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. 2019 Oct 15;25(20):6080-6088.
doi: 10.1158/1078-0432.CCR-19-1135. Epub 2019 Aug 1.

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

Abdallah Flaifel  1 , Wanling Xie  2 , David A Braun  3 , Miriam Ficial  1 , Ziad Bakouny  3 , Amin H Nassar  3 , Rebecca B Jennings  1 , Bernard Escudier  4 , Daniel J George  5 , Robert J Motzer  6 , Michael J Morris  6 , Thomas Powles  7 , Evelyn Wang  8 , Ying Huang  9 , Gordon J Freeman  3 , Toni K Choueiri #  10 , Sabina Signoretti #  11   9
Affiliations

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

Abdallah Flaifel et al. Clin Cancer Res. .

Abstract

Purpose: Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents.

Experimental design: IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR (n = 306) and CABOSUN (n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated.

Results: Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients (P = 0.034) and for patients treated with cabozantinib only (P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression.

Conclusions: Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: D.A. Braun is a consultant/advisory board member for Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnership, Charles River Associates/KC2 Medical, and Schlesinger Trinity Group. B. Escudier is a consultant/advisory board member for Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, and Roche, and reports receiving speaker’s bureau honoraria from Pfizer and Novartis. D.J. George reports receiving commercial research support from Acerta Pharmaceuticals, Astellas, Bayer H/C Pharmaceuticals, Bristol-Meyers Squibb, Calithera, Dendreon, Exelixis, Innocrin, Janssen Pharmaceuticals, Novartis, Pfizer, and Sanofi, speakers bureau honoraria from Bayer H/C Pharmaceuticals, Sanofi, and Exelixis, and is a consultant/advisory board member for Astellas, Astrazeneca, Bayer H/C Pharmaceuticals, Bristol-Meyers Squibb, Capio Biosciences, Exelixis, Genentech, Innocrin, Janssen Pharmaceuticals, Merck Sharp & Dohme, Myovant Sciences, Pfizer, and Sanofi, receives other honorarium from EMD Serono, Michael J. Hennessey Associates, OncLive, Pfizer, and UroToday, is an independent contractor for Axess Oncology, is on the steering committees of NCI and Pfizer, and is on the independent data monitoring committees of Acceleron Pharmaceuticals and Janssen Pharmaceuticals. R.J. Motzer reports receiving commercial research grants from Bristol-Myers Squibb, Pfizer, Genentech/Roche, and Eisai, and is a consultant/advisory board member for Pfizer, Genentech/Roche, Novartis, Eisai, and Exelixis. M.J. Morris reports receiving research funding from Bayer (Inst) Corcept Therapeutics (Inst), Endocyte (Inst), Progenics (Inst), Genentech/Roche (Inst), and Sanofi (Inst); and receiving funds for travel, accommodations, and expenses from Bayer and Endocyte; and is a consulting/advisory board member for Advanced Accelerator Applications, Astellas Pharma, Bayer, Blue Earth Diagnostics, Endocyte, Tokai Pharmaceuticals, and Tolmar Pharmaceuticals. T. Powles is a consultant/advisory board member for Novartis, Pfizer, and GlaxoSmithKline; has received company speaker honoraria from Novartis, Pfizer, GlaxoSmithKline, and Genentech; has participated in trials for GlaxoSmithKline, Pfizer, BMS, Genentech, and Genetech; and has received grants/research support from GlaxoSmithKline, Pfizer, and Novartis. E. Wang is an employee of Exilexis. G.J. Freeman reports receiving commercial research grants from Bristol-Myers Squibb, Roche/ Genentech, Novartis, VCB, and Ipsen; holds ownership interest (including patents) in Novartis, Roche/Genentech, Bristol-Myers Squibb, Amplimmune/ AstraZeneca, Merck, EMD Serono, Beohringer Ingelheim, and Dako; and is a consultant/advisory board member for Novartis, Lilly, Roche/Genentech, Bristol-Myers Squibb, Bethyl Laboratories, Xios Therapeutics, Quiet Therapeutics, and Seattle Genetics. T.K. Choueiri reports receiving commercial research grants from AstraZeneca, Alexion, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis, Ipsen, Tracon, Genentech, Roche, Hoffman-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; and is a consultant/advisory board member for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Heron Therapeutics, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus, Corvus, Ipsen, Up-to Date, NCCN, and Analysis Group. S. Signoretti reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, and Exelixis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; and receives royalties from Biogenex. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1:
Figure 1:
Kaplan Meier estimates of PFS and OS by PD-L1 expression on tumor cells: (A) PFS (B) OS in METEOR study; (C) PFS (D) OS in CABOSUN study.
Figure 2:
Figure 2:
Kaplan Meier estimates of PFS according to treatment, subgroup by (A) TC PD-L1 (–), (B) TC PD-L1 (+) in METEOR study; (C) TC PD-L1 (–), (D) TC PD-L1(+) in CABOSUN study.
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