Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study

Marabelle, Aurélien; Fakih, Marwan; Lopez, Juanita; Shah, Manisha H.; Shapira‐Frommer, Ronnie; Nakagawa, Kazuhiko; Chung, Hyun Cheol; Kindler, Hedy L.; López-Martín, José A.; Miller, Wilson H.; Italiano, Antoîne; Kao, Steven; Piha-Paul, Sarina A.; Delord, Jean Pierre; McWilliams, Robert R.; Fabrizio, David; Aurora-Garg, Deepti; Liu, Xu; Jin, Fan; Norwood, Kevin; Bang, Yung Jue

doi:10.1016/s1470-2045(20)30445-9

Cited by 1,710 publications

(1,324 citation statements)

References 22 publications

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“…Higher PD-L1 expression of tumor cells have been showed to be associated with a better objective response to pembrolizumab, while good anti-tumor response to nivolumab occurred in patients regardless of PD-L1 expression ( 18 , 19 ). Additionally, patients with high level of TMB prior to starting therapy may respond to immune checkpoint inhibition ( 20 ). Nevertheless, the percentage of patients with high TMB was low in HCC, and its application as a predictive marker for PD-1 therapy is not recommended in our current clinical practice ( 20 , 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, patients with high level of TMB prior to starting therapy may respond to immune checkpoint inhibition ( 20 ). Nevertheless, the percentage of patients with high TMB was low in HCC, and its application as a predictive marker for PD-1 therapy is not recommended in our current clinical practice ( 20 , 21 ). Therefore, more studies are needed to identify robust predictors as useful tools to allow clinicians to tailor therapy for patients who may fail to respond to PD-1/PDL1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…However, only a fraction of patients benefits from the PD-1/PD-L1 monotherapy, indicating it is very important to excavate a curative effect predictor for precise immunotherapy of advanced HCC (13)(14)(15)(16)(17). According to the limited researches (18)(19)(20)(21), tumor mutational burden (TMB) and PD-L1 expression are the most extensively studied predictive markers for the efficacy of PD-1/PD-L1 treatment. Nevertheless, the percentage of patients with high TMB was low in HCC, and its value as a predictive marker for PD-1 therapy is not reported in the CheckMate-040 and KEYNOTE-224 study (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients

Yuan

Song

et al. 2021

Front. Immunol.

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BackgroundThere is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC.AimThe aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients.MethodsA total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility.ResultsEight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797–0.991) and 0.883 (95% CI, 0.716–0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness.ConclusionsThis study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients

Yuan

Song

et al. 2021

Front. Immunol.

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“…The approval of Pembrolizumab for the treatment of high TMB tumors was based on the results of the KEYNOTE-156 basket study. Results of the study demonstrated that among 790 evaluable patients throughout a 37-month median follow-up period, objective response to Pembrolizumab treatment was observed in 29% of patients with high TMB versus 6% in the non-high TMB cohort [82].…”

Section: Immunotherapy Optionsmentioning

confidence: 99%

Neuroendocrine and Aggressive-Variant Prostate Cancer

Spetsieris

Boukovala

Patsakis

et al. 2020

Cancers

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In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.

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“…This process increases the number of tumor‐infiltrating immune cells (IC) in the tumor microenvironment and bolsters cytotoxic T‐cell responses. TMB was found to correlate with response to ICIs in a cross‐study analysis of 27 tumor types 11 and in a prospective multicohort evaluation, 12 and correlations with overall survival have further reinforced the predictive value of TMB in many cancers 11,13‐15 . Given the association of TMB with response to ICIs, the substantial number of ongoing clinical trials surveying TMB as a potential biomarker is unsurprising 13 …”

Section: Introductionmentioning

confidence: 96%

Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden

Shemesh¹,

Chan²,

Legrand³

et al. 2020

Pharmacology Res & Perspec

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Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study

Cited by 1,710 publications

References 22 publications

Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients

Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients

Neuroendocrine and Aggressive-Variant Prostate Cancer

Pan‐cancer population pharmacokinetics and exposure‐safety and ‐efficacy analyses of atezolizumab in patients with high tumor mutational burden

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