Agents Under Examination Demonstrate Success in Gastric Cancer

Josep Tabernero, MD, PhD

Josep Tabernero, MD, PhD, gave a synopsis, in a talk at the 2015 World Congress on GI Cancer, of novel agents that are under examination for the treatment of 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 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.

“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 druggable 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 to 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,¹the 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 three cohorts, which will enroll 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 to 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 or not 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

In the phase Ib/II trial, the ORR was 31% and the DCR was 75% in 20 untreated patients with metastatic gastric cancer treated with BBI608 in combination with paclitaxel. The median PFS was 20.6 weeks and the median OS was 39.3 weeks. In 26 patients who failed a median of 3three prior treatments, the ORR was 11% and the DCR was 68%. The median PFS was 12.6 weeks and the median OS was 33.1 weeks.

Molecular Strategies Largely Unsuccessful

Taberno stressed the need for new therapeutics in this difficult to treat disease, and also the importance of developing biomarkers to enable better patient selection. PI3K/mTOR is an important pathway in gastric cancer, representing an area of high interest for molecularly targeted therapies. The pathway is an important regulator of cell growth, survival, proliferation, and angiogenesis.

“50% to 60% of gastric cancers demonstrate dysregulation of this pathway, and mTOR inhibitors have demonstrated preclinical and early clinical activity in gastric cancer,” Tabernero explained.

In the phase III randomized GRANITE-1 study, everolimus was used to target the PI3K/mTOR pathway as second-line therapy in patients with gastric cancer (n = 435) compared with best supportive care (n = 217). A trend toward prolonged survival was demonstrated; however, it did not reach statistical significances.³

In the trial, patients receiving everolimus had a median OS of 5.4 months compared with 4.3 months with placebo (HR,0.90;P= .124). The median PFS was 1.7 versus 1.4 months with everolimus and placebo, respectively (HR, 0.66;&nbsp;P<.001).

Other molecular approaches are looking at HER3, due to its interaction with EGFR and HER2. A number of monoclonal antibodies targeting HER3 are under development in phase I studies, including U3-1287 (NCT00730470), MM-121 (NCT00734305), and LJM716 (NCT01598077). Also being evaluated in phase I is MEHD7945A, a dual inhibitor of EGFR and HER3 (NCT01207323) and MCLA128, a dual HER2 and HER3.

&ldquo;HER3 has been identified as a potential therapeutic target in breast cancer and non-small cell lung cancer and has been associated with resistance to agents targeting EGFR or HER2,&rdquo; Tabernero explained. &ldquo;Currently, the role of HER3 as a potential mechanism of resistance of EGFR/HER2 inhibitors is being investigated.&rdquo;

Another emerging target in gastric cancer is the fibroblast growth factor receptor 2 (FGFR2). This strategy has been explored across studies, with mixed results. In the phase II randomized SHINE clinical trial, AZD4547 was compared with paclitaxel in metastatic gastric cancer. AZD4547 is a biological agent that blocks cancer cell division by targeting FGFR2, which is expressed on the surface of cancer cells.

SHINE screened 961 patients with gastric cancer who failed first-line chemotherapy. Of these, 71 patients were FGFR2 amplified or polysomy (by FISH) and were randomized to receive either AZD4547 (n = 41) or paclitaxel (n = 30). However, no difference was observed in PFS between the two treatments.⁴

The median PFS in the AZD4547 arm was 1.8 months compared with 3.5 months with paclitaxel. Of those with FGFR2 amplified tumors, only 21% had elevated FGFR2 expression. However, in this group of those with elevated expression, the results remained similar (1.5 vs 2.3 months).

In addition to AZD4547, Tabernero noted that clinical studies are exploring the FGFR2 inhibitor dovitinib for patients with gastric cancer. This therapy is being explored as a monotherapy in the second- and third-line setting (NCT01719549) and in combination with docetaxel in the second-line setting (NCT01921673).

1. &nbsp;&nbsp; Bang Y-J, Chung HC, Shankaran V, et al. Clinical outcomes and their correlation with gene expression in patients with advanced gastric cancer treated with pembrolizumab (MK-3475): KEYNOTE-012.&nbsp;Ann Oncol. 2015;26 (suppl 4; LBA-04).

2. &nbsp;&nbsp; Becerra C, Stephenson J, Jonker DJ, et al. Phase Ib/II study of cancer stem cell (CSC) inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.&nbsp;J Clin Oncol. 2015;33 (suppl; abstr 4069).

3. &nbsp;&nbsp; Ohtsu A, Ajani JA, Bai Y-X, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 Study [published online September 16, 2013].&nbsp;J Clin Oncol. 2013;31(31):3935-3943.

4. &nbsp;&nbsp; Bang Y-J, Van Cutsem E, Mansoor W, et al. A randomized, open-label phase II study of AZD4547 (AZD) versus Paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with Fibroblast Growth Factor Receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study.&nbsp;J Clin Oncol.2015; 33 (suppl; abstr 4014).