Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy.

Peters, Solange; Cho, Byoung Chul; Reinmuth, Niels; Lee, Ki Hyeong; Luft, Alexander; Ahn, Myung‐Ju; Baas, Paul; Dols, M. Cobo; Smolin, Alexey Yu.; Vicente, David; Moiseyenko, Vladimir; Antonia, Scott; Nakagawa, Kazuhiko; Goldberg, Sarah B.; Kim, Edward; Raja, Rajiv; Brohawn, Philip Z.; Clemett, Delyth; Thiyagarajah, Piruntha; Scheuring, Urban; Liu, Feng; Rizvi, Naiyer A.

doi:10.1158/1538-7445.sabcs18-ct074

Cited by 38 publications

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“…Moreover, the cut-off for the bTMB and the exact panel of genes may be questionable and need further validation and standardization [52]. Furthermore, bTMB seems to be independent of tissue TMB and thus new thresholds would need to be evaluated for the stratification of patients [102][103][104].…”

Section: Analysis Of Circulating Free Ctdnamentioning

confidence: 99%

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

2019

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The emergence of immunotherapy in oncology requires the discovery, validation and subsequent adoption of robust, sensitive and specific predictive and prognostic biomarkers for daily practice. Until now, anti-PD-L1 immunohistochemistry (IHC) on tissue sections has been the only validated companion diagnostic test for first-line immunotherapy for advanced and metastatic cancer, notably non-small-cell lung cancer (NSCLC). However, detection of this biomarker presents limitations that have stimulated the development of other biomarkers and other approaches. Within this context, the use of a liquid biopsy (LB) could provide an important complementary or alternative added value to PD-L1 IHC. In this review, we discuss how LBs have been used in the field of immuno-oncology (I-O) to predict response, relapse or adverse advents for patients undergoing immune-checkpoint inhibitor (ICI) therapy (anti-PD-1/PD-L1 and CTLA-4) and we highlight recent developments. Circulating tumor cells (CTCs), cell-free DNA (cfDNA), proteins and cytokines detected in plasma as well as circulating T-lymphocytes are discussed as potential sources for developing new I-O biomarkers. The quantification of cfDNA as a predictive biomarker, as well as its sequencing for the determination of tumor mutational burden, is already well advanced. Additionally, the quantification of PD-L1 from CTCs, bound on exosomes or free in plasma, as well as the determination of cytokines, are also being actively investigated with promising results having recently been published. Lastly, analysis of T-lymphocytes, especially by analyzing the T-cell receptor, has recently emerged as a valuable biomarker that might become relevant for the prediction of response to ICIs. While LBs have not yet been implemented in routine I-O clinical practice, recent promising data and rapidly advancing technologies indicate that this approach has the potential to soon personalize the clinical management of cancer patients receiving ICIs.

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Section: Analysis Of Circulating Free Ctdnamentioning

confidence: 99%

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

2019

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“…[18][19][20] High TMB has also been associated with improved outcomes in patients treated with a combination of PD-1/PD-L1 and CTLA-4 inhibitors. [21][22][23][24] Initial assessments of TMB involved whole exome sequencing (WES) of matched tumor tissue and normal specimens using next-generation sequencing (NGS). 3 8-10 However, WES is not currently routine in clinical practice due to substantial cost and turnaround time, which has led assay manufacturers and commercial and academic labs to develop targeted NGS panels.…”

Section: Introductionmentioning

confidence: 99%

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project

Merino

McShane

Fabrizio³

et al. 2020

J Immunother Cancer

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BackgroundTumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.MethodsEleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.ResultsStudy results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.ConclusionsIncreasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

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“…Due to the poor prognosis of patients with metastatic NSCLC and the limited availability of effective treatments, clinical research on treatment options such as immunotherapy must continue. Currently, dual blockade of the CTLA-4 and PD-1/PD-L1 pathways using immunotherapies is being explored in metastatic NSCLC [16][17][18][19][20][21][22][23][24]. Durvalumab + tremelimumab combination regimens have shown encouraging tolerability and clinical activity in a Phase Ib study [16], and the combination of nivolumab + ipilimumab as first-line therapy improved progression-free survival (PFS) in patients with metastatic NSCLC with a high tumor mutational burden (TMB), in both PD-L1 TC <1 and ≥1% subgroups [17].…”

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confidence: 99%

“…In the Phase III MYSTIC trial (NCT02453282), the combination of durvalumab + tremelimumab did not statistically significantly improve overall survival (OS) or PFS vs. chemotherapy in patients with PD-L1 TC ≥25% [18][19][20]. However, in exploratory analyses, the combination showed clinical activity in patients with high blood TMB (bTMB), with improvements in OS observed at bTMB thresholds from ≥12 to ≥20 mut/Mb [20,21].…”

mentioning

confidence: 99%

“…To complement the emergence of immunotherapy in metastatic NSCLC [12][13][14][15][16][17][18][19][20][21][22][23][24][25], it is important to understand the effectiveness of newer treatments and determine further treatment needs. Specifically, there remains an unmet need for real-world evidence documenting treatment patterns and survival outcomes following the approval and uptake of immunotherapy into the metastatic NSCLC setting.…”

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confidence: 99%

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Treatment Patterns and Overall Survival in Metastatic Non-Small-Cell Lung Cancer in a Real-World, US Setting

et al. 2019

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Aim: To conduct a retrospective analysis of electronic medical record data to understand real-world treatment patterns and overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC). Materials & methods: We included n = 9656 adults (≥18 years) with metastatic NSCLC and no prior therapy. Data from 1 January 2013 to 31 January 2017 were analyzed. Results: Carboplatin plus paclitaxel was the most common first-line therapy (18.6%), and nivolumab was the most common second- (31.0%) and third-line (38.4%) therapy; 26.7% of all patients were untreated. Median OS from initial metastatic diagnosis was 11.1 months (95% CI: 10.8–11.5). Second-line immunotherapy extended OS by over 3 months versus second-line chemotherapy. Conclusion: Platinum-based therapy was the most common first-line therapy, and immunotherapy was the most common second- and third-line therapy. Median OS of patients with metastatic NSCLC was <1 year.

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Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy.

Cited by 38 publications

References 0 publications

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project

Treatment Patterns and Overall Survival in Metastatic Non-Small-Cell Lung Cancer in a Real-World, US Setting

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