Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

The Impact of Poorly Differentiated Histology on Immunotherapy in Advanced Gastrointestinal Cancers.

INTRODUCTION: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have shown a correlation between immune cell infiltration and poorly differentiated cancers. This study evaluated the impact of poorly differentiated histology on survival in patients with advanced gastrointestinal cancers treated with immunotherapy. METHODS: This study was a retrospective, single-center analysis of patients with gastrointestinal cancers treated with CPIs between 2016 and 2021. Univariate and multivariable analyses were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor and patient characteristics, progression-free survival, and overall survival. RESULTS: A total of 123 patients were eligible and included in the analysis. Median age was 66 years (23-88 years). Majority had stage IV disease (89%), were white (65.5%), and were male (64.5%). Most common diagnoses were hepatocellular carcinoma (30.5%), gastric adenocarcinoma (16.5%), esophageal adenocarcinoma (17%), and colorectal cancer (19.8%). About 32% of the tumors were microsatellite instability-high (MSI-High/dMMR), with BRAF V600E mutation rate of 10%. About 25% of the patients received CPIs as initial treatment, while 35.5% had received two or more prior lines of therapy. Compared with well and moderately differentiated histology, patients with poorly differentiated tumors had a shorter median overall survival (mOS) (not reached [NR] vs. NR vs. 9.3 months, p = 0.0264). There was no statistically significant difference in median progression-free survival (mPFS) between histology types (2.5 vs. 4.2 vs. 2 months, p = 0.1314). On univariate survival analysis, moderately differentiated tumors correlated with a significantly longer mOS (HR: 0.48, CI: 0.24-0.93, p = 0.030) and mPFS (HR: 0.62, 95% CI: 0.38-1.00, p = 0.048) compared to poorly differentiated histology. Female patients (HR: 0.55, 95% CI: 0.34-0.90, p = 0.018) and the Eastern Cooperative Oncology Group (ECOG) of 1 (vs. ≥2) had significantly longer mPFS (HR: 0.58, 95% CI: 0.35-0.97, p = 0.036). ECOG of 1 also correlated with longer mOS (HR: 0.47, 95% CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, 95% CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, 95% CI: 1.64-18.12, p = 0.006). The number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, 95% CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, 95% CI: 1.01-1.50, p = 0.045). On multivariable analyses, ECOG status of 0/1 versus ≥2 and MSI-High/dMMR versus MSS remained significantly associated with longer mPFS and mOS. There was no correlation with histologic differentiation status, race, or mutations such as BRAF V600E or KRAS. CONCLUSION: Results from this study demonstrate that poorly differentiated histology was associated with shorter mOS but was not associated with improved PFS in patients treated with CPI. Treatment-naïve patients, moderately differentiated tumors, female gender, ECOG 1, and MSI-High/dMMR were most likely to benefit from CPI.

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.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer Living With HIV: A Perspective on Recent Progress and Future Needs.

Recent studies have identified durable responses with the use of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). The dramatic improvement in clinical outcomes led to the US Food and Drug Administration approval of pembrolizumab, nivolumab, and nivolumab in combination with ipilimumab in metastatic patients with MSI-H/MMR-D CRC who previously experienced progression on cytotoxic therapies. In the clinical trials investigating these agents, HIV-seropositive patients were not included and therefore the clinical efficacy of these agents in patients with metastatic MSI-H/MMR-D CRC living with HIV is unclear. On the basis of growing evidence, immune checkpoint blockade therapies seem to be a safe approach in patients with well-controlled HIV infection. Research on immunotherapeutic approaches in patients living with HIV and cancer is an area of unmet medical need that can be addressed by clinical trial designs that are inclusive of patients with well-controlled seropositive HIV and trials that specifically evaluate immune therapies in patients living with HIV.

Pancreatic Ductal Adenocarcinoma: Characteristics of Tumor Microenvironment and Barriers to Treatment.

Pancreatic ductal adenocarcinoma remains a highly aggressive disease, with a 5-year relative survival rate of 10%. Numerous barriers to treatment exist, such as dense desmoplasia, infiltration of immune suppressor cells, inhibitory cytokines, low effector T-cell infiltration, and low tumor mutational burden. These factors help form a highly suppressive tumor microenvironment unique to pancreatic ductal adenocarcinoma. This review outlines barriers to treatment of pancreatic ductal adenocarcinoma by discussing the unique characteristics of the pancreatic tumor microenvironment and the factors that contribute to making pancreatic ductal adenocarcinoma such a challenging disease to treat.