This study describes the validation of a clinical RNA expression panel with evaluation of concordance between gene copy gain by a next-generation sequencing (NGS) assay and high gene expression by an RNA expression panel. The RNA Salah Targeted Expression Panel (RNA STEP) was designed with input from oncologists to include 204 genes with utility for clinical trial prescreening and therapy selection. RNA STEP was validated with the nanoString platform using remnant formalin-fixed, paraffin-embedded-derived RNA from 102 patients previously tested with a validated clinical NGS panel.
View Article and Find Full Text PDFBackground: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor ()-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative TKI sequencing strategies may produce similar outcomes.
View Article and Find Full Text PDFBackground: Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation.
Methods: In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1.
Rationale: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics.
View Article and Find Full Text PDFOncolytic virus therapies induce the direct killing of tumor cells and activation of conventional dendritic cells (cDC); however, cDC activation has not been optimized with current therapies. We evaluated the adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNβ to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNβ expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner.
View Article and Find Full Text PDFPurpose: We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial.
Methods And Materials: Eligible patients had unresectable stage III NSCLC.
Background And Purpose: The study objective was to determine whether longitudinal changes in patient-reported outcomes (PROs) were associated with survival among early-stage, non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT).
Materials And Methods: Data were obtained from January 2015 through March 2020. We ran a joint probability model to assess the relationship between time-to-death, and longitudinal PRO measurements.
Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence.
View Article and Find Full Text PDFRationale: Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.
View Article and Find Full Text PDFInt J Radiat Oncol Biol Phys
February 2021
Purpose: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.
Methods And Materials: Eligibility required stable disease or better after platinum doublet chemotherapy.
Small-cell lung cancer (SCLC) accounts for 13-15% of all new lung cancer cases in the US. The tumor has a tendency to disseminate early resulting in 80-85% of patients being diagnosed with extensive disease (ES-SCLC). Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades.
View Article and Find Full Text PDFSmall cell lung cancer (SCLC) is an aggressive malignancy and carries a poor prognosis with limited effective treatments in the advanced setting. SCLC is characterized by a high tumor mutation burden and alterations in Notch signaling and DNA damage repair pathways, providing rationale for the use of immunotherapy and targeted therapies. Immunotherapies have led to the most significant advances in treating SCLC in decades, and several promising targeted approaches have emerged from the increased understanding of the biology of SCLC.
View Article and Find Full Text PDFPurpose Of Review: Treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) has recently been revolutionized by the incorporation of immunotherapy to standard platinum-based concurrent chemoradiation. This review examines the current standard practices and ongoing studies on the management of locally advanced, unresectable NSCLC.
Recent Findings: Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC.
Purpose: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer.
Patients And Methods: Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day).
Mucin 1 (MUC1) is a cell membrane glycoprotein overexpressed in non-small cell lung cancer (NSCLC) and has been implicated in carcinogenesis of premalignant lung lesions. Thus, MUC1 has been a target of interest for vaccine strategies for lung cancer treatment and prevention. Here, we assessed MUC1 expression by immunohistochemistry using tumor samples from patients with biopsy-proven NSCLC.
View Article and Find Full Text PDFImmune checkpoint inhibitors enhance the activation and antitumor activity of the immune system, resulting in durable response rates in a select group of patients. Cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors target the inhibitory interaction between CTLA4 and CD80 or CD86. Programmed death 1 (PD1) inhibitors target the interaction between PD1 receptors on T-cells and PD-ligand 1 (PD-L1) and PD-ligand 2, blocking the inhibitory signaling and resulting in activation of T-cell effector function.
View Article and Find Full Text PDFLung cancer is a heterogeneous diagnosis that encompasses a spectrum of histologic and molecular subgroups. A paradigm shift favoring selection of treatment based on histologic and molecular makeup has positively affected prognosis for patients with metastatic lung cancer, with select patients experiencing durable responses to treatment. However, prognosis remains poor for the majority of patients.
View Article and Find Full Text PDFBackground: Over the past 15 years, the use of cell phones has increased 8-fold in the United States. Cell phone use has been shown to increase crash risks for drivers, but no systematic analyses have described injuries related to ambulatory cell phone use.
Objective: The purpose of this study is to describe and quantitate injuries and deaths among persons using cell phones while walking.