebo, nivolumab significantly improved the OS
(5.3 months vs 4.1 months, HR 0.63; p < 0.0001), progression-
free survival (PFS) (1.6 months vs 1.5 months, HR 0.6; p < 0.0001),
and objective response rate (ORR) (11.2% vs 0%, p < 0.0001). The
rate of drug-related adverse events was 11.5% with nivolumab.
Although monotherapy with anti-PD-1 monoclonal anti-
bodies is generally well tolerated, the clinical activity is modest
and more effective strategies are urgently needed. One such
strategy is to adopt dual immune-checkpoint blockade, and the
approach has achieved a remarkable success in melanoma [ 46 ,
47 ]. A phase I/II study of nivolumab with or without ipilimumab
in patients not selected by PD-L1 expression was reported [ 54 ].1.7 Immune
Checkpoint
Ka-On Lam and Dora L. W. Kwong