Abstract 155P
Background
Prior studies have evaluated molecular profiles for advanced RCC patients treated with immunotherapy to inform personalized treatment strategies; limited data are available for targeted therapies.
Methods
Eligible patients included 240 advanced clear-cell (cc) and 45 non-clear cell (ncc) RCC patients treated with targeted therapies at Aarhus University Hospital between 2006 and 2016. Four gene signatures (T-cell-inflamed GEP, myeloid-derived suppressor cells [mMDSC, gMDSC], angiogenesis) and PD-L2 as a single gene were analysed in tumour specimens, with correlations evaluated by histology subtype using Spearman correlation coefficients. For ccRCC patients, association with best overall response (BOR) (% complete or partial response) defined by clinician-assessment, and progression-free and overall survival (PFS, OS) were examined. Multivariate modeling was used, adjusted for International mRCC Database Consortia (IMDC) scores, age, and other covariates, with no multiplicity adjustments.
Results
Among 240 ccRCC patients, median age was 63 years, with 68% male, 46%/34% IMDC int./poor scores, and majority treated with VEGF inhibitors. Compared with ccRCC, nccRCC patients had worse prognosis, functional status, and greater mTOR inhibitor use. There were differences between histology subtypes in biomarker expression with higher levels in cc (gMDSC [p=0.03], p≤0.0009 other comparisons). For each subtype, moderate-strong (rho≥0.6-0.9) correlations were consistently observed, except for angiogenesis and gMDSC (Table). For ccRCC patients, angiogenesis and T-cell inflamed GEP were significantly associated with BOR and PFS (Table).
Conclusions
Angiogenesis and T-cell inflamed GEP gene signatures were associated with response in ccRCC patients receiving VEGF inhibitors. Results are hypothesis-generating, and further exploration of correlates of response for nccRCC patients is warranted. Table: 155P
| Correlations (cc, ncc) (Spearman rho)1 | ||||||||||
| GEP | mMDSC | PDL-2 | gMDSC | angio | ||||||
| cc | Ncc | cc | ncc | cc | ncc | cc | ncc | cc | ncc | |
| GEP | 0.74 | 0.90 | 0.72 | 0.87 | ** | 0.70 | ** | ** | ||
| mMDSC | 0.74 | 0.90 | 0.77 | 0.78 | 0.59 | 0.89 | ** | ** | ||
| PD-L2 | 0.72 | 0.87 | 0.77 | 0.78 | ** | 0.64 | ** | ** | ||
| gMDSC | ** | 0.70 | 0.59 | 0.89 | ** | 0.64 | ** | ** | ||
| angio | ** | ** | ** | ** | ** | ** | ** | ** | ||
| Outcomes Association(ccRCC only) | ||||||||||
| BOR, % (95%)1 | biomarker high vs low | |||||||||
| PFS, HR2 (95% CI) | OS, HR (95% CI) | |||||||||
| Angio | ||||||||||
| 16.7% (0.10, 0.25) | 0.72 (0.55, 0.95) | 0.76 (0.57, 1.01) | | |||||||
| ≥median | 31.0% (0.23, 0.40) | |||||||||
| T-cell-inflamed GEP | ||||||||||
| 17.0% (0.11, 0.25) | 0.64 (0.46, 0.88) | 0.84 (0.62, 1.15) | | |||||||
| ≥median | 31.2% (0.23, 0.41) |
1p≤0.001 or 2p≤0.02 after multivariate adjustment, **rho≤0.4; HR, hazard ratio; CI, confidence interval.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
F. Donskov: Research grant/Funding (institution): MSD; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Ipsen. C.A. Pinto: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. R. Predoui: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. F. Kong: Full/Part-time employment: Merck & Co., Inc. C. Fox: Full/Part-time employment: Merck & Co., Inc. K. Skaarup: Full/Part-time employment: MSD. R. Perini: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. T. Steiniche: Research grant/Funding (institution): MSD. All other authors have declared no conflicts of interest.