Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma.
Biomarker
Cabozantinib
Everolimus
METEOR
Renal cell carcinoma
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
07 Aug 2021
07 Aug 2021
Historique:
received:
30
03
2021
accepted:
16
07
2021
entrez:
8
8
2021
pubmed:
9
8
2021
medline:
21
10
2021
Statut:
epublish
Résumé
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. 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 p 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. 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. ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).
Sections du résumé
BACKGROUND
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
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 p
RESULTS
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
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
BACKGROUND
ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).
Identifiants
pubmed: 34364385
doi: 10.1186/s12885-021-08630-w
pii: 10.1186/s12885-021-08630-w
pmc: PMC8349489
doi:
Substances chimiques
Anilides
0
Biomarkers, Tumor
0
Pyridines
0
cabozantinib
1C39JW444G
Everolimus
9HW64Q8G6G
Banques de données
ClinicalTrials.gov
['NCT01865747']
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
904Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
Références
Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376(4):354–66. https://doi.org/10.1056/NEJMra1601333 .
doi: 10.1056/NEJMra1601333
pubmed: 28121507
Loo V, Salgia M, Bergerot P, Philip EJ, Pal SK. First-line systemic therapy for metastatic clear-cell renal cell carcinoma: critical appraisal of emerging options. Target Oncol. 2019;14(6):639–45. https://doi.org/10.1007/s11523-019-00676-y .
doi: 10.1007/s11523-019-00676-y
pubmed: 31595385
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–23. https://doi.org/10.1056/NEJMoa1510016 .
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27. https://doi.org/10.1016/S1470-2045(16)30107-3 .
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115–25. https://doi.org/10.1016/j.ejca.2018.02.012 .
Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308. https://doi.org/10.1158/1535-7163.MCT-11-0264 .
Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14(15):4726–34. https://doi.org/10.1158/1078-0432.CCR-07-4921 .
Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23(1):18–25. https://doi.org/10.1016/j.semcancer.2012.06.001 .
doi: 10.1016/j.semcancer.2012.06.001
pubmed: 22705278
Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111(37):13373–8. https://doi.org/10.1073/pnas.1404848111 .
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347–61. https://doi.org/10.1016/S1535-6108(03)00085-0 .
doi: 10.1016/S1535-6108(03)00085-0
pubmed: 12726861
Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, et al. C-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 2013;24(2):343–9. https://doi.org/10.1093/annonc/mds463 .
Gustafsson A, Martuszewska D, Johansson M, Ekman C, Hafizi S, Ljungberg B, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009;15(14):4742–9. https://doi.org/10.1158/1078-0432.CCR-08-2514 .
Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35(21):2687–97. https://doi.org/10.1038/onc.2015.343 .
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–9. https://doi.org/10.1200/JCO.2008.21.4809 .
doi: 10.1200/JCO.2008.21.4809
pubmed: 19826129
Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9(2):802–11.
Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13(8):827–37. https://doi.org/10.1016/S1470-2045(12)70241-3 .
Pena C, Lathia C, Shan M, Escudier B, Bukowski RM. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res. 2010;16(19):4853–63. https://doi.org/10.1158/1078-0432.CCR-09-3343 .
doi: 10.1158/1078-0432.CCR-09-3343
pubmed: 20651059
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. J Clin Oncol. 2009;27(20):3312–8. https://doi.org/10.1200/JCO.2008.19.5511 .
Voss MH, Chen D, Marker M, Hakimi AA, Lee CH, Hsieh JJ, et al. Circulating biomarkers and outcome from a randomised phase II trial of sunitinib vs everolimus for patients with metastatic renal cell carcinoma. Br J Cancer. 2016;114(6):642–9. https://doi.org/10.1038/bjc.2016.21 .
Harmon CS, DePrimo SE, Figlin RA, Hudes GR, Hutson TE, Michaelson MD, et al. Circulating proteins as potential biomarkers of sunitinib and interferon-alpha efficacy in treatment-naive patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2014;73(1):151–61. https://doi.org/10.1007/s00280-013-2333-4 .
doi: 10.1007/s00280-013-2333-4
pubmed: 24220935
Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829–41. https://doi.org/10.1056/NEJMoa2026982 .
Tolaney SM, Ziehr DR, Guo H, Ng MR, Barry WT, Higgins MJ, et al. Phase II and biomarker study of cabozantinib in metastatic triple-negative breast cancer patients. Oncologist. 2017;22(1):25–32. https://doi.org/10.1634/theoncologist.2016-0229 .
Leibowitz-Amit R, Pintilie M, Khoja L, Azad AA, Berger R, Laird AD, et al. Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: A post hoc analysis of an extension cohort of a phase II trial. J Transl Med. 2016;14(1):1–8.
doi: 10.1186/s12967-015-0747-y
Kontovinis LF, Papazisis KT, Touplikioti P, Andreadis C, Mouratidou D, Kortsaris AH. Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers. BMC Cancer. 2009;9(1):82. https://doi.org/10.1186/1471-2407-9-82 .
doi: 10.1186/1471-2407-9-82
pubmed: 19284623
pmcid: 2662874
Flaifel A, Xie W, Braun DA, Ficial M, Bakouny Z, Nassar AH, et al. PD-L1 expression and clinical outcomes to cabozantinib, everolimus, and sunitinib in patients with metastatic renal cell carcinoma: analysis of the randomized clinical trials METEOR and CABOSUN. Clin Cancer Res. 2019;25(20):6080–8. https://doi.org/10.1158/1078-0432.CCR-19-1135 .
Marshall SW. Power for tests of interaction: effect of raising the type I error rate. Epidemiol Perspect Innov. 2007;4(1):4. https://doi.org/10.1186/1742-5573-4-4 .
doi: 10.1186/1742-5573-4-4
pubmed: 17578572
pmcid: 1910596
D'Aniello C, Berretta M, Cavaliere C, Rossetti S, Facchini BA, Lovane G, et al. Biomarkers of prognosis and efficacy of anti-angiogenic therapy in metastatic clear cell renal cancer. Front Oncol. 2019;9:1400. https://doi.org/10.3389/fonc.2019.01400 .
doi: 10.3389/fonc.2019.01400
pubmed: 31921657
pmcid: 6917607
Lee CH, Motzer RJ, Glen H, Michaelson MD, Larkin J, Minoshima Y, et al. Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. Br J Cancer. 2020;124:237–46.
doi: 10.1038/s41416-020-01092-0