Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer.

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.

Changes in Prescribing Patterns in Stage III Colon Cancer.

BACKGROUND: For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. PATIENTS AND METHODS: To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. RESULTS: A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). CONCLUSIONS: Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report.

INTRODUCTION: Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported; however, there are no established systemic therapy regimens for unresectable or metastatic FLC. CASE PRESENTATION: We report a case of a 23-year-old woman with FLC who presented with a 11.5 × 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. DISCUSSION/CONCLUSION: For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.

Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology.

Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.

Evolving Role of Immunotherapy in Advanced Biliary Tract Cancers.

Biliary tract cancers (BTC) comprise a rare and diverse group of malignancies that involve the gallbladder and biliary tree. These cancers typically present in later stages because they are aggressive in nature and affected patients are often asymptomatic in earlier stages of disease. Moreover, BTCs are generally refractory to cytotoxic chemotherapy, which further contributes to their associated poor survival outcomes. Novel therapy approaches are clearly needed. Molecular targeted agents have been developed based on our expanding knowledge of the genetic mutations underlying BTCs and represent a promising treatment strategy in molecularly selected subgroups of patients. In addition, the advent of immunotherapy over recent years has dramatically changed the bleak outcomes observed in malignancies such as melanoma. Our growing understanding of the complex tumor microenvironment in BTC has identified mechanisms of tumor immune evasion that could potentially be targeted with immunotherapy. As a result, different immunotherapeutic approaches including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, have been investigated. The use of immunotherapeutic agents is currently only approved for a small subset of treatment-refractory BTCs based on microsatellite instability (MSI) status and tumor mutational burden (TMB), but this will likely change with the potential approval of immunotherapy plus chemotherapy as a result of the TOPAZ-1 trial.

Total neoadjuvant therapy approach in rectal adenocarcinoma.

The treatment of locally advanced rectal cancer has improved over the years owing to advancements in surgical techniques and chemoradiation, developing into a multidisciplinary approach that has contributed to markedly reduced rates of local recurrence. Despite these advances, however, distant metastatic recurrence continues to be the main cause of rectal cancer-related death. Unfortunately, the former standard of care of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy is still associated with significant morbidity and distant relapse rates. Many trials have studied the optimal sequence, timing, and duration of the individual components of treatment, more recently shifting both chemoradiation and systemic chemotherapy to the preoperative setting in an approach termed total neoadjuvant therapy (TNT). Some of the potential advantages of TNT include improved adherence to treatment, early treatment of micrometastases, and tumor downstaging, with the possibility of observation instead of surgery for those patients with a complete clinical response. This review provides the historical context for the shift to TNT in the treatment paradigm and discusses the critical clinical trials supporting the newer strategy. It also addresses the recent focus on the personalization of care that TNT makes possible by allowing the selective omission of radiation therapy and nonoperative management with a watch-and-wait strategy.

A case report of paraneoplastic syndrome in ß-hCG-secreting duodenal adenocarcinoma.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is used in clinical practice to detect pregnancy and serves as a sensitive marker for trophoblastic tumors. Other organs besides placental trophoblasts naturally express the hormone at low levels, which can be elevated in nontrophoblastic malignancies. Some studies have suggested that elevated ß-hCG levels in nontrophoblastic tumors are a sign of aggressive disease and strongly associated with poor prognosis. We describe a case of a 50-year-old post-menopausal woman with metastatic duodenal adenocarcinoma who presented with a negative pregnancy test that later changed to positive. Biopsy of the primary duodenal mass showed positive immunohistochemical expression of ß-hCG. The patient was also found to have multiple brain metastases, which is uncommon in gastrointestinal cancer. This is a rare case of paraneoplastic syndrome in a ß-hCG-secreting duodenal adenocarcinoma.

Distinct Effects of Left or Right Atrial Cannulation on Left Ventricular Hemodynamics in a Swine Model of Acute Myocardial Injury.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and the TandemHeart left ventricular (LV) assist device are increasingly employed as mechanical circulatory support devices during acute LV injury. We examined the effects of right atrial to femoral artery (RA-FA; VA-ECMO) bypass versus left atrial to femoral artery (LA-FA; TandemHeart) bypass using a centrifugal pump (Cardiac Assist Inc, Pittsburgh, PA) on LV hemodynamics in a swine model of acute LV injury. In eight male swine, the RA-FA bypass group employed a 21 Fr inflow cannula in the right atrial (RA) and a 17 Fr FA outflow cannula. The LA-FA bypass group employed a 21 Fr inflow cannula in the LA and a 17 Fr FA outflow cannula. Both pump configurations were activated at 3,500 rotations per minute (RPMs) followed by balloon angioplasty-mediated occlusion of the left circumflex (LCx) artery. After 30 minutes of LCx occlusion, RPMs through the centrifugal pump were increased from 3,500, 5,500 then to a maximum at 7,500 RPMs. At 7,500 RPMs, RA-FA and LA-FA bypass generated 3.5 ± 0.1 and 3.6 ± 0.2 liters/minute (LPM) of flow, respectively. At maximum flow, RA unloading increased LV end-systolic pressure and estimated wall stress, whereas LA unloading reduced LV end-diastolic pressure, end-diastolic volume, and native stroke volume without changing estimated wall stress. Veno-arterial extracorporeal membrane oxygenation acutely increases mean arterial pressure (MAP) without unloading the LV, whereas the TandemHeart maintains MAP and unloads the LV. These findings indicate that RA versus LA cannulation for circulatory support have distinct acute hemodynamic effects on the LV.

Gastroenterologists Have Suboptimal Hepatitis B Virus Screening Rates in Patients Receiving Immunosuppressive Therapy.

BACKGROUND AND AIMS: Hepatitis B reactivation in patients undergoing immunosuppressive therapy can lead to liver failure and death. Prior studies have shown suboptimal hepatitis B screening rates, but few have compared screening rates across specialties or factors associated with screening. METHODS: A retrospective study was performed using a hospital-based chemotherapy database and outpatient pharmacy records from January 1999 to December 2013. HBV screening rates prior to initiation of immunosuppression were determined. Multivariate analysis was used to determine predictors of HBV screening. RESULTS: Of the 4008 study patients, 47 % were screened prior to receiving immunosuppressive therapy; only 48 % on rituximab and 45 % of those on anti-TNF therapy were screened. Transplant specialists screened most frequently (85 %) while gastroenterologists screened the least (34 %). Factors significantly associated with HBV screening were younger age, Asian race, use of anti-rejection therapy, and treatment by a transplant specialist (p < 0.001). CONCLUSION: HBV screening prior to immunosuppressive therapy is suboptimal, especially among gastroenterologists. Efforts to improve screening rates in at risk populations are needed.