ESMO 2019: NIVOREN GETUG-AFU 26 Translational Study: CD8 Infiltration and PD-L1 Expression are Associated with Outcome in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Nivolumab

Barcelona, Spain ( To date, there have been no robust predictors of response to nivolumab for patients with metastatic renal cell carcinoma (mRCC). Previously, the NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in clear cell mRCC patients in a “real world setting”, noting a response rate of 21%, median PFS of 3.7 months and median OS of 24.5 months.1 Thereafter, a translational research program was launched to characterize immune cell populations in and around the tumor by immunohistochemistry (IHC) and correlate them with outcome on nivolumab treatment. At the ESMO 2019 annual congress, Dr. Vano and colleagues presented the initial results of their translational work. 

For the GETUG AFU 26 NIVOREN trial, all patients treated with nivolumab who consented for translational program and with available archived paraffin-embedded tumor tissue samples were eligible. Tumors were centrally reviewed, and densities of CD3-, CD8- and CD20-cells and tertiary lymphoid structures (TLS) were estimated by IHC. PD-L1 expression was quantified as percentage of positive tumor cells and immune cells.

Among the 720 patients in the trial, 324 patients were included in this analysis. These patients had similar baseline characteristics to the overall trial population. The median PFS was 4.5 (2.9-5.2) months and median OS was 25.4 (23.6-NE) months. Having the highest density of CD8 T cells at the invasive margin was associated with worse PFS (2.3 vs 4.6 months, HR 3.96, 95% CI 1.84-8.51, p = 0.0001) and OS (8.6 vs 25.4 months, HR 2.43, 95% CI 0.99-5.95, p = 0.0451). PD-L1 expression on tumor cells was associated with worse OS (22.7 vs 29.1 months, HR 1.51, 95% CI 1.06-2.15, p = 0.0232) but not PFS (3.5 vs 4.6 months, p = 0.5121). PD-L1 expression on immune cells was associated with shorter median OS, but was not statistically significant (24.7 months vs NR, HR 1.34, 95% CI 0.95-1.88, p = 0.0955). CD8 densities, either in the tumor or at the invasive margin were associated with high PD-L1 expression (>1%) by tumor cells or by immune cells (all p < 0.0001). Furthermore, the highest density of CD8 in the invasive margin was associated with poor PFS (p=0.0001) and OS (p=0.04). Densities of CD3, CD20 and TLS were not significantly associated with OS or PFS. 

The conclusions from this biomarker evaluation of the GETUG AFU 26 NIVOREN trial are as follows:

  • These results demonstrate the feasibility of a pathological central review and the efficient coordination of multiple scientific teams at a national level
  • There was correlation between CD8 density and PD-L1 expression
  • 46% of tumors PD-L1 negative for tumor cells were PD-L1 positive for immune cells
  • CD8 highest infiltration in the invasive margin, but not in the tumor core, was associated with poor outcomes (PFS and OS) even in this cohort treated with nivolumab. However, these results need to be validate in larger studies
  • PD-L1 expression by immune cells was associated with worse OS

Clinical trial identification NCT03013335

Presented by: Yann Vano, MD, Hopital European George Pompidou, Paris, FR

Co-Authors: N. Rioux-Leclercq 2, C. Dalban 3, C. Sautès-Fridman 4, A. Bougoüin 5, N. Chaput 6, S. Chouaib 7, B. Beuselinck 8, C. Chevreau 9, M. Gross-Goupil 10, S. Negrier 3, B. Laguerre 11, D. Borchiellini 12, I. Colina-Moreno 5, W.H. Fridman 13, S. Chabaud 3, F. Tantot 14, J. Barros Monteiro 15, B. Escudier 16, L. Albiges 17

2. CHU, Université de Rennes, France, Rennes, FR

3. Centre Léon Bérard, Lyon, FR

4. Cordeliers Research Center, Paris, FR

5. Team Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, FR

6. Gustave Roussy Institut de Cancérologie, Villejuif, FR,

7. Institut Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, FR,

8. University Hospitals Leuven - Campus Gasthuisberg, Leuven, BE

9. Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse, FR

10. CHU Bordeaux Hopital St. André, Bordeaux, FR

11. Centre Eugene - Marquis, Rennes, FR

12. Centre Anticancer Antoine Lacassagne, Nice, FR

13. INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, FR

14. Unicancer, PARIS, FR

15. UNICANCER, Paris, FR

16. Gustave Roussy - Cancer Campus, Villejuif, FR

17. Institut Gustave Roussy, Villejuif, FR

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 


1. Albiges L et al, Abstract 542, GU ASCO 2019