Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

Tackling Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer.

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.

Osimertinib and chemotherapy combination to treat brain metastasis flare and osimertinib resistance by EGFR C797S.

Chemotherapy or involvement in a clinical trial remain the standard treatment for patients with EGFR mutant non-small cell lung cancer who have disease progression while receiving Osimertinib. Rapid progression, also known as flare-phenomenon, has been described after discontinuation of tyrosine kinase inhibitors. In this case, we describe a young woman who has extracranial progressive disease due to EGFR C797S resistance mutation while being treated with osimertinib, with a rapid neurological deterioration after osimertinib withdrawal due to flare-phenomenon progression in the brain, and a prompt intracranial response with osimertinib reintroduction in addition to chemotherapy to achieve extracranial diseases control.

Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP).

INTRODUCTION: Osimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes. METHODS: This is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival. RESULTS: A total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4-18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb. CONCLUSION: Treatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.

Non-small-cell lung cancer: how to manage MET exon 14 skipping mutant disease.

Several oncogenic mechanisms have been identified for MET, including MET amplification, fusions, mutations in the tyrosine kinase domain and exon 14 skipping alterations. MET exon 14 mutations are found in about 3-5% of non-small-cell lung cancers. Dysregulation of the MET receptor leads to cell proliferation and survival by activation of the PI3K-AKT-TOR and RAS-RAF-MET-ERK canonical pathways. Targeting the MET tyrosine kinase domain in the setting of MET exon 14 mutations using effective MET tyrosine kinase inhibitors is a current targeted therapy option for patients with metastatic lung cancer. In this Review, we focus on the management of patients with MET exon 14 skipping alterations by addressing the biology of the MET receptor and exon 14 skipping mutations, current treatment strategies, and sequential treatment options based on resistance mechanisms to MET inhibitors in patients with non-small-cell lung cancer.

Coronavirus Disease 2019 Outcomes, Patient Vaccination Status, and Cancer-Related Delays During the Omicron Wave: A Brief Report From the TERAVOLT Analysis.

Introduction: The Thoracic Centers International coronavirus disease 2019 (COVID-19) Collaboration (TERAVOLT) registry found approximately 30% mortality in patients with thoracic malignancies during the initial COVID-19 surges. Data from South Africa suggested a decrease in severity and mortality with the Omicron wave. Our objective was to assess mortality of patients with thoracic malignancies with the Omicron-predominant wave and evaluate efficacy of vaccination. Methods: A prospective, multicenter observational study was conducted. A total of 28 institutions contributed data from January 14, 2022, to February 4, 2022. Inclusion criteria were any thoracic cancer and a COVID-19 diagnosis on or after November 1, 2021. End points included mortality, hospitalization, symptomatic COVID-19 infection, asymptomatic COVID-19 infection, and delay in cancer therapy. Analysis was done through contingency tables and a multivariable logistic model. Results: We enrolled a total of 346 patients. Median age was 65 years, 52.3% were female, 74.2% were current or former smokers, 86% had NSCLC, 72% had stage IV at time of COVID-19 diagnosis, and 66% were receiving cancer therapy. Variant was unknown for 70%; for those known, Omicron represented 82%. Overall mortality was 3.2%. Using multivariate analysis, COVID-19 vaccination with booster compared with no vaccination had a protective effect on hospitalization or death (OR = 0.30, confidence interval: 0.15-0.57, p = 0.0003), whereas vaccination without booster did not (OR = 0.64, confidence interval: 0.33-1.24, p = 0.1864). Cancer care was delayed in 56.4% of the patients. Conclusions: TERAVOLT found reduced patient mortality with the most recent COVID-19 surge. COVID-19 vaccination with booster improved outcomes of hospitalization or death. Delays in cancer therapy remain an issue, which has the potential to worsen cancer-related mortality.

Dyskeratosis congenita and a rare brain abscess.

Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmunodeficiencia heredable.

Dyskeratosis congenita and a rare brain abscess / Disqueratosis congénita y absceso del sistema nervioso central

Abstract Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

Resumen La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmuno deficiencia heredable.

Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer.

KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRASG12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein's mutant structure and block KRASG12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRASG12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRASG12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASG12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.