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Immunotherapies, Stemness Inhibitors Among Advances in Gastroesophageal Cancers

Gina Columbus @ginacolumbusonc
Published: Thursday, Mar 02, 2017

Daniel H. Ahn, DO

Daniel H. Ahn, DO

The armamentarium of gastroesophageal cancers is starting to expand, explains expert Daniel H. Ahn, DO, with a variety of agents being explored at a rapid pace.

For example, the double-blind, placebo-controlled phase III INTEGRATE II trial will investigate the potential of regorafenib (Stivarga) for patients with refractory advanced gastroesophageal cancer (NCT02773524). In the study, which is not yet recruiting, researchers will determine whether the oral multikinase inhibitor improves overall survival (OS).

Additionally, there is the stemness inhibitor napabucasin (BBI-608), which was granted an orphan drug designation by the FDA in June 2016 as a treatment for patients with gastric or gastroesophageal junction cancer. The designation was based on early-phase data from the BRIGHTER trial. Here, the agent showed an objective response rate (ORR) of 15% and a median progression-free survival (PFS) of 13 weeks. In patients who did not receive a taxane in the metastatic setting, the ORR was 31% and the median PFS was 20.6 weeks. The ORR was 50% in patients who received just 1 prior therapy that was not a taxane.

Immunotherapies are also demonstrating early potential in gastroesophageal cancers, Ahn adds, specifically PD-1 antibodies alone and in combination with chemotherapy.

“The main thing is to recognize that there may be better treatment strategies, in terms of providing a neoadjuvant approach and immunotherapy is a viable and relevant treatment option,” Ahn says. “Where this ultimately falls—whether it’s second-, third- or fourth-line therapy—still needs to be determined. But, it should be included somewhere along the lines and, if a patient is not really tolerating chemotherapy, I would consider moving it up to even the second-line setting.” 

Ahn, an assistant professor at Mayo Clinic, shared these updates in the gastric cancer landscape during the 2017 OncLive® State of the Science Summit on Gastrointestinal (GI) Malignancies. In an interview during the meeting, he spoke on biomarker developments, agents emerging in the pipeline, and exciting data out of the 2017 GI Cancers Symposium.

OncLive: Can you provide a summary of your presentation?

Ahn: We discussed the recent updates in esophageal and gastric cancer. We mainly focused on gastroesophageal junction cancer in the lower esophagus as well as gastric cancer—so mainly the adenocarcinomas. 

Essentially, there were discussions on biomarkers with potential targeted therapies in gastroesophageal cancer, followed by neoadjuvant approaches and, lastly, what the future direction is in treating these malignancies. 

What biomarkers are now in development?

Mainly, there are several relevant targets that are active treatment options in gastroesophageal cancer. The main one is VEGFR-2. While the AVAGAST study was negative with bevacizumab (Avastin) in the first-line setting, we see in the second-line setting that VEGFR-2 is a relevant target. We have seen that over and over again with multiple different agents, including apatinib and, most recently, ramucirumab (Cyramza).

Based on this, there are ongoing trials. It is mainly the INTEGRATE II trial, which Mayo Clinic is going to be a part of. In this study, we’re looking at the role of regorafenib in the refractory setting as a targeted agent. What we’ve seen in earlier studies, in the phase II INTEGRATE I study, is that this is a relevant target improving not only PFS, but there might be also be an OS benefit for patients with refractory gastric cancer. 

What are the challenges with biomarker development in this field?

There is still a lot of area of uncertainty and a lot of unknowns in this area. The main thing that seems to be a hot area—not just in gastric cancer, but in all GI malignancies—is PD-1/PD-L1. What we saw from a recent phase III study presented at the 2017 GI Cancers Symposium is that this is a relevant target.

What we are going to try to do is to stratify and identify which patients are going to benefit the most. Even some of those who were weak PD-1 expressers, based on early phase I data, still had some benefit. We are trying to extrapolate who may benefit and who may benefit even further. 

What updates are occurring in the neoadjuvant setting?

There have been a lot of interesting developments in the neoadjuvant setting, mainly with the combination of PD-1 inhibitors plus chemotherapy. Currently, the treatment strategy is chemotherapy, usually with carboplatin/paclitaxel, in combination with concurrent chemoradiation. This is based off of the CROSS trial.

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