Targeting Molecular Pathways in Gastric Cancer: Current Status and Future View

Targeting Molecular Pathways in Gastric Cancer: Current Status and Future View

By Salah-Eddin Al-Batran, MD

Article Highlights

  • Progress has been made in understanding the biology behind esophagogastric cancer, and several targeted strategies have been developed or are under development.
  • Trastuzumab has become standard of care in first-line therapy for HER2-positive disease. A number of new HER2-directed drugs, such as pertuzumab, are under clinical development for gastric cancer.
  • Two randomized trials have shown that targeting the VEGFR pathway with ramucirumab is effective in late-stage, refractory gastric and GEJ cancers.
  • Immunotherapy against gastric cancer includes antibodies, adoptive cell therapy, and vaccination.  Recently, promising data were presented for immunomodulatory antibodies targeting the PD-1 pathway.

Esophagogastric cancer is a major cause of cancer-related mortality worldwide. Annually, approximately 1.4 million individuals are diagnosed with esophagogastric cancer, and 1.1 million individuals die from the disease.1 Chemotherapy is a widely accepted treatment for advanced disease, leading to objective responses and prolonged survival. However, median survival time after first-line treatment is still between 9 and 11 months. As with other cancers, esophagogastric cancer is promoted by genomic alterations that may represent targets for specific drugs. Recently, progress has been made in understanding the biology behind esophagogastric cancer, and as a result, several targeted strategies have been developed or are under development.

HER2-Positive Esophagogastric Cancer

Approximately 15% to 20% of all gastric and gastroesophageal junction (GEJ) cancers are HER2-positive. Tumors located in the proximal stomach or in the lower esophagus, as well as tumors of the intestinal type histology are more likely to be HER2-positive than tumors located in the lower stomach or diffuse-type tumors.2 Patients with HER2-positive disease derive additional benefit from the HER2 antibody trastuzumab. In the landmark study ToGA, trastuzumab was added to combination cisplatin/fluoropyrimidine chemotherapy and compared with chemotherapy alone in previously untreated patients with HER2-positive tumors.3 Patients were eligible when they had HER2-positive tumors, defined as HER2 overexpression in IHC or HER2-gene amplification as assessed by fluorescence in situ hybridization (FISH+). In total, 594 patients were assigned to study treatment. Trastuzumab prolonged median progression-free survival (PFS) and overall survival (OS) times (PFS, 6.7 vs. 5.5 months, p = 0.0002; OS, 13.8 vs. 11.1 months, p = 0.0046), and improved response rate (RR, 47.3% vs. 34.5%; p = 0.0017). Patients whose tumors were IHC negative (IHC 0) or marginally IHC positive (IHC 1+) did not benefit from the addition of trastuzumab, although they were FISH+. In contrast, median OS increased from 11.8 to 16.0 months in the IHC 3+ or IHC 2+ and FISH+ group. In patients with highest expression (IHC 3+), OSimproved from 12.3 to 17.9 months.

A number of new HER2-directed drugs are under early- or late-stage clinical development for gastric cancer. The most prominent candidate is pertuzumab, a monoclonal antibody against HER2 that inhibits the dimerization of HER2 with other HER receptors. Pertuzumab is currently under investigation in a phase III trial, in which pertuzumab is added to trastuzumab and chemotherapy for previously untreated advanced HER2-positive gastric and gastroesophageal junction (GEJ) cancers (NCT01461057). The trastuzumab-chemotherapy conjugate T-DM1 failed to improve results in second-line treatment for HER2-positive, advanced stomach cancer compared to paclitaxel chemotherapy.

Targeting Angiogenesis and the VEGF Pathway

Several randomized trials have shown that targeting the VEGF pathway is effective in late-stage, refractory gastric and GEJ cancers. Ramucirumab, a monoclonal antibody targeting VEGFR-2, has shown survival benefits in patients with advanced gastric and GEJ cancers whose disease progressed during or after combination platinum and fluoropyrimidine first-line chemotherapy. In the randomized phase III trial REGARD, 355 patients whose platinum- or fluoropyrimidine-containing first-line treatment failed, were randomly assigned (2:1) to receive ramucirumab and best supportive care every 2 weeks or placebo and best supportive care. Ramucirumab significantly improved median OS (5.2 vs. 3.8 months; p = 0.047) and PFS (2.1 vs. 1.3 months; p = 0.0001).4 Ramucirumab was well tolerated, with hypertension (ramucirumab, 15%; placebo, 8%) being the only relevant side effect observed more frequently in the ramucirumab group.

The phase III RAINBOW study randomly assigned 665 patients with metastatic gastric cancer whose first-line therapy (platinum and fluoropyrimidine) had failed to paclitaxel plus ramucirumab or paclitaxel plus placebo.5 In this study, ramucirumab improved OS, PFS, and RR significantly. Median OS was 9.6 months for ramucirumab plus paclitaxel and 7.4 months for paclitaxel plus placebo (p = 0.017). The ramucirumab/paclitaxel group had more grade 3 or 4 neutropenia (40.7% vs. 18.8%), hypertension (14.1% vs. 2.4%), and fatigue (11.9% vs. 5.5%) than the paclitaxel plus placebo group. A placebo-controlled phase III trial conducted in Chinese patients observed similar results (prolongation of OS and PFS) using the oral small-molecule tyrosine-kinase inhibitor apatinib as a single agent in patients who had two previous therapy lines fail.6 Regorafenib, a small chemical that targets multiple tyrosine kinases, including VEGFR-2, delivered promising results in phase II study, and a phase III study is planned.7

The role of VEGF-pathway inhibitors in earlier-stage treatment (e.g., first-line or adjuvant setting) remains unclear. Bevacizumab combined with chemotherapy improved PFS and RR but not OS in the randomized, international phase III AVAGAST trial.8 RAINFALL, a phase III trial with ramucirumab in combination with chemotherapy in the first-line setting, has started recruiting patients (NCT02314117).

