Dataset Information

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

ABSTRACT: Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

SUBMITTER: Anagnostou V

PROVIDER: S-EPMC6432636 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Anagnostou Valsamo V Forde Patrick M PM White James R JR Niknafs Noushin N Hruban Carolyn C Naidoo Jarushka J Marrone Kristen K Sivakumar I K Ashok IKA Bruhm Daniel C DC Rosner Samuel S Phallen Jillian J Leal Alessandro A Adleff Vilmos V Smith Kellie N KN Cottrell Tricia R TR Rhymee Lamia L Palsgrove Doreen N DN Hann Christine L CL Levy Benjamin B Feliciano Josephine J Georgiades Christos C Verde Franco F Illei Peter P Li Qing Kay QK Gabrielson Edward E Brock Malcolm V MV Isbell James M JM Sauter Jennifer L JL Taube Janis J Scharpf Robert B RB Karchin Rachel R Pardoll Drew M DM Chaft Jamie E JE Hellmann Matthew D MD Brahmer Julie R JR Velculescu Victor E VE

Cancer research 20181212 6

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (<i>N</i> = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had ...[more]

PMID: 30541742

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Project description:Purpose:Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response. Methods:Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months. Results:TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point. Conclusion:Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.

Dataset Information

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Publications

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

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