Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations.

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

Background: Gastric squamous cell carcinoma (GSCC) and gastric adenosquamous carcinoma (GASC) comprise less than 2% of gastric cancers. The current knowledge about clinical presentation, treatment modalities and outcomes of GSCC and GASC is limited. The aim of this study is to characterize the clinicopathological features, treatment modalities, and outcomes of GSCC and GASC in comparison to gastric adenocarcinoma (GAC) in National Cancer Database (NCDB). Methods: Patients with GSCC, GASC and GAC between 2004 and 2013 were identified using ICD-O-3 histology and topography codes 8070/3, 8560/3, 8140/3 and C16.0-9. Univariate, and multivariate analysis were performed, and Kaplan-Meier curves was used to compare survival based on histological subtype. Results: A total of 61,215 patients were identified, 836 (1.4%) GSCC, 327 (0.5%) GASC, 60,052 (98.1%) GAC between 2004 and 2013, in which 77.4% was Caucasian and 68.7% was male, 46.6% of tumors were in gastric cardia and 13.7% in gastric antrum. Neoadjuvant and adjuvant chemotherapy was administered in 11.2%, 14.1%, 8.9% vs. 2.9%, 11.9%, 9.5% for GSCC, GASC, GAC. Surgery was performed in 26.0%, 54.4%, 45.2% of GSCC, GASC, GAC. Radiotherapy was administered in 48.1%, 37.6%, 31.6% of GSCC, GASC, GAC. Median overall survival was 8.9, 9.9 and 13.2 months for GSCC, GASC, GAC. On multivariate analysis squamous cell (HR =1.14; 95% CI, 1.06–1.24, P=0.001) and adenosquamous cell histology (HR =1.52; 95% CI, 1.35–1.73, P<0.001) was associated with worse survival compared to adenocarcinoma. Conclusions: GSCC and GASC have poorer survival outcomes compared to GAC. Less patients with GSCC received surgery and adjuvant chemotherapy, more patients with GSCC received radiation therapy.