Maximum Somatic Allele Frequency in Combination With Blood-Based Tumor Mutational Burden to Predict the Efficacy of Atezolizumab in Advanced Non-small Cell Lung Cancer: A Pooled Analysis of the Randomized POPLAR and OAK Studies

Chen, Yutong; Seeruttun, Sharvesh Raj; Wu, Xiang-yuan; Wang, Zixian

doi:10.3389/fonc.2019.01432

Cited by 24 publications

(29 citation statements)

References 29 publications

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“…Many studies support the viewpoint that bTMB can be used as a biomarker to predict clinical efficacy in anti-PD-1/PD-L1 immunotherapy. Patients with high bTMB have a better ORR and PFS than patients with low bTMB ( 1 , 40 ). However, a retrospective analysis of the POPLAR and OAK studies found that bTMB may not effectively distinguish the benefit in OS of patients receiving immunotherapy at second-line or higher ( 1 , 41 ).…”

Section: Discussionmentioning

confidence: 99%

ctDNA Concentration, MIKI67 Mutations and Hyper-Progressive Disease Related Gene Mutations Are Prognostic Markers for Camrelizumab and Apatinib Combined Multiline Treatment in Advanced NSCLC

Chen

et al. 2020

Front. Oncol.

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Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, P = 0.003), MIKI67 mutation (HR = 114.11, P = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, P = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, P = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.

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Section: Discussionmentioning

confidence: 99%

ctDNA Concentration, MIKI67 Mutations and Hyper-Progressive Disease Related Gene Mutations Are Prognostic Markers for Camrelizumab and Apatinib Combined Multiline Treatment in Advanced NSCLC

Chen

et al. 2020

Front. Oncol.

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“…On the basis of the tissue sample, the tissue TMB (tTMB) is recognized as an accurate molecule as an approximation of tumor load, and the blood TMB (bTMB) could be a substitute for tTMB if necessary ( 65 ). Compared to tTMB, bTMB has easier access and less affected by biopsy.…”

Section: Tumor Mutational Burden As a Biomarkermentioning

confidence: 99%

“…Compared to tTMB, bTMB has easier access and less affected by biopsy. Analyzing the POPLAR trial (NCT01903993) and the OAK trial (NCT02008227), a positive-associated correlation between tTMB and bTMB is observed ( 65 ). More importantly, the accuracy of TMB detection, neither tTMB nor bTMB, requires to be further improved and harmonized as well.…”

Section: Tumor Mutational Burden As a Biomarkermentioning

confidence: 99%

Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

2021

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Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.

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“…A high MSAF is the prerequisite to precise detection of variants and a low MSAF has been shown to greatly contribute to the discordance between bTMB and tTMB [1,9]. Chen et al surprisingly found that NSCLC patients with both low bTMB and low MSAF could derive survival benefits from ICI over chemotherapy [10], in accordance with another study showing both low and high bTMB were associated with better OS than medium bTMB [11]. These results suggested that a proportion of patients might be wrongly classified into low-bTMB group due to a low MSAF value.…”

Section: Current Advancesmentioning

confidence: 99%

Viewpoint: The Current Advances and Future Optimization of Blood-based Tumor Mutation Burden as a Biomarker for Cancer Immunotherapy

A¹

2021

Preprint

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Instead of tissue-based detection, blood-based tumor mutation burden (bTMB) is becoming an alternative promising alternate to predict the response of immune checkpoint inhibitor in cancers, especially non-small-cell lung cancer. Although bTMB is more convenient and less invasive, many evidences identified its limited predictive ability and less accurate discrimination of candidates to receive immunotherapy. Several ways of adjustments have been applied to improve the clinical usefulness of bTMB, such as setting restriction for threshold of allele frequency to exclude some unwanted mutations. But many questions remained to be explored such as the number and the type of mutations that should be incorporated into the bTMB estimation. This viewpoint summarized the current attempts to modify bTMB and provided granular aspects that have implications for further enhancement of bTMB’s predictive capability.

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Maximum Somatic Allele Frequency in Combination With Blood-Based Tumor Mutational Burden to Predict the Efficacy of Atezolizumab in Advanced Non-small Cell Lung Cancer: A Pooled Analysis of the Randomized POPLAR and OAK Studies

Cited by 24 publications

References 29 publications

ctDNA Concentration, MIKI67 Mutations and Hyper-Progressive Disease Related Gene Mutations Are Prognostic Markers for Camrelizumab and Apatinib Combined Multiline Treatment in Advanced NSCLC

ctDNA Concentration, MIKI67 Mutations and Hyper-Progressive Disease Related Gene Mutations Are Prognostic Markers for Camrelizumab and Apatinib Combined Multiline Treatment in Advanced NSCLC

Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

Viewpoint: The Current Advances and Future Optimization of Blood-based Tumor Mutation Burden as a Biomarker for Cancer Immunotherapy

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