KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): Characteristics, treatment patterns and overall survival from a Danish nationwide observational register study.

OBJECTIVES: We aimed to characterize the advanced NSCLC population in terms of KRAS G12C prevalence, patient characteristics, and survival outcomes after the introduction of immunotherapies. MATERIALS AND METHODS: We identified adult patients diagnosed with advanced NSCLC between January 1, 2018 and June 30, 2021 using the Danish health registries. Patients were grouped by mutational status (any KRAS mutation, KRAS G12C, and KRAS/EGFR/ALK wildtype [Triple WT]). We analyzed KRAS G12C prevalence, patient and tumor characteristics, treatment history, time-to-next-treatment (TTNT), and overall survival (OS). RESULTS: We identified 7,440 patients of whom 40% (n = 2,969) were KRAS tested prior to the first line of therapy (LOT1). Among the KRAS tested, 11% (n = 328) harbored KRAS G12C. More KRAS G12C patients were women (67%), smokers (86%), had a high (≥50%) level of PD-L1 expression (54%), and more frequently received anti-PD-L1 treatment than any other group. From the date of the mutational test result, OS (7.1-7.3 months) was similar between the groups. OS from LOT1 (14.0 months) and LOT2 (10.8 months), and TTNT from LOT1 (6.9 months) and LOT2 (6.3 months) was numerically longer for the KRAS G12C mutated group compared to any other group. However, from LOT1 and LOT2, the OS and TTNT were comparable when stratifying the groups by PD-L1 expression level. Regardless of the mutational group, OS was markedly longer for patients with high PD-L1 expression. CONCLUSION: In patients diagnosed with advanced NSCLC after the implementation of anti-PD-1/L1 therapies, the survival in KRAS G12C mutated patients is comparable to patients with any KRAS mutation, Triple WT, and all NSCLC patients.

Immunotherapy in pituitary carcinomas and aggressive pituitary tumors.

After temozolomide failure, no evidence-based treatment option is currently available for aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs). Moreover, once temozolomide has failed, the survival of these patients is very poor. The use of immune-checkpoint inhibitors (ICIs) has been so far reported in a large cohort, a small phase 2 clinical trial, and in another five isolated cases (24 cases in total). Here, we review the available evidence on the efficacy and potential predictors of response to ICIs in PCs and APTs, namely the histological type (corticotroph versus lactotroph), the tumor type (PC versus APT), the presence of uncontrolled endogenous hypercortisolism, the type of protocol (combined ICIs versus monotherapy), programmed death-ligand 1 (PD-L1) expression, CD8+ cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) status. We also discuss key clinical aspects that can already be implemented in the everyday practice and identify future research needs.

Clinical observation of pulmonary lymphoepithelioma-like carcinoma.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) of the lung is a rare type of non-small cell lung cancer (NSCLC), and researches of it are still not enough. METHODS: In this study, we retrospectively analyzed 36 patients with LELC diagnosed in the Fifth Affiliated Hospital of Sun Yat-sen University and Zhaoqing First People's Hospital from January 2014 to June 2021, to investigate the clinical manifestations, tumor markers, treatment, and prognosis of LELC. Clinical data including age, gender, smoking history, family history of cancers, Epstein-Barr virus (EBV) encoding RNA (EBER) status, gene mutations, programmed death-ligand 1 (PD-L1) expression, treatment, and prognosis. RESULTS: There was a total of 36 participants in this study, 16 males and 20 females, the median age was 57 years (37-76 years). A total of 22 cases (61.1%) were advanced (stage III and IV), and EBER was 94.4% positive. Most patients were treated with surgery, platinum chemotherapy, or radiotherapy. At the time of 31 June 2021, 33 participants had survived, and the longest survival time was 72 months. Lung LELC was more common in old participants (≥59 years) and was not associated with smoking history. Expression of PD-L1 was positive in the majority (27 cases, 75%) and participants with positive PD-L1 expression tended to have longer progression-free survival (PFS) and overall survival (OS) time than those with negative PD-L1 expression. CONCLUSIONS: Pulmonary LELC usually occurs in non-smoking patients and is associated with EBV infection. Common treatments for tumors include multimodal therapy. The expression of PD-1 may be related to the prognosis of LELC, but more studies are needed to support further optimization of the treatment of LELC.

Clinical outcomes of pembrolizumab therapy in advanced-NSCLC patients with poor performance status (≥3) and high PD-L1 expression (TPS ≥50%): A case series.

Pembrolizumab is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression tumor proportion score (TPS) ≥50%. The benefit of pembrolizumab in patients with advanced NSCLC and poor performance status (PS ≥3) is limited, even when the tumor is PD-L1-expression-positive. We retrospectively reviewed a total of four NSCLC cases with high PD-L1 expression (TPS ≥50%) and poor PS. The only patient with very high PD-L1 expression (TPS 100%) responded to pembrolizumab, but none of the three patients with high PD-L1 expression (50%-80%) responded to pembrolizumab. In conclusion, pembrolizumab can serve as a treatment option for patients with poor PS, if PD-L1 expression TPS is 100%.

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.

BACKGROUND: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-ß levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-ß could be a predictive biomarker for response to pembrolizumab.

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC.

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Predictive biomarkers of immunotherapy for non-small cell lung cancer: results from an Experts Panel Meeting of the Italian Association of Thoracic Oncology.

Unleashing the potential of immune system to fight cancer has become one of the main promising treatment modalities for advanced non-small cell lung cancer (NSCLC). The knowledge of numerous factors that come into play in the cancer-immunity cycle provide a wide range of potential therapeutic targets, including monoclonal antibodies that inhibits the programmed death-1 (PD-1) checkpoint pathway. Over the last two years, nivolumab, pembrolizumab and atezolizumab received approval for treatment of pretreated advanced NSCLC, and more recently, immunotherapy with pembrolizumab is the new standard of care as first-line in patients with high levels of programmed death-ligand 1 (PD-L1) expression. Selection of patients is mandatory and PD-L1 is the only biomarker currently available in clinical practice. However, PD-L1 staining is an imperfect marker, whose negativity does not exclude a response to immunotherapy, as well as the roughly half of patients are "not-responders" despite high tumor PD-L1 levels. The right cut-off, the differences among various immune checkpoint inhibitors and among various antibody clones, and a not trivial activity reported even in PD-L1 negative tumors are questions still open. New biomarkers beyond to PD-L1 assays as well as new strategies, including combination of immune checkpoint inhibitors are under investigation.