Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma

Lee, Chung-Han; Motzer, Robert J.; Glen, Hilary; Michaelson, M. Dror; Larkin, James; Minoshima, Yukinori; Kanekiyo, Michio; Ikezawa, Hiroki; Sachdev, Pallavi; Dutcus, Corina E.; Funahashi, Yasuhiro; Voss, Martin H.

doi:10.1038/s41416-020-01092-0

Cited by 12 publications

(12 citation statements)

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“…Evaluation of interaction terms for predictive biomarkers requires anywhere from 4 to 16 times the sample size needed for testing main effects, and one approach to address this is to raise the cutoff for the p -value when considering interactions [ 26 ]. Clear predictive biomarkers for treatment of RCC have not been reported [ 27 ], and some studies have taken the approach of using multiple biomarkers to calculate a composite biomarker score for benefit, including for everolimus versus sunitinib [ 19 ] and more recently, for lenvatinib plus everolimus versus everolimus alone [ 28 ]. Additional studies are needed to identify predictive biomarkers in advanced RCC.…”

Section: Discussionmentioning

confidence: 99%

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma

et al. 2021

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Background In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. Methods In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. Results Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. Conclusions PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. Trial registration ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).

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Section: Discussionmentioning

confidence: 99%

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma

et al. 2021

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“…We could not identify markers for non-Responders, but many such transcripts that changed in Responders included an increase in IL-18 mRNA that was also detectable in serum protein levels. A differential increase in serum IL-18 associated with longer OS was also reported for lenvatinib plus everolimus, 38 but a decrease was reported for atezolizumab. 37 IL-18 synergizes with IL-12 to increase transcript level for IFNG, 39 and IFNG is among the 565 genes expressed at higher levels in the CheckMate 009 Responders at day 28 ( online supplemental table S5 ).…”

Section: Discussionmentioning

confidence: 79%

“… 37 IL-18 synergizes with IL-12 to increase transcript level for IFNG, 39 and IFNG is among the 565 genes expressed at higher levels in the CheckMate 009 Responders at day 28 ( online supplemental table S5 ). The conflicting observations for association between serum IL-18 levels and OS with nivolumab, 25 lenvatinib plus everolimus, 38 or atezolizumab 37 may reflect the importance of assay timing relative to therapeutic response. In sum, IL-18 is a nivolumab mechanistic marker that potentially allows monitoring of response in the periphery.…”

Section: Discussionmentioning

confidence: 99%

Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC

Ross‐Macdonald

Walsh

Chasalow

et al. 2021

J Immunother Cancer

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BackgroundNivolumab is an immune checkpoint inhibitor targeting the programmed death-1 receptor that improves survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). In contrast to other tumor types that respond to immunotherapy, factors such as programmed death ligand-1 (PD-L1) status and tumor mutational burden show limited predictive utility in ccRCC. To address this gap, we report here the first molecular characterization of nivolumab response using paired index lesions, before and during treatment of metastatic ccRCC.MethodsWe analyzed gene expression and T-cell receptor (TCR) clonality using lesion-paired biopsies provided in the CheckMate 009 trial and integrated the results with their PD-L1/CD4/CD8 status, genomic mutation status and serum cytokine assays. Statistical tests included linear mixed models, logistic regression models, Fisher’s exact test, and Kruskal-Wallis rank-sum test.ResultsWe identified transcripts related to response, both at baseline and on therapy, including several that are amenable to peripheral bioassays or to therapeutic intervention. At both timepoints, response was positively associated with T-cell infiltration but not associated with TCR clonality, and some non-Responders were highly infiltrated. Lower baseline T-cell infiltration correlated with elevated transcription of Wnt/β-catenin signaling components and hypoxia-regulated genes, including the Treg chemoattractant CCL28. On treatment, analysis of the non-responding patients whose tumors were highly T-cell infiltrated suggests association of the RIG-I-MDA5 pathway in their nivolumab resistance. We also analyzed our data using previous transcriptional classifications of ccRCC and found they concordantly identified a molecular subtype that has enhanced nivolumab response but is sunitinib-resistant.ConclusionOur study describes molecular characteristics of response and resistance to nivolumab in patients with metastatic ccRCC, potentially impacting patient selection and first-line treatment decisions.Trial registration numberNCT01358721.

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“…However, the differences did not reach statistical significance. Recently, Lee et al also found the blood levels of angiopoietin-2 to have predictive and prognostic properties in their biomarker analysis [ 28 ]. In another study comparing everolimus alone vs. lenvatinib alone vs. everolimus plus lenvatinib, angiogenesis- and inflammatory-related proteins, including angiopoietin-2 and IL-18BP, were also associated with the PFS or OS [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

Zeuschner

Hölters

Stöckle

et al. 2021

Cancers

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There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.

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Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma

Cited by 12 publications

References 47 publications

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma

Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC

Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

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