Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.

Purpose Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety. Methods Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators. Results Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%). Conclusions Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events.

Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 -74%] for cobas tumor T790M-positive and 44% (95% CI, 25 -63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to 10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. Ó2016 AACR.

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Background: Treatment options for patients with advanced esophageal or esophagogastric junction (EGJ) cancer are limited. Current guidelines for first-line treatment of advanced esophageal or EGJ cancer recommend chemotherapy containing a platinum and a fluoropyrimidine agent. Pembrolizumab demonstrated antitumor activity in previously treated patients with advanced esophageal cancer and in patients with gastroesophageal junction cancer. Aim: To describe the design and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-590 study, which will be conducted to investigate pembrolizumab in combination with chemotherapy as first-line treatment in patients with advanced esophageal or EGJ cancer.Clinical trial registry & ID: ClinicalTrials.gov: NCT03189719.

Introduction: EGFR-mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because cooccurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patients' outcomes using a comprehensive gene panel is potentially important.

Purpose: To investigate blood-based dynamic biomarkers that predict responses to anti-programmed cell death protein 1 (PD-1) therapy in solid tumors.Experimental Design: Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; n ¼ 31) who received pembrolizumab. The biomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab (NSCLC cohort 1; n ¼ 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; n ¼ 46). Peripheral blood samples were obtained immediately before treatment (D0) and 7 days after the first dose (D7) and analyzed using multi-color flow cytometry.Results: A higher fold-change in the percentage of Ki-67 þ cells among PD-1 þ CD8 þ T cells 7 days after the first dose (Ki-67 D7/D0 ) significantly predicted durable clinical benefit (DCB; P < 0.001) and prolonged progression-free survival (PFS; P ¼ 0.027) in patients with TETs. Ki-67 D7/D0 ! 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all P < 0.05). Ki-67 D7/D0 was subsequently validated in NSCLC cohort 2, and Ki-67 D7/D0 ! 2.8 significantly predicted better DCB (P ¼ 0.001), PFS (P ¼ 0.002), and OS (P ¼ 0.037). Ki-67 D7/D0 had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67 D7/D0 .Conclusions: The proliferative response of peripheral blood PD-1 þ CD8 þ T cells, measured as the fold-change in the percentage of Ki-67 þ cells 7 days after treatment (Ki-67 D7/D0 ), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.

Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression should be further validated in a prospective randomized study.