The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer

Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.

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Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer

Cancers ◽

10.3390/cancers12123625 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3625

Author(s):

Boris Duchemann ◽

Jordi Remon ◽

Marie Naigeon ◽

Laura Mezquita ◽

Roberto Ferrara ◽

...

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Circulating Biomarkers ◽

Liquid Biopsies ◽

Technical Requirements ◽

Mutational Burden ◽

Tumor Mutational Burden

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.

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P09.25 Role of Immune Checkpoint Inhibitors (ICPi) in KRAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.453 ◽

2021 ◽

Vol 16 (3) ◽

pp. S300-S301

Author(s):

M. Peravali ◽

C. Gomes-Lima ◽

E. Tefera ◽

M. Baker ◽

M. Sherchan ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung

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Tumor mutational burden assessed by a targeted NGS assay to predict benefit from immune checkpoint inhibitors in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e15075 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e15075-e15075

Author(s):

Sacha Rothschild ◽

Philip Jermann ◽

Spasenija Savic ◽

Kirsten Mertz ◽

Alfred Zippelius ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Mutational Burden ◽

Targeted Ngs ◽

Tumor Mutational Burden

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Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive‐Stage Small Cell Lung Cancer

The Oncologist ◽

10.1634/theoncologist.2020-0193 ◽

2020 ◽

Vol 25 (11) ◽

pp. 981-992

Author(s):

Barbara Melosky ◽

Parneet K. Cheema ◽

Anthony Brade ◽

Deanna McLeod ◽

Geoffrey Liu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Extensive Stage

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Tumor mutational burden assessed by a targeted NGS assay to predict clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14266 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14266-e14266 ◽

Cited By ~ 1

Author(s):

Sacha Rothschild ◽

Ilaria Alborelli ◽

Katharina Leonards ◽

Laura P Leuenberger ◽

Spasenija Savic Prince ◽

...

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Predictive Power ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Nsclc Patients

e14266 Background: In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here we evaluated the predictive power of TMB measured through / by the Oncomine Tumor Mutational Load (TML - Thermo Fisher Scientific) targeted sequencing assay in 71 NSCLC patients treated with ICIs. Methods: TMB was assessed retrospectively in 71 metastatic NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were characterized as either having durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. Results: TMB was significantly higher in patients with DCB compared to patients with NDB (median TMB = 9.2 versus 5.3 mutations/Mb, Mann-Whitney p = 0.014). 70% of patients with high TMB (cutoff = 3rd tertile, TMB ≥ 9.2) were responders (DCB) compared to 29% of patients with low TMB (cutoff = 1st tertile, TMB ≤ 4.5). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log rank test, p = .0030 for PFS and 0 .0375 for OS, respectively). Combining PD-L1 expression and TMB value increased the predictive power of TMB. Conclusions: Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. We believe that a combination of biomarkers will maximize the precision of patient selection.

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Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs) : The Role of Checkpoint Inhibitors

Current Cancer Drug Targets ◽

10.2174/1568009622666220114124335 ◽

2022 ◽

Vol 22 ◽

Author(s):

Giulia Arrivi ◽

Nicola Fazio

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Response Assessment ◽

Neuroendocrine Neoplasms ◽

Precision Oncology ◽

Disease Characteristics

Background: The treatment options for GEP-NENs includes various drugs and is based on grading, morphology and location of the primary Objective: The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs. Method: A scientific literature search from 2015 to January 2020 was performed by using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included Results: several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays the current knowledge in this field is mainly based on a phase I-II studies. Immunotherapy showed limited antitumor activity, but higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment Conclusion: Immunotherapy appears as a powerful possibility to help our patients, but nowadays we see many gaps in this field. We must balance therapeutic possibility offered by precision oncology with the understanding the limitations of application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to candidate for immunotherapy in term of disease characteristics and previous treatments, and how to select them with accurate biomarkers.

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Clinical efficacy of immune checkpoint inhibitors in patients with brain metastases

Immunotherapy ◽

10.2217/imt-2020-0208 ◽

2021 ◽

Vol 13 (5) ◽

pp. 419-432

Author(s):

Vincenzo Di Nunno ◽

Giacomo Nuvola ◽

Mirta Mosca ◽

Ilaria Maggio ◽

Lidia Gatto ◽

...

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Standard Treatment ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Clinical Role ◽

Negative Prognostic Factor ◽

Solid Malignancies

Brain metastases (BMs) represent a negative prognostic factor for patients with solid malignancies. BMs are generally approached with loco-regional treatments and the blood–brain barrier limits the efficacy of some systemic drugs. The aim of this review is to summarize current knowledge about the role of immune checkpoint inhibitors for the management of brain metastases in patients with solid malignancies. We performed a review of available literature. Immune checkpoint inhibitors represent the standard treatment for several advanced solid malignancies. However, with the exception of melanoma their clinical role in other solid malignancies is not completely clear due to the exclusion of patients with BM from approval clinical trials. Immune-checkpoint inhibitors may be an effective treatment of brain metastases of melanoma while their clinical role on brain metastases from other solid malignancies is uncertain.

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VEGF and Immune Checkpoint Inhibition for Prevention of Brain Metastases: Systematic Review and Meta-analysis

Neurology ◽

10.1212/wnl.0000000000012642 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012642

Author(s):

Alireza Mansouri ◽

Varun Padmanaban ◽

Dawit Aregawi ◽

Michael Glantz

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Vegf Inhibitors

Objective:We conducted a systematic review and meta-analysis to investigate the role of VEGF inhibitors and immune checkpoint inhibitors (ICIs) in preventing the development of brain metastasis (BMs).Methods:We searched MEDLINE, EMBASE, Cochrane Database, Google Scholar between January 1, 2000 and June 1, 2020. Included studies were randomized controlled trials (RCTs) of adults with systemic cancer which reported incidence of BMs treated with and without VEGF inhibitors, and observational studies of adults with systemic cancer which reported incidence of BMs treated with and without ICIs (there were no RCTs addressing the ICI question). Pooled relative risks (RR) were computed utilizing a binary random-effects model.Results:A search for VEGF and incidence of new BMs revealed 7 studies (6212 patients with breast, colon and non-small cell lung cancer). Meta-analysis showed a lower incidence of new BMs compared to control (RR 0.71, 95% CI: 0.56-0.89, p=0.003). A search for ICIs and incidence of new BMs yielded 8 studies (732 patients with non-small cell lung cancer or metastatic melanoma) where ICIs were used as an adjunct to radiosurgery. Meta-analysis showed a lower incidence of out-of-treatment-field BMs with ICI inhibitors compared to controls at 1 year (RR 0.65, 95% CI: 0.49-0.88, p=0.005). The overall GRADE score for the evidence evaluating the role of bevacizumab and immune checkpoint inhibitors was high and moderate, respectively.Conclusion:VEGF and immune checkpoint inhibitors may have a role in prophylaxis against brain metastases in patients with solid tumors.

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