Abstract 658: Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC)
Authors: Davis Andrew A. , Chae Young Kwang , Agte Sarita , Pan Alan , Mohindra Nisha , Villaflor Victoria , Raparia Kirtee , Giles Francis J. 
Published: July 2017

Background:

Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in non-small cell lung cancer (NSCLC) is critical. Tumor mutational burden (TMB) is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to examine the association of TMB with overall survival for patients treated with checkpoint blockade and to correlate TMB with mutational status, including DNA repair mutations.

Methods:

We retrospectively examined TMB using next-generation sequencing (FoundationOne) for 82 patients with NSCLC in our institution. TMB included coding base substitutions and indel alterations, but excluded potentially functional mutations. TMB high versus low was stratified based on 15 mutations per megabase pair. We correlated TMB with DNA repair mutations, mutational status, and smoking history. In addition, survival data were obtained for 35 patients who were treated with anti-PD-1/PD-L1 therapy.

Results:

TMB was associated with significantly longer overall survival for patients treated with checkpoint blockade (Table 1, p &lt; 0.04). In addition, TMB was independently correlated with direct and indirect (Chae et al. 2016) DNA repair mutations (p &lt; 0.03). TMB was also significantly associated with smoking, number of coding region mutations, and treatment with at least two prior lines of therapy (p &lt; 0.02). A trend toward lower TMB was found for patients with mutations in EGFR, ALK, or KRAS (p = 0.06).

Conclusions:

Higher TMB was associated with improved survival for patients treated with anti-PD-1/PD-L1 therapies. In addition, TMB was correlated with DNA repair mutations, number of coding mutations, prior treatment, and smoking. Our results indicate that TMB can be used as a biomarker for response to checkpoint blockade in NSCLC.

Table 1.Tumor mutational burden (TMB) by patient characteristic and mutation statusPatient CharacteristicTMB (mutations per megabase)PTMB (&lt;15)TMB (≥15)AllSmoking HistoryMinimal/Never (N)25126P = 0.011+Current/Former (N)381856All (N)631982Number of Treatment Lines Prior to Checkpoint Blockade (Excluding Targeted Therapy)0-1 (N)20424P = 0.017+2+ (N)4711All (N)241135Presence of EGFR/ALK/KRAS MutationsYes27330P = 0.061+No361652All (N)631982Number of Potentially Functional Direct + Indirect DNA Repair MutationsMean (N)0.76 (N=63)1.26 (N=19)0.88 (N=82)P = 0.027*Number of VUS Direct + Indirect DNA Repair MutationsMean (N)1.30 (N=63)2.26 (N=19)1.52 (N=82)P = 0.011*Number of Direct DNA Repair MutationsMean (N)1.08 (N=63)2.42 (N=19)1.39 (N=82)P = 0.001*Number of Total DNA Repair MutationsMean (N)2.06 (N=63)3.53 (N=19)2.40 (N=82)P = 0.005*Number of Potentially Functional MutationsMean (N)4.79 (N=63)8.00 (N=19)5.54 (N=82)P = 0.002^Number of VUS MutationsMean (N)9.13 (N=63)25.00 (N=19)12.80 (N=82)P &lt; 0.001^Total Reported MutationsMean (N)13.92 (N=63)33.00 (N=19)18.34 (N=82)P &lt; 0.001^Overall SurvivalKaplan-Meier Log-Rank TestP = 0.020Cox Proportional Hazards Regression ModelHR = 0.1995% CI: [0.04 - 0.88]P = 0.034VUS, Variant of Unknown Significance; HR, Hazard Ratio; + Pearson’s Chi-Squared; * Logistic regression; ^ Welch’s two-sample t-test

Citation Format: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Nisha Mohindra, Victoria Villaflor, Kirtee Raparia, Francis J. Giles. Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2017-658