Tumor mutational burden assessment as a predictive biomarker for immunotherapy in lung cancer patients: getting ready for prime-time or not?

Heeke, Simon

doi:10.21037/tlcr.2018.08.04

Cited by 70 publications

(72 citation statements)

References 49 publications

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“…TMB, alone or in association with PD-L1 IHC, has been demonstrated to have good predictive value for immunotherapy efficiency in late stage NSCLC [50,51] and has been proposed to be equally effective in other cancers, too [48]. However, clinical and technical validation, as well as cross laboratory standardization, must be established before TMB can be transferred into routine clinical practice [52][53][54]. Furthermore, approval of TMB as a novel biomarker has recently been withdrawn from FDA while approval from the EMA is still ongoing [55].…”

Section: Pd-l1 Cps !1%mentioning

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: Pd-l1 Cps !1%mentioning

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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“…Previous studies have shown that the use of PD‐L1 expression status alone is insufficient to determine which patients should be offered PD‐1 or PD‐L1 blockade therapy and TMB might serve as a complementary diagnostic tool . High TMB is related with increased tumor‐infiltrating lymphocytes, expression of proinflammatory cytokines and immune‐related genes, but the impact on clinical outcome has yet to be clarified .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the use of PD-L1 expression status alone is insufficient to determine which patients should be offered PD-1 or PD-L1 blockade therapy 37 and TMB might serve as a complementary diagnostic tool. 38 High TMB is related with increased tumor-infiltrating lymphocytes, expression of proinflammatory cytokines and immunerelated genes, but the impact on clinical outcome has yet to be clarified. 39 For the patients with high TMB, the nivolumab monotherapy or in combination with ipilimumab showed no obvious difference in terms of OS compared with chemotherapy alone, while the combination of nivolumab and ipilimumab showed benefit in PFS and ORR.…”

Section: Discussionmentioning

confidence: 99%

Rational application of the first‐line chemotherapy and immune checkpoint inhibitors in advanced nonsmall cell lung cancer: A meta‐analysis

Cao

Zhang

et al. 2019

Cancer Medicine

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Objective To compare the relative efficacy of immune checkpoint inhibitors (ICIs) or chemotherapy (CT) alone, or their combination modality in the first‐line treatment of advanced nonsmall cell lung cancer (NSCLC). Methods This meta‐analysis was performed on the eligible randomized controlled trials (RCTs) after searching web databases and meeting abstracts. The main research endpoints were the comparisons of median overall survival (mOS), the OS rate of 6 months (OSR6m), 1 year (OSR1y) and 2 years (OSR2y), median progression‐free survival (mPFS), the PFS rate of 6 months (PFSR6m) and 1‐year (PFSR1y), objective response rates (ORR), and treatment‐related adverse events (TRAEs). Results Eleven RCTs comprising 6278 cases were included. In the subgroup of programmed death‐ligand 1 (PD‐L1) ≥50%, compared with chemotherapy, the ICIs showed similar OSR6m ( P > 0.05), but significantly improved efficacy in mOS, OSR1y, OSR2y, and ORR (all P < 0.05), also had less grade ≥ 3 TRAEs. Compared with pembrolizumab alone, pembrolizumab plus CT in the subgroup of PD‐L1 ≥ 50% had similar mOS, OSR6m, OSR1y, and PFSR1y (all P > 0.05), but significantly improved mPFS, PFSR6m, and ORR (all P < 0.05 for interaction). Compared with the CT group, ICIs plus CT group with PD‐L1 ≥ 50% or <1% showed significant benefit in OS, PFS, and ORR (all P < 0.05). However, in the ICIs plus CT group with 1% ≤ PD‐L1 ≤ 49%, only PFS and ORR showed significant benefit compared with CT group (all P < 0.05), but not for results of OS. Conclusions The findings support the rationale for using pembrolizumab alone in the first‐line treatment of PD‐L1 ≥ 50% advanced NSCLC due to the similar OS and lower grade ≥ 3 TRAEs. However, the combination of ICIs and chemotherapy is strongly recommended in patients with PD‐L1 ≤ 49% for significant survival benefit.

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“…Tumor Mutation Burden (TMB), a factor similar to MAF, is defined as a total number of non-synonymous mutations of the genome's coding regions (68). Its correlation with OS survival was tested by Owada-Ozaki et al who found out that high TMB was a very poor prognostic factor both for OS (HR=12.31) and PFS (HR=6.07) (69).…”

Section: Revision Of Novel Prognostic Factors In Lung Cancermentioning

confidence: 99%

Novel prognostic molecular markers in lung cancer (Review)

2020

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Lung carcinoma, especially in its most commonly diagnosed non-small cell histological form, is a challenge to diagnose and treat worldwide, due to the prognosis in patients with this type of cancer being poor and mortality rates being high. However, a number of patients with this type of lung carcinoma exhibit a longer than average overall survival. The specific molecular background of non-small-cell lung cancer that favors longer survival has not yet been determined. The aim of the current study was to review articles published in the years 2017-2018 and create a list of the most important and strongest non-conventional factors that could be used in the future assessment of the prognosis of patients with adenocarcinoma and squamous cell carcinoma of the lung who cannot undergo current targeted therapy. Analysis identified multiple prognostic factors in non-small cell lung carcinoma, including tumor mutational burden, which was revealed to be independent of the tumor stage or grade as well as other factors, including age, sex or targeted therapy effects. The selected molecular factors exhibit the potential to be used in the treatment of patients with specific problematic lung cancer, and may contribute to setting recommendations for the diagnosis, prognosis and treatment of individual patients with lung cancer.

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Tumor mutational burden assessment as a predictive biomarker for immunotherapy in lung cancer patients: getting ready for prime-time or not?

Cited by 70 publications

References 49 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?

Rational application of the first‐line chemotherapy and immune checkpoint inhibitors in advanced nonsmall cell lung cancer: A meta‐analysis

Novel prognostic molecular markers in lung cancer (Review)

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