Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer

Hellmann, Matthew D.; Callahan, Margaret K.; Awad, Mark M.; Calvo, Emiliano; Ascierto, Paolo A.; Atmaca, Akin; Rizvi, Naiyer A.; Hirsch, Fred R.; Selvaggi, Giovanni; Szustakowski, Joseph D.; Sasson, Ariella; Golhar, Ryan; Vitazka, Patrik; Han, Chang; Geese, William J.; Antonia, Scott

doi:10.1016/j.ccell.2019.01.011

Cited by 175 publications

(152 citation statements)

References 0 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…The increase in TMB assessment by various methods has brought with it a confusing array of information that documents how TMB has been determined and reported. The wide variation in TMB estimation and reporting methods across studies that have already been published demonstrates an evident lack of standardization and harmonization of current TMB assessment methods (Table ) . These extensive differences may arise from the theoretic framework, technical methods applied, and the way that TMB data are reported, and will be described in more detail in the later sections of this article.…”

Section: The Need For Standardization and Harmonization Of Tmb Assessmentioning

confidence: 99%

“…However, calling indels can be challenging and their inclusion may depend on the sensitivity of the methods used to detect them . Other bioinformatic parameters that impact TMB estimation and reporting include quality control metrics and various data‐filtering procedures for inclusion/exclusion of a variant in the TMB estimation . Filtering algorithms and cutoffs for putative germline variants, variant allele frequency (VAF), and FFPE‐induced deamination artefacts vary between assays and can be affected by biological and preanalytical factors.…”

Section: Variation In Tmb Assessment and Factors That Impact Tmb Outputmentioning

confidence: 99%

See 1 more Smart Citation

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

Stenzinger

Allen

Maas³

et al. 2019

Genes Chromosomes & Cancer

188

161

View full text Add to dashboard Cite

Characterization of tumors utilizing next‐generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence‐based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.

show abstract

Section: The Need For Standardization and Harmonization Of Tmb Assessmentioning

confidence: 99%

Section: Variation In Tmb Assessment and Factors That Impact Tmb Outputmentioning

confidence: 99%

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

Stenzinger

Allen

Maas³

et al. 2019

Genes Chromosomes & Cancer

188

161

View full text Add to dashboard Cite

show abstract

“…Patients with high mutation loads, ie, the number of mutations per million bases (mb) in target regions, are more susceptible to immune checkpoint inhibitors (eg PD‐1 or PD‐L1‐mediated immunotherapy) than the patients with low mutation loads in lung and other cancers . Some mutations in mismatch repair genes, homologous recombination genes, or POLE have been associated with high mutation load .…”

Section: Discussionmentioning

confidence: 99%

Targeted deep sequencing from multiple sources demonstrates increased NOTCH1 alterations in lung cancer patient plasma

Liao

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

Introduction Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer‐associated genes across varying sample sites in lung cancer patients. Materials and Methods Targeted deep sequencing for 48 tumor‐related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin‐fixed paraffin‐embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. Results Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV‐dominated, CNV‐dominated, and codominated groups. Conclusions Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.

show abstract

“…The mechanisms of immune checkpoints blockade support the rational design of their combinations in cancer immunotherapy . Clinical trials by far have verified the favorable objective response rate of the combination of the PD‐1/PD‐L1 blockade and CTLA‐4 blockade in patients with lung cancer and melanoma . Nivolumab plus ipilimumab showed manageable safety profiles in CheckMate 032 .…”

Section: Improving the Efficiency Of Checkpoint Blockadementioning

confidence: 98%

Checkpoint blockade‐based immunotherapy in the context of tumor microenvironment: Opportunities and challenges

2018

View full text Add to dashboard Cite

A dynamic and mutualistic interaction between tumor cells and tumor microenvironment (TME) promotes the progression and metastasis of solid tumors. Cancer immunotherapy is becoming a major treatment paradigm for a variety of cancers. Although immunotherapy, especially the use of immune checkpoint inhibitors, has achieved clinical success, only a minority of patients exhibits durable responses. Clinical studies directed at identifying appropriate biomarkers and immune profiles that can be used to predict immunotherapy responses are presently being conducted. Combining treatment strategies tailored to cancer‐immune interactions are designed to increase the rate of durable clinical response in patients. It is essential to establish a reasonable tumor classification strategy according to TME to improve cancer immunotherapy. In the current review, a modified classification of TME is proposed, and optimization of TME classification is needed through detailed and integrated molecular characterization of large patient cohorts in the future.

show abstract

Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer

Cited by 175 publications

References 0 publications

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

Targeted deep sequencing from multiple sources demonstrates increased NOTCH1 alterations in lung cancer patient plasma

Checkpoint blockade‐based immunotherapy in the context of tumor microenvironment: Opportunities and challenges

Contact Info

Product

Resources

About