2108 - Biomarker analyses of ramucirumab in patients with platinum refractory urothelial cancer from RANGE, a global, randomized, double-blind, phase 3 study.

Background

RANGE previously reported positive progression-free survival¹ and a trend towards improved overall survival (OS)² in ramucirumab (RAM) treated patients. Exploratory biomarker analysis of efficacy by programmed death-ligand 1 (PD-L1) expression revealed a hazard ratio (HR) for OS of 0.519, p = 0.0048 in patients with a PD-L1 combined positive score (CPS)≥10 compared to HR of 0.999, p = 0.9955 in patients with a PD-L1 CPS<10. We aim to understand prognostic and predictive factors related to survival outcomes in RANGE, and to identify patients who may benefit from RAM therapy using PD-L1 immunohistochemistry and gene expression analysis, defining molecular subtypes, and tumour microenvironment signatures.

Methods

Archival tumour specimens that met assay stability requirements (238/530 ITT patients in RANGE) were analyzed with the 22C3 PD-L1 antibody with CPS based on tumour cell (TC) and immune cell (IC) staining. RNA expression analysis on archival tumour tissue (394/530 ITT patients) was done by GenomeDx (RNA microarray)³. PD-L1 groups, urothelial carcinoma molecular subtypes, and immune⁴ and stromal phenotypes⁵ were determined and analyzed for association with OS outcome.

Results

Overall, RAM had the greatest improvement in OS in patients with TC ≥ 1, IC ≥ 4 or CPS≥10 PD-L1 status. OS was also more improved in patients with basal subtypes, with considerable overlap noted between basal subtypes and TC ≥ 1, IC ≥ 4, or CPS ≥10 PD-L1 status. In the subgroup with both basal/basal claudin-low subtype and CPS≥10 PD-L1 status, median OS was 9.2 months with RAM and 6.0 months with placebo (stratified hazard ratio 0.47; 95% confidence interval: 0.27-0.84, p = 0.01, n = 79).

Conclusions

Our analysis suggested significant improvement in OS in RAM treated patients with platinum refractory urothelial carcinoma, and with both basal subtype and positive PD-L1 status. References: ¹Petrylak et al, Lancet 2017; 390:2266-77; ²Petrylak et al, Ann Oncol 2018; 29:viii304-5; ³Seiler et al, Eur Urol 2017; 72:544-54; ⁴Charoentong et al, Cell Rep 2017; 18:248-62; ⁵Uhlik et al Cancer Res 2016; 76:2573-86.

Clinical trial identification

NCT02426125.

Editorial acknowledgement

Lisa Cossens and Antonia Baldo of Syneos Health, funded by Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

T.B. Powles: Research grant / Funding (self), Personal fees: Roche; Research grant / Funding (self), Personal fees: AZ; Licensing / Royalties, Personal fees: Merck; Licensing / Royalties, Personal fees: Eli Lilly and Company; Licensing / Royalties, Personal fees: BMS; Licensing / Royalties, Personal fees: Pfizer. D.P. Petrylak: Research grant / Funding (self): Eli Lilly and Company; Licensing / Royalties, Personal fees: Bayer; Research grant / Funding (self), Licensing / Royalties, Personal fees: Bellicum; Research grant / Funding (self), Licensing / Royalties, Personal fees: Dendreon; Research grant / Funding (self), Licensing / Royalties, Personal fees: Sanofi Aventis; Research grant / Funding (self), Licensing / Royalties, Personal fees: Johnson and Johnson; Licensing / Royalties, Personal fees: Exelixis; Licensing / Royalties, Personal fees: Ferring; Research grant / Funding (self), Licensing / Royalties, Personal fees: Millineum; Licensing / Royalties, Personal fees: Medivation; Licensing / Royalties, Personal fees: Pfizer; Research grant / Funding (self), Licensing / Royalties, Personal fees: Roche Laboratories; Research grant / Funding (self), Licensing / Royalties, Personal fees: Tyme Pharmaceuticals; Research grant / Funding (self): Oncogenix; Research grant / Funding (self): Progenics; Research grant / Funding (self): Merck; Research grant / Funding (self): Agensys. R. de Wit: Licensing / Royalties: Eli Lilly and Company; Licensing / Royalties: Merck; Licensing / Royalties: Roche; Licensing / Royalties: Sanofi. K.N. Chi: Research grant / Funding (institution): Eli Lilly and Company. A. Necchi: Research grant / Funding (self), Licensing / Royalties, Non-remunerated activity/ies: Roche; Licensing / Royalties: Merck; Licensing / Royalties: AstraZeneca; Licensing / Royalties: Seattle Genetics; Licensing / Royalties: Bayer. C.N. Sternberg: Licensing / Royalties: Eli Lilly and Company; Licensing / Royalties: BMS; Licensing / Royalties: Merck/Pfizer; Licensing / Royalties: Clovis. S.A. Hussain: Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS. A. Bamias: Licensing / Royalties: AstraZeneca; Licensing / Royalties: BMS; Research grant / Funding (self), Licensing / Royalties: Roche. M.S. Xia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. E. Rasmussen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.A. Aggarwal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S.R. Wijayawardana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. K. Bell-McGuinn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. All other authors have declared no conflicts of interest.