Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels.

Importance: Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC). Objectives: To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC. Design, Setting, and Participants: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022. Exposures: Treatment with PD-1/PD-L1 inhibition without chemotherapy. Main Outcomes and Measures: Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures. Conclusions and Relevance: These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment. METHODS: Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes. RESULTS: Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase. CONCLUSION: In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping.

INTRODUCTION: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK-positive NSCLC. METHODS: The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK-positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied. RESULTS: Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction. CONCLUSIONS: Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response.

Understanding the Self in Individuals with Autism Spectrum Disorders (ASD): A Review of Literature.

When the system of self is explored in individuals with Autism Spectrum Disorders (ASDs), it is important to measure it via both their own perceptions of the self and their understanding of others' perceptions on themselves at a multidimensional level. This paper reviews existing research in this area using a three-dimension approach. Researchers have found that impairments in the self-system are usually correlated with these individuals' social and cognitive functioning levels: high functioning individuals with ASD who have higher IQ are found to have better awareness of their limitations in social and communication domains than those with lower IQ. Many researchers believe that there are impairments in the psychological (but not physical) self in individuals with ASD, such as theory of mind deficits due to social and communicative impairments. On the other hand, some researchers argue that individuals with ASD have selective rather than global impairments in the self. In other words, the impairment usually lies in a specific aspect of functioning in individuals with ASD. Insights from the review of existing literature on this topic may be able to shed some lights on the development of effective intervention programs to improve social communication deficits in this population.