Challenges in the treatment of small cell lung cancer in the era of immunotherapy and molecular classification.

For many years the standard of care for small cell lung cancer (SCLC) has remained unchanged. Despite decades of active research, current treatment options are limited and the prognosis of patients with extended disease (ED) SCLC remains poor. The introduction of immune checkpoint inhibitors (ICIs) represents an exception and the only recent approval for ED-SCLC. However, the magnitude of benefit obtained with immunotherapy in SCLC is much more modest than that observed in other malignancies. Different pro-immunogenic or immunosuppressive features within the tumor microenvironment of SCLC may either modulate the sensitivity to immunotherapy or conversely dampen the efficacy of ICIs. Beside immunotherapy, a deeper understanding of the molecular biology of SCLC has led to the identification of new therapeutic targets for this lethal malignancy. Recent epigenetic and gene expression studies have resulted into a new molecular classification of four distinct subtypes of SCLC, defined by the relative expression of key transcription regulators and each characterized by specific therapeutic vulnerabilities. This review discusses the rationale for immunotherapy in SCLC and summarizes the main ICIs-trials in this tumor. We provide also an overview of new potential therapeutic opportunities and their integration with the new molecular classification of SCLC.

Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors.

Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.

Prognostic value of normal sodium levels in patients with metastatic renal cell carcinoma receiving tyrosine kinase inhibitors.

Background: Although serum sodium concentration, particularly hyponatremia, has been shown to be a prognostic marker of survival in metastatic renal cell carcinoma (mRCC), the impact of normal sodium levels has not been investigated. Herein, we investigate the influence of normonatremia in mRCC patients treated with tyrosine kinase inhibitors (TKIs). Materials and methods: For this retrospective study, the clinical and biochemical data of patients treated with first-line TKIs for mRCC were available from seven Italian cancer centers. We collected natremia levels at baseline and first evaluation after treatment excluding patients with sodium levels outside the normal range (<135 or >145 mEq/L). The remaining patients were subdivided into two groups according to the median sodium value: natremia patients with <140 mEq/L (n = 132) and baseline natremia patients with ≥140 mEq/L (n = 185). Subsequently, we analyzed the impact of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). PFS and OS were estimated through the Kaplan-Meier method, and differences between groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the prognostic factors for PFS and OS. Results: Of the 368 patients, 317 were included in the analysis, 73.1% were men, and the median age was 67 years (range 36-89). When comparing patients with baseline natremia ≥140 mEq/L (n = 185) to patients with natremia <140 mEq/L (n = 132), the PFS was 15 vs. 10 months (p < 0.01) and the OS was 63 vs. 36 months, respectively (p = 0.02). On the first evaluation, patients with serum sodium ≥140 mEq/L had longer PFS (15 vs. 10 months, p < 0.01) and OS (70 vs. 32 months, p < 0.01) than patients with levels <140 mEq/L. Moreover, clinical outcomes showed a significant improvement in patients with natremia ≥140 mEq/L compared with patients with levels <140 mEq/L both at baseline and first evaluation: PFS was 19 vs. 11 months (p < 0.01) and OS was 70 vs. 36 months (p < 0.01), respectively. Conclusions: To the best of our knowledge, this is the first study to investigate the impact of normonatremia in mRCC. We found that serum sodium levels <140 mEq/L at baseline and first assessment are independently associated with worse PFS and OS in mRCC patients treated with TKIs in the first-line setting.

Absolute eosinophil count predicts clinical outcomes and toxicity in non-small cell lung cancer patients treated with immunotherapy.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in non-small cell lung cancer (NSCLC) treatment. We investigated absolute eosinophil count (AEC) as a predictor of clinical outcomes and toxicity in NSCLC patients receiving ICIs. MATERIALS AND METHODS: AEC was retrospectively collected at baseline and during treatment from 158 advanced NSCLC patients treated with single agent anti-PD1/anti-PDL1 monoclonal antibody in first or subsequent line of therapy at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between January 2016 to October 2020. RESULTS: We found a significant association between high baseline AEC (≥130/µL) and better clinical outcomes. The response rates were 64.4% and 35.6% for patients with high and low AEC, respectively (p = 0.009). The high-AEC group showed a significantly longer PFS and OS than the low-AEC group (mPFS = 7.0 months, 95% CI 5.0-10.0 vs 2.5 months, 95% CI 2.0-4.0, p = 0.007 and mOS = 9.0 months, CI 95% 7.0-15.0 vs 5.5 months, 95% CI 4.0-8.0, p = 0.009, respectively). An increased risk of immune-related adverse events (irAEs) was reported in the high-AEC group (p = 0.133). IrAEs resulted an independent prognostic factor for both better outcomes (mPFS = 8.0 months, 95% CI 7.0-12.0 vs 2.0 months, 95% CI 2.0-3.0, p<0.001; mOS = 13.0 months 95% CI 9.0-19.0 vs 4.0 months 95% CI 3.0-6-0, p<0.001) and response to ICIs (response rate = 33.8% vs 14.9%, disease control rate = 72.0% vs 32.1%, p<0.001). CONCLUSION: High baseline AEC value (≥130/µL) is a predictive biomarker of clinical benefit and irAEs occurrence in NSCLC patients treated with ICIs.

Castration-resistant prostate cancer with bone metastases: toward the best therapeutic choice.

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients.

Beyond Conventional: The New Horizon of Targeted Therapy for the Treatment of Advanced Non Small Cell Lung Cancer.

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.