Pembrolizumab is widely used in first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC) with high PD-L1 expression. The activity of pembrolizumab in NSCLC patients with rare molecular alterations is poorly characterised. RET gene rearrangements are identified in 1–2% of lung cancer patients. Here, we present two cases of RET-rearranged NSCLC patients with high PD-L1 expression (>50%), treated with pembrolizumab within routine clinical practice. Pembrolizumab was ineffective in both cases—single-agent immunotherapy seems to be of limited value in this group of patients. Selective RET-inhibitors, if available, are the optimal treatment for patients with RET fusion nowadays. The best sequence of the therapy is still not defined.
Advanced squamous-cell lung carcinoma remains a disease with an unfavorable prognosis. Until recently, chemotherapy was used in systemic treatment, and its effectiveness was limited. Implementation of immune check-point inhibitors allowed for an improvement in treatment results. The KEYNOTE-407 study included patients with squamous-cell lung cancer who received 4 immunochemotherapy cycles followed by maintenance treatment with pembrolizumab. Median overall survival of 17.2 months versus 11.6 months for chemotherapy was obtained (risk of death reduction by 29%) while the percentage of patients remaining in follow-up was 18%. Analysis of patients with good performance status treated in clinical practice confirms the results from the registration study and emphasizes the importance of taking into consideration clinical factors while qualifying patients for treatment.
Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC.
Background: The biology of thymic epithelial tumors (TETs), in particular, the extent of dysregulation in their molecular landscape is poorly understood. Development of newer therapies based on genomic alterations could potentially revolutionize treatment of TETs and result in improved clinical outcomes. The frequency and specificity of candidate biomarkers should be evaluated according to distinct TET types and stages. The aim of our pilot study was to evaluate thymic carcinomas and thymomas by next-generation sequencing (NGS) for single nucleotide variants (SNVs) in 15 genes that are commonly mutated in solid tumors. Methods: Formalin-fixed paraffin-embedded tumor tissue specimens were collected from 40 cases of TETs (33 thymic carcinomas, 7 thymomas) and analyzed for SNVs in 15 genes using targeted NGS. DNA libraries were constructed using the TruSight Tumor 15 assay (Illumina) and sequenced on the MiSeq instrument (Illumina). Results were analyzed using the BaseSpace Variant Interpreter software (Illumina) and the reference genome version hg19/GRCh37. Results: SNVs were identified in genes TP53, ERBB2, KIT and KRAS. In thymic carcinomas, the most frequent SNVs were: TP53 p.(Pro72Arg) (32/33, 97%), ERBB2 p.(Ile655Val) (16/33, 48%) and KIT p.(Met541Leu) (3/33, 9%), mostly in squamous cell subtype. In thymomas, TP53 p.(Pro72Arg) (6/7, 86%), ERBB2 p.(Ile655Val) (3/7, 43%) and KIT p.(Met541Leu) (2/7, 29%) showed also the highest frequency. Rare pathogenic missense variants in TP53 [p.(Gly154Val), p.(Arg158Pro), p.(Arg273Cys), p.(Leu194His)], ERBB2 [p.(Val773Met)], KIT [p.(Leu576Pro), p.(Ile690Val)] and KRAS [p.(Gln61Leu)], and pathogenic stop-gained variants in TP53 [p.(Arg306Ter, p.(Gln317Ter)) were found across the samples. The median read frequency of altered variants reached 58% (range, 5–100%) in carcinomas and 54% (range, 51–100%) in thymomas. Conclusions: The NGS analysis of TET specimens revealed a vast number of SNVs in genes playing important role in p53, AKT, MAPK and K-Ras signaling pathways, which are deregulated in many solid tumor types. The uncertain biological and clinical importance of TP53 p.(Pro72Arg) and ERBB2 p.(Ile655Val) variants in TET development awaits further investigation. Detecting druggable KIT alterations in TETs showed promise for possible therapeutical targeting. The high-quality data gained in this pilot study provided a strong rationale for carrying out more comprehensive genomic profiling of TETs. The study is ongoing.
KRAS regulates several cellular processes, such as cell proliferation, cell cycle regulation, metabolic changes, cell survival, and cell differentiation. Abnormalities in the KRAS gene are found in approximately 30% of patients with non-small cell lung cancer, usually in patients diagnosed with nonsquamous cancer and more often in Caucasian patients, women, and smokers. The p.G12C variant is most frequently found in KRAS-positive patients. Sotorasib is the first drug approved for this population. The superiority of sotorasib over docetaxel after failure of immunochemotherapy was demonstrated in the CodeBreak 200 phase III study for the primary endpoint — median progression-free survival was 5.6 months [95% confidence interval (CI) 4.3–7.8] vs . 4.5 months (3.0–5.7); hazard ratio = 0.66 (95% CI 0.51–0.86; p = 0–0017), while the 12-month progression-free survival rate was 24.8% for sotorasib and 10.1% for docetaxel. Currently, sotorasib monotherapy, at an initial dose of 960 mg/day, is indicated for use in adults with advanced non-small cell lung cancer with the KRAS p.G12C mutation who have experienced disease progression after at least one previous line of systemic treatment. More randomized trials are needed to determine the optimal place of sotorasib in the systemic treatment sequence in this patient population.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignancies. Toxicities of immunotherapy are variable, can involve almost every organ, therefore appropriate diagnosis and management of Immune Related Adverse Events (irAEs) is important. Immune-mediated pneumonitis is an uncommon, but potentially life-threatening toxicity of ICIs. Pre-existing lung disease, a history of lung radiotherapy, age > 70 years and male gender are suggested as the risk factors of pneumonitis. Dyspnoea, dry cough, fever and chest pain are typical symptoms. Diagnostic algorithms recommend radiological investigation with a chest computed tomography scan. Additional diagnostic procedures – such as pulse oximetry, spirometry, measurement of carbon monoxide diffusing capacity, bronchoscopy with BAL may be helpful. The therapeutic approach is determined by the intensity of the symptoms and CT findings. Corticosteroids and antibiotics are the drugs of choice. Hospitalisation is necessary in severe cases, and other forms of immunosuppression (infliximab, mycophenolate mofetil) may be considered. Continuation of immunotherapy can be considered with caution in patients with G1-2 toxicity, when clinical improvement was achieved and steroids were tapered.
Based on the results of the CheckMate 017 and CheckMate 057 studies, nivolumab therapy has become a new standard treatment for both squamous and non-squamous non-small-cell lung cancer (NSCLC). However, due to the specific inclusion criteria of these clinical trials, the efficacy and safety of nivolumab in real-world practice were not certain. In general, the real-world results of nivolumab treatment have been consistent with those obtained in clinical trials. Additional analyses of the real-world data have made the identification of prognostic factors possible. Good performance status is the most significant predictor of clinical benefit. Brain metastases, liver metastases, EGFR mutation, malignant pleural effusion, and a high number of metastatic sites were identified as negative prognostic factors. By contrast, a longer time to disease progression (>6 months) from the beginning of prior chemotherapy and an objective response to chemotherapy seem to have positive prognostic value in the case of nivolumab treatment. In terms of patient age, the data are inconclusive. Some blood biomarkers can also be considered significant prognostic factors.
Malignant pleural mesothelioma (MPM) is a rare, asbestos-related neoplasm with a poor prognosis. Men are more often affected than women and the incidence in males in the US is 1.5/100,000/year (according to data in the SEER database), in Turkey it is 2.88/100,000/year and in Great Britain it is 5.4/100,000/year (1,2).
