Delayed immune-related hepatitis after 24 months of pembrolizumab treatment: a case report and literature review.

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1) pathway have revolutionized cancer immunotherapy by enhancing the immune system's ability to combat cancer cells. However, this innovative approach comes with a distinctive set of challenges, as these therapies can lead to immune-related adverse events (irAEs) due to their mechanism of action. The most common irAEs involve the skin, gastrointestinal tract, liver, endocrine system, and lungs. These events can range from mild skin rashes to severe colitis, pneumonitis, or even autoimmune organ damage. These adverse effects usually appear with an average of 5-15 weeks from the start of treatment depending on the affected organ. This article presents a case report of a delayed related-mediated hepatitis, after 24 months of treatment with pembrolizumab and almost 3 months after its termination, and a review of the scientific literature on cases of delayed immune-related hepatitis caused by anti-PD1. This case highlights the importance of monitoring patients treated with immune checkpoint inhibitors after cessation as a growing number of patients stop treatment due to achieving durable responses.

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Lung cancer patients with COVID-19 in Spain: GRAVID study.

INTRODUCTION: Patients with cancer may be at increased risk of more severe COVID-19 disease; however, prognostic factors are not yet clearly identified. The GRAVID study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. METHODS: Prospective observational study that included medical records of patients with lung cancer and PCR-confirmed COVID-19 diagnosis across 65 Spanish hospitals. The primary endpoint was all-cause mortality; secondary endpoints were hospitalization and admission to intensive care units (ICU). RESULTS: A total of 447 patients with a mean age of 67.1 ± 9.8 years were analysed. The majority were men (74.3 %) and current/former smokers (85.7 %). NSCLC was the most frequent type of cancer (84.5 %), mainly as adenocarcinoma (51.0 %), and stage III metastatic or unresectable disease (79.2 %). Nearly 60 % of patients were receiving anticancer treatment, mostly first-line chemotherapy. Overall, 350 (78.3 %) patients were hospitalized for a mean of 13.4 ± 11.4 days, 9 (2.0 %) were admitted to ICU and 146 (32.7 %) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-end-of-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. CONCLUSIONS: Mortality rate was higher among patients treated with corticosteroids during hospitalization, while anticancer therapy was not associated with an increased risk of hospitalization or death. Tailored approaches are warranted to ensure effective cancer management while minimizing the risk of exposure to SARS-CoV-2.

The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer.

Introduction: Lung cancer is the leading cancer-related cause of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has significantly improved the outcome of these patients. Pembrolizumab, a monoclonal IgG4-kappa antibody against programmed-death-1 (PD-1) protein, nowadays represents a standard of care for NSCLC patients. Although it has a favorable toxicity profile, some immune-related adverse events (irAEs) can be life-threatening, therefore its knowledge may help to optimize the care of these patients.Areas covered: The authors review data regarding the efficacy and safety of pembrolizumab from the most relevant clinical trials as well as toxicities reported in the clinical use. Special considerations of use in special populations will be noted. Finally, its toxicity profile will be compared with other ICIs used in NSCLC.Expert opinion: In the scenario of NSCLC, pembrolizumab shows a favorable safety profile with less than 10% serious immune-related adverse events (irAEs) when used in monotherapy and without adding relevant extra-toxicity to chemotherapy when used in combination. Monotherapy with pembrolizumab is associated with better health-related quality of life than chemotherapy. Early recognition and appropriate treatment of irAEs is of prime importance as most are reversible if correctly managed. Rechallenge with pembrolizumab is frequently feasible.