Impact of baseline steroids on efficacy of programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade in patients with advanced non-small cell lung cancer

Immune checkpoint inhibitors (ICI) have become part of the standard of care of patients with locally advanced and advanced non-small cell lung cancer (NSCLC) (1). Corticosteroids are broadly used as premedication for most chemotherapy regimens and are frequently used to alleviate pain or dyspnea, to stimulate appetite, or to palliate symptoms associated with brain or epidural metastases. However, corticosteroids have anti-inflammatory and immunosuppressive effects that act over both innate and adaptive immunity. Based on this, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone or equivalent have been systematically excluded from clinical trials of ICI

Exploiting metabolic vulnerabilities of Non small cell lung carcinoma

Lung cancer is the main cause of cancer death worldwide. Non-Small Cell Lung Carcinoma (NSCLC) is the most common subtype of lung cancer, and the prognosis of NSCLC patients in advanced stages is still very poor. Given the need for new therapies, the metabolism of NSCLC has been widely studied in the past two decades to identify vulnerabilities that could be translated into novel anti-metabolic therapeutic approaches. A number of studies have highlighted the role of glucose and mitochondrial metabolism in the development of NSCLC. The metabolic properties of lung tumors have been characterized in detail in vivo, and they include high glucose and lactate use and high heterogeneity regarding the use of nutrients and mitochondrial pathways. This heterogeneity has also been observed in patients infused with labeled nutrients. We will summarize here the knowledge about the use of amino acids, fatty acids and carbohydrates in NSCLC that could lead to new combination treatments

Induction treatment in patients with stage III non-small cell lung cancer

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogeneous group of patients defined according to the extent and localization of disease. Patients with discrete N2 involvement identified preoperatively with resectable disease are candidates for multimodal therapy either with definitive chemoradiation therapy, induction chemotherapy, or chemoradiotherapy (CTRT) followed by surgery. Neoadjuvant chemotherapy has yielded comparable survival benefit to adjuvant chemotherapy in patients with stage II-III disease and may allow for downstaging the tumor or the lymph nodes, an earlier delivery of systemic treatment, and better compliance to systemic therapy. The use of immune checkpoint inhibitors (ICIs) as induction therapy shows encouraging activity and a favorable safety profile in patients with resectable early stage or locally advanced NSCLC. An unprecedented rate of pathological response and downstaging has been reported in single-arm clinical trials, especially when immunotherapy is combined with neoadjuvant chemotherapy. Ongoing randomized phase II/III clinical trials assessing the efficacy and safety of induction with immunotherapy plus chemotherapy have the potential to establish this therapeutic approach as a novel standard of care. These trials aim to validate pathological response as a surrogate marker of survival benefit and to demonstrate that this therapeutic strategy can improve the cure rate in patients with stage II-III NSCLC

Systematic review of stereotactic body radiotherapy in stage III non-small cell lung cancer

Despite adequate treatment, 50% of stage III locally advanced inoperable non-small cell lung cancer (NSCLC) patients have a locoregional relapse. Local control on early stages on the contrary, is as high as 85-90% with stereotactic body radiotherapy (SBRT). The addition of SBRT to conventional chemoradiation or its use in monotherapy in stage III NSCLC is a novel strategy to decrease local failure that has been explored by various authors. This is a systematic review of studies using SBRT in inoperable stage III NSCLC. Search results obtained 141 articles of which only 6 original studies were pointed as relevant. Three of these studies were prospective, of which 2 were phase I dose-scalation studies and remaining 3 were retrospective. In summary, SBRT outcomes on 134 patients were included. Median dose in the SBRT treatment was 22.5 Gy in 2 to 7 fractions. Obtained global toxicity was 3.7% grade 5 and 14.17% grade 3. Dose-escalation studies proposed a 2 fraction SBRT schedule of 20-24 Gy, obtaining a 78% local control rate at 1 year and an OS of 67%. Initial improvement in local control with this innovative therapeutic strategy has led to ongoing phase II and III clinical trials that will evaluate the efficiency of SBRT in stage III NSCLC clinical scenario

Generating valid test data through data cloning

One of the most difficult, time-consuming and error-prone tasks during software testing is that of manually generating the data required to properly run the test. This is even harder when we need to generate data of a certain size and such that it satisfies a set of conditions, or business rules, specified over an ontology. To solve this problem, some proposals exist to automatically generate database sample data. However, they are only able to generate data satisfying primary or foreign key constraints but not more complex business rules in the ontology. We propose here a more general solution for generating test data which is able to deal with expressive business rules. Our approach, which is entirely based on the chase algorithm, first generates a small sample of valid test data (by means of an automated reasoner), then clones this sample data, and finally, relates the cloned data with the original data. All the steps are performed iteratively until a valid database of a certain size is obtained. We theoretically prove the correctness of our approach, and experimentally show its practical applicability.This work is partially supported by the SUDOQU project, PID2021-126436OB-C21 from MCIN/AEI, 10.13039/501100011033, FEDER, UE and by the Generalitat de Catalunya, Spain (under 2017-SGR-1749); Sergi Nadal is partly supported by the Spanish Ministerio de Ciencia e Innovación , as well as the European Union - NextGenerationEU, under project FJC2020-045809-I.Peer ReviewedPostprint (published version

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial

Background Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy.Methods In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. Results Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn evelopment was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). Conclusions Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy

BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13

The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with BAP1 tumor predisposition syndrome (TPDS). BAP1 is a tumor suppressor gene whose alterations in cancer are commonly caused by gene mutations leading to protein loss of function. By CRISPR-Cas, we have generated mutations in ubh-4, the BAP1 ortholog in Caenorhabditis elegans, to model the functional impact of BAP1 mutations. We have found that a mimicked BAP1 cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of ubh-4 deletion mutants. Despite ubh-4 being ubiquitously expressed, the gene is not essential for viability and its deletion causes only mild phenotypes without affecting 20S proteasome levels. Such viability facilitated an RNAi screen for ubh-4 genetic interactors that identified rpn-9, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. ubh-4[A87D], similarly to ubh-4 deletion, cause a synthetic genetic interaction with rpn-9 inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how ubh-4 inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study BAP1 cancer-related mutations in C. elegans, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of BAP1 tumors

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy

Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05)

Atezolizumab; Non-small-cell lung cancer; Brain metastasesAtezolizumab; Cáncer de pulmón de células no pequeñas; Metástasis cerebralAtezolizumab; Càncer de pulmó de cèl·lules no petites; Metàstasi cerebralPURPOSE The Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) with untreated brain metastases, a population traditionally excluded from trials. METHODS This single-arm phase II clinical trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years. The primary end points were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria. RESULTS Forty patients were enrolled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2 but five patients (12.5%) experienced grade 3-4 neurologic events. With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS) was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI, 16.6 to 45.5). CONCLUSION Atezolizumab plus carboplatin and pemetrexed demonstrates activity in patients with advanced nonsquamous NSCLC with untreated brain metastases with an acceptable safety profile