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Proceedings ArticleDOI

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)

01 Jul 2017-Cancer Research (American Association for Cancer Research)-Vol. 77, pp 658-658
TL;DR: The results indicate that TMB can be used as a biomarker for response to checkpoint blockade in NSCLC, and higher TMB was associated with improved survival for patients treated with anti-PD-1/PD-L1 therapies.
Abstract: 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 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. 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
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Journal ArticleDOI
TL;DR: It is indicated that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes and that ct DNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
Abstract: Background Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC). Materials and methods A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length. Results Higher ctDNA TMB was significantly correlated with smoking history (p Conclusion The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes. Implications for practice Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.

68 citations

Journal ArticleDOI
TL;DR: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness to encourage recruitment of patients into biomarker-driven combination trials.
Abstract: Introduction: Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients.Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness. The rationale for the combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology drugs in order to improve efficacy will be provided.Expert opinion: There are near-endless permutations of combination strategies of these agents with ICPI that have become feasible treatment strategies. Development of an understanding of resistance mechanisms to ICPI by a shift towards translational approaches to comprehensive genomic...

21 citations


Cites background from "Abstract 658: Association of tumor ..."

  • ...TMB was independently associated with significantly longer overall survival [47]....

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Journal ArticleDOI
12 Jun 2020-Medicine
TL;DR: The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients’ different baseline characteristics, and support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.

16 citations


Cites background from "Abstract 658: Association of tumor ..."

  • ...6 microsatellite instability play a vital role in predicting the efficacy of immunotherapy in many clinical trials.([27,28]) KEYNOTE-010 was the first prospective study to confirm that PD-L1 expression is a useful biomarker for predicting the efficacy of pembrolizumab, while the use of TMB, microsatellite instability and other biomarkers as predictors of the efficacy of immunological checkpoint inhibitors is attracting increasing attention....

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