Analysis of Circulating Tumor DNA Predicts Outcomes of Short Course Consolidation Immunotherapy in Unresectable Stage III Non-Small Cell Lung Cancer.

INTRODUCTION: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiotherapy (CRT) followed by one year of checkpoint inhibitor (CPI) therapy. However, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of unresectable locally advanced NSCLC patients treated on a phase 2 trial of short course consolidation immunotherapy after CRT, with the goal of testing if ctDNA may be able to identify patients who do not require a full year of treatment. PATIENTS AND METHODS: Plasma samples for ctDNA analysis were collected from patients on the BTCRC LUN 16-081 trial after completion of CRT, prior to C2D1 of CPI (i.e. 1 month after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using CAPP-Seq. Levels of ctDNA at each time point were correlated with clinical outcomes. RESULTS: Detection of ctDNA predicted significantly inferior progression-free survival (PFS) after completion of CRT (24-month 29% vs 65%, P = 0.0048), prior to C2D1 of CPI (24-month 0% vs 72%, P < 0.0001) and at the end of CPI (24-month 15% vs 67%, P = 0.0011). Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 72% vs 0%, P < 0.0001). Progression of disease occurred within <12 months of starting CPI in all patients with increasing ctDNA levels at C2D1. CONCLUSION: Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment.

A phase 2 trial of chemotherapy plus pembrolizumab in patients with advanced non-small cell lung cancer previously treated with a PD-1 or PD-L1 inhibitor: Big Ten Cancer Research Consortium BTCRC-LUN15-029.

BACKGROUND: Immunotherapy using a checkpoint inhibitor (CPI) alone or in combination with chemotherapy is the standard of care for treatment-naive patients with advanced non-small cell lung cancer (NSCLC) without driver mutations for which targeted therapies have been approved. It is unknown whether continuing CPI treatment beyond disease progression results in improved outcomes. METHODS: Patients who experienced progressive disease (PD) after a clinical benefit from chemotherapy plus a CPI were enrolled. Patients received pembrolizumab (200 mg every 3 weeks) plus next-line chemotherapy. The primary end point was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Key secondary end points included the overall survival (OS), clinical benefit rate, and toxicity. The authors' hypothesis was that continuing pembrolizumab beyond progression would improve the median PFS to 6 months in comparison with a historical control of 3 months with single-agent chemotherapy alone. RESULTS: Between May 2017 and February 2020, 35 patients were enrolled. The patient and disease characteristics were as follows: 51.4% were male; 82.9% were current or former smokers; and 74.3%, 20%, and 5.7% had adenocarcinoma, squamous cell carcinoma, and NSCLC not otherwise specified, respectively. The null hypothesis that the median PFS would be 3 months was rejected (p < .05). The median PFS was 5.1 months (95% confidence interval [CI], 3.6-8.0 months). The median OS was 24.5 months (95% CI, 15.6-30.9 months). The most common treatment-related adverse events were fatigue (60%), anemia (54.3%), and nausea (42.9%). There were no treatment-related deaths. CONCLUSIONS: Pembrolizumab plus next-line chemotherapy in patients with advanced NSCLC who experienced PD after a clinical benefit from a CPI was associated with statistically significant higher PFS in comparison with historical controls of single-agent chemotherapy alone.

Airway epithelial versus immune cell Stat1 function for innate defense against respiratory viral infection.

The epithelial surface is often proposed to actively participate in host defense, but evidence that this is the case remains circumstantial. Similarly, respiratory paramyxoviral infections are a leading cause of serious respiratory disease, but the basis for host defense against severe illness is uncertain. Here we use a common mouse paramyxovirus (Sendai virus) to show that a prominent early event in respiratory paramyxoviral infection is activation of the IFN-signaling protein Stat1 in airway epithelial cells. Furthermore, Stat1-/- mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF-alpha and neutrophil chemokine CXCL2. Poor control of viral replication as well as TNF-alpha and CXCL2 overproduction were both mimicked by infection of Stat1-/- airway epithelial cells in culture. TNF-alpha drives the CXCL2 response, because it can be reversed by TNF-alpha blockade in vitro and in vivo. These findings pointed to an epithelial defect in Stat1-/- mice. Indeed, we next demonstrated that Stat1-/- mice that were reconstituted with wild-type bone marrow were still susceptible to infection with Sendai virus, whereas wild-type mice that received Stat1-/- bone marrow retained resistance to infection. The susceptible epithelial Stat1-/- chimeric mice also exhibited increased viral replication as well as excessive neutrophils, CXCL2, and TNF-alpha in the airspace. These findings provide some of the most definitive evidence to date for the critical role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication.