Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

Introduction: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort.

Methods: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.

Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

Background: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes.

Association of sarcopenia with survival in advanced NSCLC patients receiving concurrent immunotherapy and chemotherapy.

Background: Frailty, sarcopenia and malnutrition are powerful predictors of clinical outcomes that are not routinely measured in patients with non-small cell lung cancer (NSCLC). The primary aim of this study was to investigate the association of sarcopenia, determined by the psoas muscle index (PMI) with overall survival (OS) in patients with advanced NSCLC treated with concurrent immune checkpoint inhibitor (ICI) and chemotherapy (CTX).

Methods: We retrospectively reviewed data from a cohort of patients with locally advanced or metastatic NSCLC who were treated between 2015 and 2021 at the University of Virginia Medical Center.

A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139.

Introduction: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC).

Patients And Methods: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

Background: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.

Bayesian Design for Identifying Cohort-Specific Optimal Dose Combinations Based on Multiple Endpoints: Application to a Phase I Trial in Non-Small Cell Lung Cancer.

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts.

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with Exon 20 Insertion Mutations from a Phase I/II Trial.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting gene mutations, including exon 20 insertions (ex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose.

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.

Patients And Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field.

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2).

Phase IB Study of Osimertinib in Combination with Navitoclax in -mutant NSCLC Following Resistance to Initial Therapy (ETCTN 9903).

Purpose: Osimertinib is an effective therapy in -mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of -mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance.

Do Patients Regret Having Received Systemic Treatment for Advanced Non-Small Cell Lung Cancer: A Prospective Evaluation.

Background: Thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision-making parameters, or clinical progress early in the treatment course predicts regret.

Materials And Methods: Patients receiving systemic treatment for advanced NSCLC completed every 3-week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS-QL), including the 3-Item Global Index (3-IGI; assessing overall distress, activities, and quality of life [QL]).

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC.

Introduction: In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study.

Methods: Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks.

Severe combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series.

Background: Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner.

Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases.

Purpose/objective(s): Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor burden and outcomes in patients with brain metastases treated with TKIs.

Materials/methods: We identified and retrospectively reviewed cases of EGFR-mutant or ALK-rearranged lung cancer with brain metastases at any time during their cancer course.