Background Metformin is one of the biguanides commonly used in patients with type II Diabetes Mellitus. Apart from its hypoglycemic properties, metformin also inhibits the cell cycle by restricting protein synthesis and cell proliferation via regulating the LKB1/AMPL pathway. Furthermore, it also enhances the PD-1 blockade through a reduction of tumor hypoxia. Metformin has shown a significant favorable impact on treatment-related outcomes in solid tumors, but these outcomes have not been replicated in the limited clinical studies done on malignant melanoma. Moreover, none of these studies have reported on the efficacy of the combined use of metformin and immune checkpoint inhibitors (ICIs). Methods This is a retrospective cohort study that includes patients diagnosed with metastatic malignant melanoma and treated with ipilimumab, nivolumab, and/or pembrolizumab (Cohort A); or ipilimumab, nivolumab, and/or pembrolizumab plus metformin (Cohort B) between January 1st 2011 through December 15th 2017. In this study, patients are stratified based on anti-PD-1 only and anti-CTLA4/anti-PD-1 combination therapies in each cohort. Objective response rate (ORR) is the primary endpoint. Disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) are the secondary endpoints. Results Cohort A had 33 patients (60%), while cohort B had 22 (40%). Overall patient characteristics were similar between both cohorts. ORR was higher in cohort B (68.2% vs. 54.5%, P = 0.31). The DCR was higher in cohort B as well (77.3% vs. 60.6%, P = 0.19). Median OS (46.7 months vs. 28 months), and median PFS (19.8 months vs. 5 months) were longer in cohort B. However, on univariate and multivariate analyses, none of these differences were statistically significant. The mean number of new metastatic sites which appeared during therapy were significantly higher in cohort A (A:1.51 vs. B:0.59, P = 0.009). Conclusion We have observed favorable treatment-related outcomes (ORR, DCR, median PFS and median OS) in patients who have received metformin in combination with ICIs without reaching significance, probably, due to small sample size. Hence, large prospective clinical trials are required to study the synergistic effect of metformin in combination with ICIs before it can be recommended as routine additive therapy.

Aim: To study the clinical benefits of concurrent metformin and immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer patients. Materials & methods: This is a retrospective review of 50...

Denosumab is a monoclonal antibody against RANK ligand with a role in the prevention of skeletal-related events and is also known to possess antitumor properties. In this retrospective review, we aim to evaluate the synergist effect of a combination therapy with immune checkpoint inhibitors and denosumab in malignant melanoma patients. Patients of 18 years of age or older with a diagnosis of malignant melanoma who have received immune checkpoint inhibitors and denosumab between June 2015 and May 2017 were divided into two cohorts: cohort A (immune checkpoint inhibitors only) and cohort B (immune checkpoint inhibitors and denosumab). Overall survival, progression-free survival, objective response rate, and safety analysis were performed. Stratified analysis based on metastatic (M) status was performed as well. Eleven (29.72%) out of 37 patients received immune checkpoint inhibitors and denosumab combination. Median overall survival in cohort B was 57 months compared with 22.8 months in cohort A and 22 months in M1c patients from cohort A. Median progression-free survival was 4.15 months in cohort B compared with 11.6 months in cohort A and 5.12 months in M1c patients from cohort A. The mean number of distant sites involved in metastasis were significantly higher in cohort B (3.54 vs. 2.23, P=0.0015). Cohort B also had more patients with more than two distant metastatic sites (90.9 vs. 30.8%, P=0.001). A combination therapy with denosumab and immune checkpoint inhibitors may have a beneficial effect on survival and progression as in our study; the patients receiving combination therapy did not behave poorly despite having poor prognostic features.

Background: Randomized phase II and III studies showed the promising results of the combination of carboplatin/pemetrexed with pembrolizumab in non-squamous non-small cell lung cancer patients. Patients with brain metastases were excluded from the phase II study. After FDA approval, this regimen was adopted early at our institution, including a use in patients with brain metastases. We report real-world use of this regimen in a single medical center. Methods: This is a retrospective cohort study that includes patients with advanced non-squamous non-small cell lung cancer diagnosed and treated with carboplatin/pemetrexed (Cohort A) or carboplatin/pemetrexed plus pembrolizumab (Cohort B) between January 1st, 2016 till December 15th, 2017. Objective response rate (ORR) was the primary endpoint. Progression-free survival (PFS), disease control rate (DCR) were the secondary endpoints. Results: A total of 54 patients were included (cohort A =37 vs. cohort B =17). ORR was 53.3% in cohort B vs. 40.5% in cohort A (P=0.41). DCR was significantly higher in cohort B (86.7% vs. 54%, P=0.02). PFS was also higher in cohort B (P= 0.009, HR 0.22). Similar proportion of patients had brain metastases in each cohort (A: 32.4% vs. B: 35.3%, P=0.83). ORR was higher in patients with brain metastases from cohort B (B: 80% vs. A: 58.3%, P=0.75). Significantly higher proportion of the patients with brain metastases progressed in cohort A (A: 91.7% vs. B: 33.3%, P=0.009). Conclusions: The combination of carboplatin and pemetrexed with pembrolizumab showed promising results in a real world setting in patients with NSCLC with and without brain metastases that are in line with the reported results of phase II and III studies. Most significant benefit was observed in preventing progression and achieving the disease control.

Background Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. Case Presentation A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months9 post-treatment and continues to do well without any evidence of active disease. Conclusion Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.

The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors’ effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions.