Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Sterotactic Ablative Radiotherapy in a Multicentric Series of Oligometastatic SCLC: The SAMOS Cohort.

AIMS: SCLC is the most aggressive lung cancer histology with a 5-year OS <10%. At the diagnosis, almost two-thirds of the SCLC an Extended Disease presentation. Two randomized studies (CASPIAN and ImPower133) demonstrated an OS improvement, when immunotherapy was prescribed as maintenance therapy after standard chemotherapy. To date, SABR has had a limited indication in managing metastatic SCLC, although recent reports proposed it as a valid treatment option in selected patients. We propose a retrospective multicentric analysis of patients treated with SABR for oligometastatic SCLC. METHOD: Data of patients affected by oligometastatic-SCLC treated with SABR between 2017 and 2022 in 11 Italian centers were collected. Clinical and therapeutic variables together with OS and time to next treatment were analyzed. Univariate analysis with Kaplan-Meier curve were calculated, and log-rank test were applied. Cox proportional hazard model was used for multivariate analysis. RESULTS: Data from 93 patients and 132 metastatic lesions were analyzed. The median age was 64 years (36-86) and all but 1 had Performance Status 0 or 1. Fifty-two patients presented ED at diagnosis. The first line treatment was radiochemotherapy in 42%, CHT alone in 24% and CHT-IO in 28%, others treatment accounts for 4% and only 2% of patients underwent best supportive care. Of the 132 lesions treated with SBRT 55 were in brain, 27 in lung, 11 in liver, 10 in lymph nodes, 8 in bones and 20 in adrenal gland. Median OS was 14 months, 1 year-OS and 2 years OS were 53% and 27%, respectively. The median TtNT was 14 months for the entire population. Of all the analyzed variables only, the anatomical site of the metastases and their number showed statistical significance in the univariate analysist, confirmed in the subsequent multivariate. CONCLUSION: SABR seems to play a role in delaying further systemic lines in oligometastatic disease and to extend the use of ongoing treatment in oligoprogressive state. Prospective studies are needed to confirm these findings.

Novel Therapeutic Options for Small Cell Lung Cancer.

PURPOSE OF REVIEW: The aim of this review is to focus on the recent advances in the molecular knowledge of small cell lung cancer (SCLC) and potential promising new treatment strategies, like targeting the DNA damage pathway, epigenetics, angiogenesis, and oncogenic drivers. RECENT FINDINGS: In the last few years, the addition of immunotherapy to chemotherapy has led to significant improvements in clinical outcomes in this complex neoplasia. Nevertheless, the prognosis remains dismal. Recently, numerous genomic alterations have been identified, and they may be useful to classify SCLC into different molecular subtypes (SCLC-A, SCLC-I, SCLC-Y, SCLC-P). SCLC accounts for 10-20% of all lung cancers, most patients have an extensive disease at the diagnosis, and it is characterized by poor prognosis. Despite the progresses in the knowledge of the disease, efficacious targeted treatments are still lacking. In the near future, the molecular characterisation of SCLC will be fundamental to find more effective treatment strategies.

An Overview of PARP Resistance in Ovarian Cancer from a Molecular and Clinical Perspective.

Epithelial ovarian cancer (EOC), a primarily high-grade serous carcinoma (HGSOC), is one of the major causes of high death-to-incidence ratios of all gynecological cancers. Cytoreductive surgery and platinum-based chemotherapy represent the main treatments for this aggressive disease. Molecular characterization of HGSOC has revealed that up to 50% of cases have a deficiency in the homologous recombination repair (HRR) system, which makes these tumors sensitive to poly ADP-ribose inhibitors (PARP-is). However, drug resistance often occurs and overcoming it represents a big challenge. A number of strategies are under investigation, with the most promising being combinations of PARP-is with antiangiogenetic agents and immune checkpoint inhibitors. Moreover, new drugs targeting different pathways, including the ATR-CHK1-WEE1, the PI3K-AKT and the RAS/RAF/MEK, are under development both in phase I and II-III clinical trials. Nevertheless, there is still a long way to go, and the next few years promise to be exciting.

Duration of Immunotherapy in Non-Small Cell Lung Cancer Survivors: A Lifelong Commitment?

Lung cancer is one of the most common human malignancies and the leading cause of cancer-related death worldwide. Novel therapeutic approaches, like targeted therapies against specific molecular alterations and immunotherapy, have revolutionized in the last decade the oncological outcomes in patients affected by non-small cell lung cancer (NSCLC). The advent of immunotherapy for the treatment of NSCLC has significantly improved overall and progression-free survival, as well as the patient's quality of life in comparison to traditional chemotherapy. Currently, it is estimated that long-term survival can be achieved in more than 15% of NSCLC patients treated with immunotherapy. Therefore, the optimal duration of immunotherapy in long survivors needs to be established to avoid overtreatment, side effects, and high costs and at the same time, protect them from potential disease relapse or progression. We performed a narrative review to discuss all the aspects related to the optimal duration of immunotherapy in long survivors with NSCLC. Data regarding the duration of immunotherapy in the most impacting clinical trials were collected, along with data regarding the impact of toxicities, side effects, and costs for healthcare providers. In addition, the two-year immunotherapy scheme in patients who benefit from first-line or subsequent treatment lines are examined, and the need for biomarkers that can predict outcomes during and after immunotherapy cessation in patients affected by NSCLC are discussed.

Harnessing DLL3 inhibition: From old promises to new therapeutic horizons.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. The combination of chemotherapy and immune-checkpoint inhibitors brings a new therapeutic era, although the lack of predictive biomarkers of response reduces the efficacy of applying the treatment to the entire population of patients with SCLC. The lack of treatments able to bind to a specific target has always been a substantial difference to the non-small cell lung cancer (NSCLC) counterpart. Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.

A Cast of Shadow on Postoperative Radiotherapy for pIIIA-N2 Non-Small Cell Lung Cancer?

This Viewpoint discusses 2 recent randomized clinical trials evaluating the role of mediastinal postoperative radiotherapy in patients with non­small cell lung cancer.

Sneaky Diagnosis of Pleural Malignant Mesothelioma in Thoracic Surgery: All That Glitters Is Not Gold.

Malignant Pleural Mesothelioma (MPM) is a highly aggressive disease whose diagnosis could be challenging and confusing. It could occur with atypical presentations on every examined level. Here, we present three unconventional cases of the complex diagnostic process of MPM that we have experienced during routine practice: a patient with reactive mesothelial hyperplasia mimicking MPM, an unexpected presentation of MPM with persistent unilateral hydropneumothorax, a rare case of MPM in situ. Then, we review the relevant literature on each of these topics. Definitive biomarkers to confidently distinguish MPM from other pleural affections are still demanded. Patients presenting with persistent hydropneumothorax must always be investigated for MPM. MPM in situ is now a reality, and this raises questions about its management.

Anti PD-L1 antibody: is there a histologic-oriented efficacy? Focus on atezolizumab in squamous cell non-small cell lung cancer.

Squamous cell lung cancer (SqCLC) is the second most common histotype of non-small cell lung cancer (NSCLC) and is characterized by severe prognosis and lack of specific target agents. Atezolizumab is the first anti Programmed Death Ligand-1 (PDL-1) inhibitor approved for NSCLC patients of both histology in case of disease progression after first or further lines of therapy. Numerous studies are investigating the potential role of atezolizumab in different therapeutic setting, including SqCLC subtype. We searched for published clinical trials in Pubmed database, using the terms "atezolizumab", "squamous cell lung cancer", "NSCLC" and "non-small cell lung cancer". We also searched for recently concluded and not yet published or ongoing trials in clinicaltrials.gov and in data from the latest international congresses. The aim of this review is to summarize current evidence on atezolizumab in SqCLC, from first line setting to novel potential indications from ongoing trials. Strengths and weaknesses of atezolizumab treatment were highlighted to speculate the role of this immune checkpoint inhibitor in novel future clinical scenarios.

Vitamin D Supplementation and Cancer Mortality: Narrative Review of Observational Studies and Clinical Trials.

Several studies have investigated the beneficial effects of vitamin D on survival of cancer patients. Overall evidence has been accumulating with contrasting results. This paper aims at narratively reviewing the existing articles examining the link between vitamin D supplementation and cancer mortality. We performed two distinct searches to identify observational (ObS) studies and randomized clinical trials (RCTs) of vitamin D supplementation (VDS) in cancer patients and cohorts of general population, which included cancer mortality as an outcome. Published reports were gathered until March 2021. We identified 25 papers published between 2003 and 2020, including n. 8 RCTs on cancer patients, n. 8 population RCTs and n. 9 ObS studies. There was some evidence that the use of VDS in cancer patients could improve cancer survival, but no significant effect was found in population RCTs. Some ObS studies reported evidence that VDS was associated with a longer survival among cancer patients, and only one study found an opposite effect. The findings do not allow conclusive answers. VDS may have the potential as treatment to improve survival in cancer patients, but further investigations are warranted. We strongly support investment in well-designed and sufficiently powered RCTs to fully evaluate this association.

Novel Cytotoxic Chemotherapies in Small Cell Lung Carcinoma.

Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum-etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC.

Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study.

INTRODUCTION: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM. METHODS: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks). RESULTS: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2. CONCLUSIONS: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.

Validation of the Italian version of the full and abbreviated Trust in Oncologist Scale.

INTRODUCTION: The Trust in Oncologist Scale (TiOS) is an 18-item questionnaire aimed to assess the cancer patients' trust in their oncologist and has been validated in Dutch and English language. This study aims to validate the Italian version of the TiOS (IT-TiOS) and the TiOS-Short Form (IT-TiOS-SF). METHODS: The IT-TiOS was administered to 194 patients recruited in an Italian oncology department from April to December 2018. Data collected included socio-demographic data, health and clinical information, satisfaction with the most recent oncology visit and trust in the regional healthcare system. Internal consistency, test-retest reliability, convergent and the structural validity of both the full and short form were tested. RESULTS: Factor analyses indicated that neither four-factor nor one-factor models of the full scale were acceptable. However, confirmatory factor analysis supported the one-dimensionality of the IT-TiOS-SF, and internal consistency assessed with Cronbach's alpha was 0.88. Mean scores on the IT-TiOS-SF correlated with satisfaction with the oncologist (rs = 0.64) and willingness to recommend the oncologist to others (rs = 0.67), confirming good construct validity. CONCLUSION: The IT-TiOS-SF demonstrates good psychometric properties and can be used to assess trust for both clinical and research purposes.

Peritoneal carcinomatosis in non-small-cell lung cancer: retrospective multicentric analysis and literature review.

AIM: We investigated outcomes in patients with advanced non-small-cell lung cancer (NSCLC) and peritoneal involvement. PATIENTS & METHODS: NSCLC patients with peritoneal carcinomatosis (PC) were included. We evaluated mOS1 (overall survival [OS] from NSCLC diagnosis) and mOS2 (OS from diagnosis of PC). RESULTS: In total, 60 NSCLC patients were diagnosed with PC, 12 (20%) patients had a diagnosis of NSCLC and synchronous PC with a median OS of 9 months. Smokers had a shorter mOS1 and mOS2 compared with never-smokers; EGFR-mutated patients on tyrosine kinase inhibitors had longer mOS1 and mOS2 than EGFR wild-type patients. CONCLUSION: Metachronous PC is correlated to a short survival, irrespective of treatment line. Never-smokers and EGFR-mutated patients had improved mOS1 and mOS2 when compared with smokers and EGFR wild-type population.

Challenges in ALK inhibition of ALK-positive non-small-cell lung cancer: from ALK positivity detection to treatment strategies after relapse.

ALK positivity, despite representing only in a small proportion of patients with non-small-cell lung cancer, is worth researching at diagnosis given the possibility to treat these patients with some targeted ALK inhibitors, which are more potent than chemotherapy. Thanks to understanding the resistance mechanisms, newer and more selective inhibitors are now available in clinical practice. Hence, this disease represents, after EGFR inhibition, a largely effective precision medicine approach. However, there are still some clinical situations in which the targeted drug seems to be ineffective. This review discusses some uncertainty about such a 'precision medicine application', focusing on some weaknesses and giving perspectives and suggestions to improve the management of this specific population.

Immune-checkpoint inhibitors in non-small cell lung cancer: A tool to improve patients' selection.

The identification of reliable predictive biomarkers of efficacy or resistance to immune-oncology (I-O) agents is a major issue for translational research and clinical practice. However, along with PDL1 and molecular features other clinical, radiological and laboratory factors can be considered for the selection of those patients who would not be the best candidate for immune-checkpoint inhibitors (ICPIs). We examined these factors, emerging from the results of currently available studies in non-small cell lung cancer (NSCLC), aiming to provide a useful and manageable tool which can help Oncologists in their everyday clinical practice. A thorough patient evaluation and close clinical monitoring, due to limited, early or inconclusive currently available data, should be deserved for patients with a pre-existing symptomatic chronic obstructive pulmonary disease, age >75 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 1, a time to progression (TTP) < three months and progressive disease (PD) as the best response to the previous treatment, hepatitis or HIV-infections, high neutrophil to lymphocyte ratio (NLR), or on treatment with high-dose steroids, when the use of ICPIs is considered. Limited data are available to consider that ICPIs are safe in patients with interstitial lung disease, bronchiolitis obliterans organizing pneumonia and autommune diseases. Early evidence on steroids, vaccinations and antibiotics suggest their possible interaction with ICPIs and need to be more investigated in clinical trials. Oncogene-addicted NSCLC harboring EGFR-mutations and low tumor-infiltrating T-lymphocytes (TILs) seems not to gain benefit from I-O.

Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme.

AIM: This analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non-small-cell lung cancer (NSCLC) enrolled in the expanded access programme (EAP) in Italy. METHODS: Nivolumab was available on physician request. Safety data included adverse events (AEs). Efficacy data included investigator-assessed tumour response, progression date and survival information. Results were analysed for patients aged <65, 65-<75 and ≥75 years and for the overall population. RESULTS: A total of 371 patients with squamous NSCLC were enrolled at 96 centres between April 2015 and September 2015; 34% (n = 126), 47% (n = 175) and 19% (n = 70) were aged <65, 65-<75 and ≥75 years, respectively. Efficacy was similar among patients aged <65, 65-<75 and ≥75 years and the overall population (objective response rates: 18%, 18%, 19% and 18%, respectively; disease control rates: 49%, 47%, 43% and 47%, respectively). Median overall survival was reduced in patients aged ≥75 years (5.8 months) versus patients aged <65; years (8.6 months), patients aged 65-<75 years (8.0 months) and the overall population (7.9 months). The incidence of grade 3-4 treatment-related AEs was low in patients aged 65, 65-<75 and ≥75 years and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4-5%). CONCLUSIONS: These EAP results suggest that elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population.

Blood cell count indexes as predictors of outcomes in advanced non-small-cell lung cancer patients treated with Nivolumab.

Lung cancer is the most common malignancy worldwide. Despite significant advances in diagnosis and treatment, mortality rates remain extremely high, close to incidence rates. Several targeted therapies have been recently introduced for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. Nivolumab, a monoclonal antibody that targets programmed death-1 (PD-1), was the first immune checkpoint inhibitor approved for the treatment of patients with advanced/metastatic NSCLC not responding to platinum-based chemotherapy. Biomarkers predicting response to these therapies would allow early identification of non-responders and timely implementation of appropriate combination strategies, avoiding inadequate and expensive therapies. The role of the neutrophil to lymphocyte ratio and other blood cell count indexes as possible biomarkers of response has been recently investigated. We discuss the encouraging results reported on the topic, provide new data from our personal experience, and discuss opportunities for further research.

Thymus neuroendocrine tumors with CTNNB1 gene mutations, disarrayed ß-catenin expression, and dual intra-tumor Ki-67 labeling index compartmentalization challenge the concept of secondary high-grade neuroendocrine tumor: a paradigm shift.

We herein report an uncommon association of intimately admixed atypical carcinoid (AC) and large cell neuroendocrine (NE) carcinoma (LCNEC) of the thymus, occurring in two 20- and 39-year-old Caucasian males. Both tumors were treated by maximal thymectomy. The younger patient presented with a synchronous lesion and died of disease after 9 months, while the other patient was associated with a recurrent ectopic adrenocorticotropic hormone Cushing's syndrome and is alive with disease at the 2-year follow-up. MEN1 syndrome was excluded in either case. Immunohistochemically, disarrayed cytoplasmic and nuclear ß-catenin expression was seen alongside an intra-tumor Ki-67 antigen labeling index (LI) ranging from 2 to 80% in the younger patient's tumor and from 3 to 45% in the other. Both exhibited upregulated cyclin D1 and retinoblastoma, while vimentin was overexpressed in the recurrent LCNEC only. Next-generation sequencing revealed CTNNB1, TP53, and JAK3 mutations in the synchronous tumor and CTNNB1 mutation alone in the metachronous tumor (the latter with the same mutation as the first tumor of 17 years prior). None of the 23 T-NET controls exhibited this hallmarking triple alteration (p = 0.003). These findings suggested that LCNEC components developed from pre-existing CTNNB1-mutated AC upon loss-of-function TP53 and gain-of-function JAK3 mutations in one case and an epithelial-mesenchymal transition upon vimentin overexpression in the other case. Both tumors maintained intact cyclin D1-retinoblastoma machinery. Our report challenges the concept of secondary LCNEC as an entity that develops from pre-existing AC as a result of tumor progression, suggesting a paradigm shift to the current pathogenesis of NET.