Nivolumab is evaluated in squamous cell carcinoma regardless of PD-L1 status, while pembrolizumab is mainly being tested in patients with squamous cell carcinoma (77%), but PDL1 positivity was set as an inclusion criteria. Gastric cancer In gastric adenocarcinomas, tremelimumab (anti-CTLA4) showed a response rate of 5% in a phase I trial. metastatic squamous cell carcinoma HA14-1 of the anal canalPrior systemic therapies20%40%NAMorris et al, 2016II/39NivolumabRefractory metastatic squamous cell carcinoma of the anal canalPreviously treated, immunotherapy na?ve21%58%NA Open in a separate window ORR: Objective response rate; OS: Overall survival; MMR: Mismatch repair; NR: Not reached; NA: Not available. CHECKPOINT INHIBITORS RESULTS IN GI CANCERS Esophageal cancer Results from two phase II trials evaluating nivolumab and pembrolizumab in esophageal cancers demonstrated an acceptable safety profile, meaningful clinical activity and RR of around 20% in heavily pretreated patients. Nivolumab is evaluated in squamous cell carcinoma regardless of PD-L1 status, while pembrolizumab is mainly being tested in patients with squamous cell carcinoma (77%), but PDL1 positivity was set as an inclusion criteria. Gastric cancer In gastric adenocarcinomas, tremelimumab (anti-CTLA4) showed a response rate of 5% in a phase I trial. A phase II trial testing nivolumab in pretreated metastatic adenocarcinoma of the stomach and the gastroesophageal junction reported response rates around 12%, independently of the PDL1 status, while a phase Ib trial evaluating pembrolizumab in pretreated metastatic adenocarcinoma of the stomach and the junction showed response rates exceeding the 30% in PD-L1 positive patients. In ASCO 2016, a trial tested avelumab as second line treatment and as maintenance treatment of advanced gastric or gastro- esophageal junction, the RR in second line setting was 18% in PD-L1 positive tumors and 9% in PD-L1 negative tumors; the disease control rate (DCR) was 29%. The combination of ipilimumab and nivolumab was tested at two different doses in phase I/II trial in gastric or gastro-esophageal adenocarcinoma, progressing after chemotherapy; the RR was 26% with the combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg and 14% with nivolumab. Pancreatic A phase II trial evaluating ipilimumab in pancreatic cancer failed to discern any clinical activity as no response were reported in a any of the 26 patients (0%). Moreover, we do not have any preliminary results with anti-PD1 agents; three ongoing HA14-1 trials are evaluating nivolumab as single agent, nivolumab in combination with ipilimumab and nivolumab in combination with gemcitabine, which might act as a stimulant for neo-antigen expression. Hepatocellular and biliary tract carcinoma The safety profile and antitumor activity tremelimumab, in patients with hepatitis-C-induced liver cirrhosis and subsequent advanced hepatocellular carcinoma (HCC), was promising with RR of approximately 17% and stable disease of 76%. Additionally, Nivolumab was tested in patients with sorafenib-refractory or sorafenib-intolerant HCC regardless of hepatitis status. Preliminary results were promising with RR of 23% (15% in uninfected HA14-1 and 32% in infected HCC). Not only do these trials highlight the efficacy of ICI in this subset of patients, but they also provide valuable information in regards to the potential use of immunotherapy in patients with less than vigorous liver function. An ongoing trial randomized, multicenter, phase III study is comparing nivolumab to sorafenib in first-line treatment in patients with advanced hepatocellular carcinoma (“type”:”clinical-trial”,”attrs”:”text”:”NCT02576509″,”term_id”:”NCT02576509″NCT02576509). Pembrolizumab was also tested in pretreated, PDL1 positive, adenocarcinoma Speer4a of the gallbladder and biliary tract – excluding ampullary carcinomas – with promising results; RR of 17% and SD of 17%. CRC As previously mentioned, various phase I trials of anti-CTLA4 or anti-PD1 agents in CRC HA14-1 came to naught, even in patients with PD-L1 positive tumors[19-21]. Only one heavily pretreated patient presented a remarkable response to nivolumab and this patient was later found to harbour a MMR-deficient CRC. As such, one phase II study demonstrated significant RR (40%) in MMR-deficient CRC patients versus 0% in MMR proficient CRC patients treated with pembrolizumab. Therefore, MMR status is now believed to be a valuable predictor of response to.