Josep Tabernero, MD
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and etiological heterogeneity, which has resulted in comparatively slow progress in the development of biomarkers and new treatments for this disease.
In a talk at the 2015 World Congress on GI Cancer, Josep Tabernero, MD, PhD, provided a summary of novel agents that are currently under exploration for patients with gastric cancer. These potential advances encompass immunotherapy approaches against PD-1 and PD-L1, along with a host of other targeted strategies, such as those against cancer stem cells, PI3K/mTOR, HER3, and FGFR2.
“Gastric cancer is a heterogeneous disease with diverse molecular characteristics,” Tabernero, head of the Medical Oncology Department at the Vall d’Hebron University Hospital, Barcelona, Spain, said during his talk. “A major role is played by genomic alterations and mutually exclusive amplification patterns of receptor tyrosine kinase (RTK)/RAS signaling components in gastric cancer.”
Checkpoint Inhibition Shows Promise
Research has uncovered several points of vulnerability in the cancer-immunity cycle that offers drugable targets, Tabernero explained. Chief among the agents under exploration are the anti-PD-1 and PD-L1 monoclonal antibodies. These agents have demonstrated a broad range of efficacy across several types of solid and liquid tumors.
In the KEYNOTE-012, 39 patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction, with ECOG PS 0-1, and tumors that were positive for PD-L1 received pembrolizumab at 10 mg/kg every 2 weeks for up to 24 months or until complete response or toxicity. Overall, PD-L1-positivity (≥1% staining) was detected in approximately 40% of patients screened for the study.
In updated results presented at the World GI Congress,1
the PD-1 inhibitor pembrolizumab demonstrated an overall response rate (ORR) of 22% by central review, with a median duration of response of 40 weeks. By investigator assessment, the ORR was 33.3%. Once stable disease was factored in, the disease control rate (DCR) was 36%.
Patients achieved a 6-month overall survival (OS) survival rate of 66% and progression-free survival (PFS) of 26%. The median PFS was 1.9 months and the median OS was not yet reached. Moreover, a trend toward an association between higher levels of PD-L1 expression and ORR, PFS, and OS was observed.
A phase II study is planned to assess pembrolizumab in advanced gastric or GEJ adenocarcinoma. This study will contain 3 cohorts, which will enrolled those with previously treated disease, untreated patients in combination with cisplatin, and untreated patients who are PD-L1-positive.
Tabernero noted that the KEYNOTE-012 is an ongoing trial, and the findings could change. Additionally, he added, several other trials are assessing PD-1 and PD-L1 agents in gastric cancer.
In a phase I trial of the PD-L1 inhibitor avelumab in 20 Japanese patients, the preliminary results show an ORR of 15% and a DCR of 65%. The 12-week PFS rate was 43.3%. At this time, these results are the most similar to those seen in the KEYNOTE-012 trial.
Targeting Stem Cells
Cancer stem cells are the progenitors of cancer cells and figure prominently into oncogenesis and metastasis, according to Tabenero. Cancer stem cells are thought to be a leading cause of varying levels of heterogeneity, cell renewal, proliferation, and evasion of the immune system. In theory, blocking this process could lead cell death and suppression of key pathways, such as Stat3, β-catenin, and immune checkpoint expression.
The phase III, randomized, double blind, international BRIGHTER study is evaluating a novel agent inhibitor of cancer cell stemness, BBI608 (NCT02178956). The study plans to enroll 680 patients with gastric or GEJ cancer who failed first-line chemotherapy. Patients enrolled into the trial will be randomized 1:1 to receive BBI608 with weekly paclitaxel or paclitaxel alone over a 36-week treatment cycle.
The goal of the phase III study is to determine whether paclitaxel plus BBI-608 as second line therapy will prolong overall survival compared to paclitaxel alone. Prior to the initiation of the phase III study, encouraging signs of anticancer activity were seen in a phase Ib/II study of patients with gastric cancer.2