Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates.

Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines.

Phase II Study of Arginine Deprivation Therapy With Pegargiminase in Patients With Relapsed Sensitive or Refractory Small-cell Lung Cancer.

Background: Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC).

Patients And Methods: Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m (36.

Real-World Clinical Impact of Immune Checkpoint Inhibitors in Patients With Advanced/Metastatic Non-Small Cell Lung Cancer After Platinum Chemotherapy.

Background: The real-world effect of anti-programmed death ligand 1 (PD-L1) therapies is unclear. We compared US patients who received second-line therapy for non-small-cell lung cancer (NSCLC) before and shortly after US Food and Drug Administration (FDA) approval of PD-L1 inhibitors.

Patients And Methods: Patients in the Flatiron Health database (≥18 years; received first-line platinum therapy for advanced/metastatic NSCLC; ≥6 months of follow-up) were assessed before ("historical": January 1, 2011 to December 31, 2013) and after ("current": January 1, 2015 to May 31, 2017) FDA approval of anti-PD-L1 therapies for NSCLC.

Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer.

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent.

A Randomized Phase II Trial of Adjuvant Galinpepimut-S, WT-1 Analogue Peptide Vaccine, After Multimodality Therapy for Patients with Malignant Pleural Mesothelioma.

Determine the 1-year progression-free survival (PFS) rate among patients with malignant pleural mesothelioma (MPM) receiving the WT1 peptide vaccine galinpepimut-S after multimodality therapy versus those receiving control adjuvants. This double-blind, controlled, two center phase II trial randomized MPM patients after surgery and another treatment modality to galinpepimut-S with GM-CSF and Montanide or GM-CSF and Montanide alone. An improvement in 1-year PFS from 50% to 70% was the predefined efficacy threshold, and 78 patients total were planned.

Patterns of failure in limited-stage small cell lung cancer: Implications of TNM stage for prophylactic cranial irradiation.

Background And Purpose: The relationship between tumor-node-metastasis (TNM) stage and patterns of failure in limited-stage small cell lung cancer (LS-SCLC) remains unclear. We hypothesized that TNM stage predicts brain metastasis risk, and could inform the use of prophylactic cranial irradiation.

Material And Methods: We reviewed 283 patients with stage I-IIIB SCLC.

Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma.

Introduction: Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicity. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) with previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D).

Methods: We analyzed 209 patients who underwent P/D and adjuvant RT (131 who received CONV and 78 who received IMPRINT) for MPM between 1974 and 2015.

A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer.

Objectives: The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC.

Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma.

Purpose: We conducted a two-center phase II study to determine the safety of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) after chemotherapy and pleurectomy-decortication (P/D) as part of a multimodality lung-sparing treatment.

Patients And Methods: Patients received up to four cycles of pemetrexed plus platinum. If feasible, P/D was performed.

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes.

Background: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC.

Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma.

Introduction: Previous prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy.

Methods: This single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013.

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors.

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.

Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.

The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers.

Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients.

Non-Small Cell Lung Cancer, Version 6.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies.

Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.

Background: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

Methods: This double-blind, randomised, placebo-controlled trial was done in 90 international centres.

Non-small cell lung cancer, version 1.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase.

Objectives: Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days.

Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma.

Purpose: We previously reported our technique for delivering intensity modulated radiation therapy (IMRT) to the entire pleura while attempting to spare the lung in patients with malignant pleural mesothelioma (MPM). Herein, we report a detailed pattern-of-failure analysis in patients with MPM who were unresectable or underwent pleurectomy/decortication (P/D), uniformly treated with hemithoracic pleural IMRT.

Methods And Materials: Sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT between November 2004 and May 2013.

Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation.

Introduction: Patients with early-stage lung cancer have a high risk of recurrence despite multimodality therapy. KRAS-mutant lung adenocarcinomas are the largest genetically defined subgroup, representing 25% of patients. GI-4000 is a heat-killed recombinant Saccharomyces cerevisiae yeast-derived vaccine expressing mutant KRAS proteins.

Small-cell lung cancers in patients who never smoked cigarettes.

Introduction: We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).

Methods: We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data.

Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.

Objectives: Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.