Current views on tumor mutational burden in patients with non-small cell lung cancer treated by immune checkpoint inhibitors

Berland, Léa; Heeke, Simon; Humbert, Olivier; Macocco, Adam; Long‐Mira, Elodie; Lassalle, Sandra; Lespinet‐Fabre, Virginie; Lalvee, Salomé; Bordone, Olivier; Cohen, Charlotte; Leroy, Sylvie; Hofman, Véronique; Hofman, Paul; Ilié, Marius

doi:10.21037/jtd.2018.11.102

Cited by 78 publications

(73 citation statements)

References 55 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is in line with the result of a smaller series including 81 immunotherapy-treated patients that detected a rate of 11% (9/81) for OPD using slightly different criteria [14]. The lower rate of OPD in IO-treated NSCLC could be related to its presumably higher genetic instability, as inferred by the higher tumor mutational burden (TMB) [15,16], and to the lower efficacy of current immunotherapies compared to molecularly targeted drugs [17][18][19][20]. Interestingly, our results suggest similar OPD rates for first-line IO monotherapy compared to first-line chemoimmunotherapy ( Figure 4A), which parallels the roughly similar efficacy of these treatments in terms of response rates and overall survival in the respective clinical studies, especially for patients with a higher PD-L1 expression, who are also more likely to develop OPD [19,20].…”

Section: Discussionsupporting

confidence: 77%

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

Rheinheimer

Heußel

Mayer

et al. 2020

Cancers

View full text Add to dashboard Cite

Oligoprogression (OPD) of non-small-cell lung cancer (NSCLC) occurs in approximately half of patients under targeted compounds (TKI) and facilitates use of regional therapies that can prolong survival. In order to characterize OPD in immunotherapy (IO)-treated NSCLC, we analyzed the failure pattern under PD-1/PD-L1 inhibitors (n = 297) or chemoimmunotherapy (n = 75). Under IO monotherapy, OPD was more frequent (20% vs. 10%, p < 0.05), occurred later (median 11 vs. 5 months, p < 0.01), affected fewer sites (mean 1.1 vs. 1.5, p < 0.05), and involved fewer lesions (1.4 vs. 2.3, p < 0.05) in the first compared to later lines. Lymph nodes (42%, mainly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, OPD occurred later (11 vs. 4 months, p < 0.001) and was associated with longer survival (26 vs. 13 months, p < 0.001) and higher tumor PD-L1 expression (p < 0.001). Chemoimmunotherapy showed a similar incidence of OPD as IO monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. Thus, NSCLC oligoprogression is less common under IO than under TKI, but also favorable. Since its frequency drops later in the disease, regular restaging and multidisciplinary evaluation are essential in order to exploit the full therapeutic potential.

show abstract

Section: Discussionsupporting

confidence: 77%

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

Rheinheimer

Heußel

Mayer

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…This would allow derivation of blood TMB [28], which has been shown to be a better biomarker of response in PD-1/PD-L1 inhibitor therapy. The assay is also performed at sufficiently high read depth to allow calculation of clonal TMB [29,30], another marker associated with more accurate identification of potential response to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants

et al. 2020

View full text Add to dashboard Cite

Introduction The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS). Methods Cancer samples derived from formalin-fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker pipeline. Either FASTQ files (PierianDx) or vcf files (OncoKDM) were processed to understand clinical actionability. Results In total, 108 samples (a mixture of colorectal, lung, oesophageal and control samples) were processed via the DNA panel. There was good correlation between TMB, single-nucleotide variants (SNVs), indels and copy-number variations as predicted by TSO500 and WGS (R 2 > 0.9) and good reproducibility, with less than 5% variability between repeated controls. For the RNA panel, 13 samples were processed, with all known fusions observed via orthogonal techniques. For clinical actionability, 72 tier 1 variants and 297 tier 2 variants were detected, with clinical trials identified for all patients. Conclusions The TSO500 assay accurately measures TMB, microsatellite instability, SNVs, indels, copy-number/structural variation and gene fusions when compared to WGS and orthogonal technologies. Coupled with a clinical annotation pipeline, this provides a powerful methodology for identification of clinically actionable variants.

show abstract

“…In the last few years, treatment of patients with non-small cell lung cancer (NSCLC) has impressively bene tted from immunotherapy, in particular from the inhibition of immune checkpoints such as programmed cell death-1 (PD-1) and its corresponding cell death ligand-1 (PD-L1) [52][53][54][55][56][57]. Subsequently, immune checkpoint inhibitors (ICI) on T-cell stimulation facilitate immune mediated elimination of tumor cells [58].…”

Section: Discussionmentioning

confidence: 99%

The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models

Ramelow

Brooks

GaO

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Lung cancer is the number one cancer killer worldwide. A major drawback in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor protein p53 are among the most common alterations in human lung cancers. Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H. Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents. Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune checkpoint inhibitors or other therapeutic strategies in the treatment of lung cancer.

show abstract

Current views on tumor mutational burden in patients with non-small cell lung cancer treated by immune checkpoint inhibitors

Cited by 78 publications

References 55 publications

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants

The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models

Contact Info

Product

Resources

About