NGS Is Critical Component in Guiding Advanced Gastric/GEJ Cancer Treatment

Manish A. Shah, MD

Next-generation sequencing (NGS) has become an important component in the management of patients with advanced gastric and gastroesophageal junction (GEJ) cancer, said Manish A. Shah, MD, opening the door to several approved and investigational targeted and immune-based therapies.

“Many options are available for patients, in terms of standard and investigational treatments,” said Shah, Bartlett Family Associate Professor in Gastrointestinal Oncology and associate professor of medicine at Weill Cornell Medical College. “When we see patients, we need to anticipate what their first-line, second-line, and third-line treatment will be [by sequencing for] targets that we may be able to exploit.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Shah, who is also an associate attending physician at NewYork-Presbyterian Hospital, discussed ongoing research evaluating immunotherapy and other novel treatments in advanced gastric/GEJ cancer.

OncLive: Could you discuss how the management of patients with advanced gastric and GEJ cancer has evolved over the years?

Shah: The field is much different now that it was even 3 years ago. [In my presentation], I discussed standard chemotherapies, as well as second- and third-line therapies. I also [highlighted advances with] immunotherapy and targeted therapy, specifically with regard to trastuzumab (Herceptin) and ramucirumab (Cyramza). The treatment of this disease has evolved over time; we have many options for patients. It’s important to consider all of the options available, so that we can provide patients with the best overall outcomes.

What is the role of ramucirumab in this space?

Ramucirumab is an important drug in gastric/GEJ tumors; it's an antibody that binds to VEGFR2. The agent has demonstrated efficacy in the second-line setting as monotherapy as well as in combination with chemotherapy. I mostly use [ramucirumab] with paclitaxel in the second-line setting. The first-line trial of ramucirumab plus chemotherapy [showed that the combination] was not [more effective] than chemotherapy alone. There's a lot of ongoing research investigating where this agent is best used; right now, that’s in the second-line setting.

What targets are being explored in gastric/GEJ cancer?

One of the key ones is Claudin 18.2, which binds cells together. When cancers develop, they lose their cell interaction, so they expose the protein. There’s an antibody against Claudin 18.2 [IMAB362] that was developed by Astellas Pharma. When the drug binds to Claudin 18.2, it activates an immune response. That antibody is now in two registrational studies, which is exciting. Another exciting avenue of research involves antibody-drug conjugates. Ado-trastuzumab emtansine (T-DM1; Kadcyla) is approved for use in breast cancer and has also been examined in gastric cancer. The agent has shown activity in HER2-overexpressing tumors; however, we don’t see much activity in HER2 low-expressing tumors. A new compound by Daiichi Sankyo called [fam-] trastuzumab deruxtecan (DS-8201) might be more effective.

Could you discuss the importance of sequencing?

Sequencing is very important in gastric and esophageal cancers. One of the key targets we need to identify early on is overexpression or amplification of HER2, as data from the phase III ToGA trial led to the approval of trastuzumab in gastric cancer. We also sequence for tumor mutational burden, PD-L1, and mismatch repair deficiency (dMMR).

NGS is very important in how we manage patients because it could lead to [an actionable target]. For example, we now have 2 new drugs for patients with NTRK fusions. If a patient has dMMR, they [can receive] immunotherapy. There is HER2-targeted therapy as well. Many targets exist and more are emerging in gastric/GEJ cancers.

About 5% of patients will have a family history of gastric/GEJ cancer. We sometimes don't remember this, but there is a genetic syndrome called hereditary diffuse gastric cancer which is caused by the CDH1 gene. If a family member has a CDH1 mutation, the standard of care is a prophylactic gastrectomy. The procedure is life-changing for the individual, but it can also reduce the risk of getting stomach cancer in the future. It is important to ask about family history. It is important to test for these potential genetic predisposition syndromes because there are therapeutic implications, the other one being Lynch syndrome. We always consider Lynch syndrome in the context of colon cancer, but there's a 10-fold higher risk in gastric cancer as well.

Could you discuss ongoing research in this space?

One of the main areas of investigation is how to improve on the activity seen with thus far with immunotherapy. We know that immunotherapy works in some patients with PD-L1—positive gastric/GEJ tumors. We know that high PD-L1 expression may increase the likelihood of response. Even so, only 10% to 15% of PD-L1–positive patients respond to this approach.

A recent study looked at immunotherapy versus chemotherapy and showed that chemotherapy is important early on in patients with advanced, symptomatic disease. However, over time, immunotherapy could help more patients. An ongoing study is evaluating a short course of chemotherapy with immunotherapy, which could help avoid any myelosuppression that might occur from longstanding chemotherapy, while still allowing the immunotherapy to work over time. As part of that study, we are also evaluating the role of radiation to see if we can further stimulate an immune response.

We also have a clinical trial where we're injecting an oncovirus into a tumor; these are viruses that are only able to grow in tumors, and they're driven by tumor-specific factors. The concept is that the creation of a viral infection in the tumor can lead to viral cell death, which is immunogenic. That approach could help boost the immune system’s response [to immunotherapy].

What are your thoughts on biosimilars for trastuzumab?

Biosimilars are really important; their advantage is that they [focus on] proven targets. We know that inhibiting HER2 signaling with trastuzumab is effective in HER2-overexpressing gastric/GEJ tumors. A biosimilar will do the same thing [as available agents but] at a reduced cost. In our current environment where more patients are experiencing financial toxicity, having access to biosimilars [is significant]. A biosimilar for bevacizumab (Avastin) is also going to be important in colon cancer. Biosimilars will have an important impact across gastrointestinal malignancies.