Other Tyrosine-Kinase Inhibitors

A large number of antibodies and small chemicals directed against tyrosine kinases, such as EGFR, FGF, IGF-IR, and c-MET, have been evaluated in phase II or phase III trials. Unfortunately, most of the trials failed to show expected results.9 A major detrimental factor was the fact that the biomarker assays used in the studies were suboptimal, resulting in poor patient selection and negative results.

P13K Pathway

The PI3K/AKT/mTOR pathway plays an important role in cell metabolism, growth, migration, survival, and angiogenesis. Ipatasertib (GDC-0068) is an oral small-molecule inhibitor of AKT. Ipatasertib is under evaluation in the JAGUAR study (NCT01896531), a randomized, double-blind, placebo-controlled, global phase II study in patients with previously untreated locally advanced or metastatic gastric and GEJ cancers. Approximately 120 patients with gastric and GEJ cancers were randomly assigned to receive mFOLFOX6 plus ipatasertib or mFOLFOX6 plus placebo. The mTOR inhibitor everolimus (RAD001) failed to improve OS in an international second-line phase III trial, although it did prolong PFS.10 As with many other targeted therapies, a major obstacle facing the development of PI3K/AKT/mTOR-directed therapies is the lack of reliable biomarkers.

Modifiers of the Inflammatory Environment

Inflammatory environment modifiers target molecules that trigger chronic inflammation and maintain an active environment that facilitates tumor progression and metastasis. Such molecules are MMPs, JAKs, and COX. A number of “older” MMP inhibitors, such as marimastat, showed promising results in preclinical studies.11 However, they performed poorly in clinical trials and were associated with significant toxicities (particularly musculoskeletal toxicity). A new MMP9-specific monoclonal antibody (GS-5745) is currently under evaluation in a randomized trial for gastric cancer (NCT02545504).

Immunotherapy

Immunotherapy against gastric cancer includes antibodies, adoptive cell therapy, and vaccination.12 Antibody-based immunotherapy can be divided into two types: antitumor antibodies and immunomodulatory antibodies. Antitumor antibodies target specific surface antigens and lead to an activation of effector cells and other components of the immune system, such as complement or antibody-dependent cell-mediated cytotoxicity. A recent example of antitumor antibody immunotherapy is IMAB362, an antibody against the tight junction protein CLDN18.2. A randomized phase II study (NCT01630083) that evaluated IMAB362 plus chemotherapy versus chemotherapy alone in the first-line treatment of patients with CLDN18.2-positive gastric and GEJ cancers has completed accrual, and results will be presented at the ASCO Annual Meeting.

On the other hand, immunomodulatory antibodies target functional antigens of the immune cells to enhance or increase the number of activated lymphocytes. Examples are monoclonal antibodies against CTLA-4 on the surface of T cells and PD-1 receptor antibodies. Recently, promising data were presented for the PD-1 antibody pembrolizumab in patients with advanced, previously treated esophageal and gastric cancers.13,14 In a cohort of 23 patients with PD-L1–positive esophageal (including squamous histology) or GEJ cancers who had received standard therapy, pembrolizumab at 10 mg/kg every 2 weeks resulted in an objective response in five patients (23%) and a stable disease in another four patients (18%).13 In another cohort, 39 patients with previously treated PD-L1–positive gastric cancer received the same regimen of pembrolizumab and showed similar results.14 The RR was 22% according to an independent review. Several phase III projects with PD-1/PD-L1 inhibitors for gastric cancer have started recruiting patients.

Future View

Fig. 1
The introduction of trastuzumab and ramucirumab has reshaped the treatment algorithm for gastric and GEJ cancers (Fig. 1). However, much still must be done. Carcinogenesis involves various genetic pathways, and new concepts must implement multitarget strategies in order to induce durable remissions. We must boost biomarker programs and link drug development to a carefully selected biomarker starting at the phase I stage. The large number of targeted drugs necessitates changing the way we test these drugs in early phase. Basket trials that enable fast-track decision making on new drugs are needed. Future trials also must be more selective, as recent reports show that gastric cancer can comprise different molecular subtypes with differences in gene and potential response profiles to therapeutic strategies.15,16

Predicting how the field of gastric cancer will evolve in the future is difficult. However, it is not too speculative to say that the treatment of this disease will certainly differ from today. HER2-positive gastric cancer will most likely follow the course set by HER2-positive breast cancer. HER2 inhibition will become part of the adjuvant, first-, and second-line setting, and HER2-positive gastric cancer will likely be associated with favorable outcomes compared to HER2-negative disease. The introduction of ramucirumab into the first-line setting is a logical step. However, clinical trials in this setting are challenging. Biomarkers identifying patients who are more likely to respond to VEGFR-2 inhibition are highly warranted.

The early clinical experience has shown encouraging activity of PD-1 pathway inhibitors in PD-L1–positive esophagogastric cancer. Further results from randomized trials are eagerly awaited. In the future, more and more subgroups that benefit from a certain treatment will be established. Gastric cancer will be fragmented into several subgroups with distinct molecular and response profiles.