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Gastrointestinal Oncology Editorial American Society of Clinical Oncology 2015— Highlights of Non-colorectal Gastrointestinal Cancers Eileen M O’Reilly, MD Medical Oncologist and Associate Director for Clinical Research, David M Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, US Abstract This editorial covers the key highlights on Non-Colorectal Gastrointestinal Cancers from American Society of Clinical Oncology Annual Meeting 2015. Keywords Non-colorectal gastrointestinal cancers, pembrolizumab, PD-1 inhibitor, KEYNOTE-012, RILOMET-1 trial, rilotumumab, erlotinib, PEGPH20 Disclosure: Eileen M O’Reilly, MD, has nothing to declare in relation to this article. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: August 25, 2015 Published Online: November 10, 2015 Citation: Oncology & Hematology Review, 2015;11(2):137–8 Correspondence: Eileen M O’Reilly, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, US. E: oreillye@mskcc.org The 2015 annual American Society of Clinical Oncology meeting brought refinements rather than major practice changes to the field of non- colorectal gastrointestinal (GI) cancers, with one notable exception and that is for the emerging endorsement of the role of immune therapies in these diseases. Arguably the most important observation from the meeting overall was the recognition of a strong signal for pembrolizumab (MK- 3475), a programmed death-1 (PD-1) antibody inhibitor, dosed at 10 mg/kg intravenously every 2 weeks, in malignancies with microsatellite instability (MSI-high) in both colorectal cancers and other non-colorectal cancers (non- CRC), and showed markedly favorable activity in the patients with MSI-high compared to no significant activity in patients with MSI-stable tumors. 1 Very specifically, in the subset of DNA mismatch repair protein-deficient, non- CRC (n=10, including, ampullary, biliary, small bowel, gastric cancers), the response rate was 60 % and the disease control rate was 70 %. About 40 % of these patients had hereditary non-polyposis colorectal cancer. While the subset of patients with non-CRC GI cancers with MSI-high status is likely to be small, single digit percent of all-comers, the results in these patients are dramatic. The implication for practice is to consider mismatch repair protein expression via immunohistochemical (IHC) evaluation or polymerase chain reaction evaluation of DNA microsatellite instability in these patients and if mismatch repair deficiency (MMR)-deficient/MSI-high consider enrollment in a PD-1 or programmed death-ligand 1 (PD-L1) antibody trial to fully understand how and when these agents should be utilized. Continuing the theme of immune therapy, the update from the KEYNOTE-012 single agent evaluation of pembrolizumab in previously treated metastatic gastric cancer further highlighted the enthusiasm for immune therapy strategies in GI cancers. 2 The rationale for their use is compelling based Tou ch MEd ica l MEdia on subsets of patients with high somatic mutational burden in gastric cancer, 3 the association of PD-1 and PD-L1 with a poor prognosis and results from the Cancer Genome Atlas Research Network suggesting that certain subsets of patients with gastric cancer with Epstein–Barr virus and MSI are more likely to benefit from immune therapies. 4 In this single- arm non-randomized evaluation of pembrolizumab, Bang and colleagues evaluated patients who had had at least two lines of prior therapy and a good functional status and for eligibility required PD-L1 expression by IHC in ≥1  % of tumor cells or stroma. For the primary endpoint of response, there was a 22  % objective response rate to pembrolizumab in gastric cancer with significant durability with a median of 40 weeks, although in some patients, the durability extended to a year and beyond, and with an overall survival of 11.4 months. A detailed analysis of PD- L1 expression and outcome suggested that an improved benefit was observed in those with greater PD-L1 expression. A similar response signal was observed in KEYNOTE-028 in an esophageal cohort. There are now a series of immune therapy trials in advanced esophagogastric malignancies including an evaluation of pembrolizumab in a third-line setting, along with an evaluation with standard platinum/frontline fluoropyrimidine therapy, a comparison to paclitaxel in a second-line setting, an evaluation as a single agent in PD-L1 positivity frontline, and with other agents evaluating the addition of a PD-1 antibody with/without anti-cytotoxic T-lymphocyte- associated protein 4 (anti-CTLA4) therapy. The next few years will more definitively clarify the disease stages and settings for optimal utility from immune therapies in esophagogastric malignancies. On a different theme, this year’s meeting has likely closed an era/strategy of development in esophagogastric malignancies with the final results of two 137