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Molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): Results from a phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC)

2018; Elsevier BV; Volume: 29; Linguagem: Inglês

10.1093/annonc/mdy424.037

1569-8041

Brian I. Rini, Mahrukh Huseni, Michael B. Atkins, David F. McDermott, T.B. Powles, Bernard Escudier, Romain Banchereau, L.-F. Liu, Ning Leng, Junjie Fan, Jennifer Doss, Sam C. Nalle, Susheela Carroll, S. Li, Christina Schiff, M. Green, Robert J. Motzer,

Cancer-related gene regulation

Background: Atezo + bev demonstrated improved PFS vs sun in pts with untreated mRCC expressing PD-L1 in Ph II (IMmotion150) and Ph III studies. Biomarker analyses in IMmotion150 suggested that T effector/IFNγ (Teff) and Angiogenesis (Angio) gene expression signatures (GEs) were associated with differential outcomes with atezo + bev and sun. We conducted genomic analyses to validate these GEs with clinical outcomes in IMmotion151 and evaluated their association with MSKCC risk groups and sarcomatoid histology. Methods: Tumour GE analysis was performed by RNASeq in 823 pts from IMmotion151. Associations of Teff and Angio GEs with clinical outcome were evaluated at pre-specified expression level cutoffs identified in IMmotion150. PD-L1 status on immune cells was assessed with the SP142 IHC assay. Results: IMmotion151 met its co-primary endpoint, demonstrating improved PFS with atezo + bev vs sun in PD-L1+ pts (HR, 0.74 [95% CI: 0.57-0.96]; P = 0.02) across MSKCC groups. PFS was also improved in pts with sarcomatoid histology (HR, 0.56 [95% CI: 0.38-0.83]). High Teff GE was associated with PD-L1 expression by IHC and longer PFS in atezo + bev vs sun pts (HR, 0.76 [95% CI: 0.59-0.99]). High Angio GE was associated with improved PFS in the sun arm (HR, 0.59 [95% CI: 0.47-0.75]) but did not differentiate clinical activity between atezo + bev vs sun (HR, 0.95 [95% CI: 0.75-1.19]). Atezo + bev improved PFS vs sun in the low Angio subset (HR, 0.68 [95% CI: 0.52-0.89]). Angio GE was higher (P = 4.28e-06) in favourable vs intermediate/poor MSKCC risk groups. PD-L1+ prevalence was higher (63% vs 39%) and Angio GE was lower (P = 4.73e-16) in sarcomatoid vs non-sarcomatoid tumours. Conclusions: These prospectively tested biomarker results validate molecular signatures that differentiate clinical outcomes with VEGF inhibition and immunotherapy in 1L mRCC. Moreover, these data identify tumour genomic profiles associated with prognostic risk groups and sarcomatoid histology. Findings from this study further our understanding of the biology of kidney cancer and inform future strategies to enable personalized therapy in mRCC pts. Clinical trial identification: NCT02420821. Editorial acknowledgement: Medical writing assistance was provided by Paige S. Davies, PhD, of Health Interactions. Legal entity responsible for the study: F. Hoffmann-La Roche AG. Funding: F. Hoffmann-La Roche AG. Disclosure: B.I. Rini: Consulting or advisory role: Pfizer, Merck, Corvus Pharmaceuticals; Travel, accommodations, expenses: Pfizer; Research funding to institution: Pfizer, Roche/Genentech, Bristol-Myers Squibb, Merck. M. Huseni: Employee of Roche/Genentech. M.B. Atkins: Consulting or advisory role: Roche/Genentech, Pfizer, Novartis, X4 Pharma, Bristol-Myers Squibb, Nektar, Merck, Exelixis, Acceleron Pharma, Peleton, Eisai, Celldex, Alexion Pharmaceuticals, AstraZeneca/MedImmune, Glactone Pharma, Agenus, Idera, Argos Therapeutics, Array BioPharma, Boehringer Ingelheim, Aduro Biotech; Research funding: Bristol-Myers Squibb. D.F. McDermott: Consulting or advisory role: Roche/Genentech, Bristol-Myers Squibb, Merck, Pfizer, Exelixis, Novartis, X4 Pharma, Array BioPharma; Research funding: Prometheus Laboratories. T.B. Powles: Consulting or advisory role: Roche/Genentech, Bristol-Myers Squibb, Merck, Novartis, AstraZeneca; Travel, accommodations, expenses: Bristol-Myers Squibb, Pfizer, Novartis; Honoraria: Bristol-Myers Squibb, Roche/Genentech, Merck; Research funding: AstraZeneca, Roche/Genentech. B. Escudier: Consulting or advisory role: Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, Bayer, Ipsen, EUSA Pharma; Travel, accommodations, expenses: Bristol-Myers Squibb, Pfizer, Novartis; Honoraria: Pfizer, Novartis, Bayer o Bristol-Myers Squibb, Roche/Genentech, Exelixis, Ipsen. R. Banchereau, L-F. Liu, N. Leng, J. Fan, J. Doss, S. Nalle, S. Li, C. Schiff, M. Green: Employee of Roche/Genentech. S. Carroll: Stock ownership and employee of Genentech, Inc. R.J. Motzer: Consulting or advisory role: Pfizer, Novartis, Eisai, Exelixis, Merck, Roche/Genentech; Travel, accommodations, expenses: Bristol-Myers Squibb; Research funding to institution: Pfizer, Roche/Genentech, Bristol-Myers Squibb, GlaxoSmithKline, Eisai, Novartis.