Metastatic Gastric Cancer: Recent Advances and Future Directions

David H. Ilson, MD, PhD: To summarize our progress in gastric cancer, I think we now have a consensus and better definition of what’s optimal first- and second-line chemotherapy. We know that in the first line, in HER2+ patients, we should include trastuzumab as part of chemotherapy. We now consider genomic profiling to identify targetable mutations, such as MSI-high status for patients that might be candidates for use of immunotherapy either early or later line, and testing of tissue for a PD-L1 expression because we know that PD-L1+ patients may get some modest benefit for late-line use of checkpoint inhibitors. We obviously hope to learn from our genomic profiling to identify new targets or new networks of targets in tumors that may be targetable. We have promising emerging data for some novel HER2-targeted therapies in later-line treatment, because that really has been a desert to date. The drugs that worked in breast cancer, except for trastuzumab, have not worked in gastric cancer. So, identifying promising and new agents either in first- or late-line treatment in HER2+ patients remains a priority, and there are some drugs that are clearly emerging that I think are going to enter our armamentarium.

We also now have defined adjuvant strategies. Perioperative chemotherapy with FLOT [5-flourouracil, leucovorine, oxaliplatin, docetaxel], postoperative adjuvant chemotherapy with either capecitabine/oxaliplatin, S-1/ oxaliplatin, or fluorinated pyrimidine and a taxane, all without radiation, are all appropriate pre and postoperative adjuvant strategies.

How best to use immunotherapy drugs? I think in MSI-high patients, it’s clear that these drugs have substantial activity and will probably be used either in first- or second-line treatment in MSI-high patients, probably without chemotherapy. In later-line treatment, we do not have convincing evidence yet that checkpoint inhibitors add to first-line chemotherapy, and we don’t have evidence in adenocarcinoma that checkpoint inhibitors are better than second-line chemotherapy. Right now, checkpoint inhibitors are used in the more refractory setting when patients are PD-L1+. We now have one trial showing that switch maintenance therapy with a checkpoint inhibitor was not better than continuing chemotherapy alone, so that’s not going to change practice.

An exciting area aside from biomarker development from genomic profiling, is the technology regarding circulating tumor DNA. Not only is it maybe a biomarker of minimal residual disease, but it may provide real-time assessment of how the patient’s cancer evolves during the course of treatment. A good example of that would be the HER2+ patients, we know that a significant percentage of patients that are HER2+ and get treated with trastuzumab-based treatment, will actually lose their expression of HER2, and that is one potential biomarker that could be assessed with a blood test, with circulating tumor DNA. Does the patient still maintain HER2 amplification based on circulating tumor DNA testing? Can we identify resistance pathways and why is a patient becoming resistant to a targeted therapy or to a chemotherapy?I think circulating tumor DNA is an exciting emerging technology, it provides real-time monitoring of patients, looking at emergence of mutations and abnormalities that might convey resistance and loss of HER2 amplification. I think we’re seeing now active trials in diseases like colorectal cancer where it’s actionable, but can we use these technologies to look at minimal residual disease in patients that have gotten curative local therapies? Would such patients be candidates for therapy intensification or novel strategies to try and reduce recurrence?

It’s an exciting time, I think we’re going to see new drugs come to the fore. Hopefully, with some ongoing trials with immunotherapy drugs, we’ll see whether there will be a defined role for these agents earlier. Also, drugs that target the claudin protein are being studied in randomized trials in first-line treatment in claudin-overexpressing patients. We await the results of the FGF trials that we talked about, looking at FGF-targeted antibodies and results of first-line immunotherapy drugs with trastuzumab in first-line treatment and whether that will convey a benefit in earlier-line treatment.

Transcript edited for clarity.