Experience of the nivolumab use in patients with metastatic renal cell carcinoma provided under the expanded access program in Russia. Subgroup analysis of the correlation between expression markers and the effectiveness of nivolumab therapy

Abstract: Nivolumab was registered in Russia in December 2016 as a monotherapy for advanced renal cell carcinoma (RCC) and it remains a second‑line treatment choice for patients with disease progression after the use of tyrosine kinase inhibitors. Even though immunotherapy has already proven to be an effective approach for the treatment of RCC, predictive biomarkers for the rational selection of patients remain unidentified.

Seventy‑five patients with metastatic renal cell carcinoma (mRCC) who received nivolumab in the 2nd and subsequent lines of therapy from 2015 to 2020 under the expanded access program were enrolled in this study. The objective response rate was 21,3 %. Median progression‑free survival (PFS) was 5,5 months. Median overall survival (OS) was not reached.

To analyze molecular biomarkers correlated with the response to immunotherapeutic treatment, we performed whole‑transcriptome RNA sequencing of 16 samples (FFPE) in 15 patients with the assessment of the expression level for individual genes (PDCD1, CD274, CD8A, CD8B, CD4) and gene signatures (Angio, Teff, Myeloid Inflammation).

Disease control rates were not different for the subgroups of patients with high and low expression of any of the signatures examined, and further principal component analysis did not reveal clustering of patients with and without objective response.

Further studies on a larger sample of patients will help confirm or deny the predictive role of biomarkers selected for analysis in a heterogeneous population of RCC patients.

1. Motzer R. J. et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5 (6):e001079. doi: 10.1136/esmoopen-2020-001079.

2. Rini B. I. et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21 (12):1563-1573. doi: 10.1016/S1470-2045 (20) 30436-8.

3. Choueiri T. K., Motzer R. J., Rini B. I. et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31 (8):1030-1039. doi: 10.1016/j. annonc. 2020.04.010.

4. Atkins M. B., Clark J. I., Quinn D. I. Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions. Annals of Oncology 28: 1484–1494, 2017. doi:10.1093/annonc/mdx151.

5. Motzer R. J., Escudier B., McDermott D. F., et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373 (19): 1803-1813.

6. Motzer R. J., Tykodi S. S. et al. Nivolumab versus Everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 Trial. Journal of Clinical Oncology doi: 10.1200/JCO. 2020.38.6_suppl. 617.

7. Kamba T., Yamasaki T., Teramukai S., Shibasaki N., Arakaki R., Sakamoto H. et al. Improvement of prognosis in patients with metastatic renal cell carcinoma and Memorial Sloan-Kettering Cancer Center intermediate risk features by modern strategy including molecular-targeted therapy in clinical practice. Int J Clin Oncol. 2014;19 (3):505-15. doi:10.1007/s10147-013-0581-2.

8. Konishi S., Hatakeyama S., Numakura K., Narita S., Inoue T., Saito M. et al. Validation of the IMDC prognostic model in patients with metastatic renal-cell carcinoma treated with first-line Axitinib: a multicenter retrospective study. Clin Genitourin Cancer. 2019 Oct;17 (5):e1080-e1089. doi: 10.1016/j. clgc. 2019.07.006.

9. Jardim D. L., Goodman A., de Melo Gagliato D., Kurzrock R. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker. Cancer Cell. 2021 Feb 8;39 (2):154-173. doi: 10.1016/j. ccell. 2020.10.001.

10. Shen X., Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018 Sep 10;362: k3529. doi: 10.1136/bmj. k3529.

11. Xu Y., Wan B., Chen X., Zhan P., Zhao Y., Zhang T., Liu H. et al. The association of PD-L1 expression with the efficacy of anti-PD-1/PD-L1 immunotherapy and survival of non-small cell lung cancer patients: a meta-analysis of randomized controlled trials. Transl Lung Cancer Res. 2019 Aug;8 (4):413-428. doi: 10.21037/tlcr. 2019.08.09.

12. Halbert B., Einstein D. J. Hot or Not: Tumor Mutational Burden (TMB) as a Biomarker of Immunotherapy Response in Genitourinary Cancers. Urology. 2021 Jan;147:119-126. doi: 10.1016/j. urology. 2020.10.030.

13. Zhu J., Armstrong A. J., Friedlander T. W., Kim W., Pal S. K., George D. J., Zhang T. Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond. J Immunother Cancer. 2018 Jan 25;6 (1):4. doi: 10.1186/s40425-018-0314-1.

14. Motzer R. J., Escudier B., McDermott D. F., George S. et al. CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373 (19):1803-13. doi: 10.1056/NEJMoa1510665.

15. Motzer R. J., Tannir N. M., McDermott D. F. et al. CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378 (14):1277-1290. doi: 10.1056/NEJMoa1712126.

16. McDermott D. F., Huseni M. A., Atkins M. B., Motzer R. J., Rini B. I. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018 Jun;24 (6):749-757. doi: 10.1038/s41591-018-0053-3.

17. Fehrenbacher L., Spira A., Ballinger M., Kowanetz M. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387 (10030):1837-46. doi: 10.1016/S0140-6736 (16) 00587-0.

18. Rosenberg J. E., Hoffman – Censits J., Powles T., van der Heijden M. S. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemo-therapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387 (10031):1909-20. doi: 10.1016/S0140-6736916)00561-4.

19. Snyder A., Makarov V., Merghoub T., Yuan J. et al. Genetic basis for clinical response to CTLA-4 blockade in mela-noma. N Engl J Med. 2014 Dec 4;371 (23):2189-2199. doi: 10.1056/NEJMoa1406498.

20. Rizvi N. A., Mazières J., Planchard D. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16 (3):257-65. doi: 10.1016/S1470-2045 (15) 70054-9.

21. Gabrilovich D. I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar;9 (3):162-74. doi: 10.1038/nri2506.

22. Robert J. Motzer et al. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Eur Urol. 2017 Dec;72 (6):962-971. doi:10.1016/j.eururo.2017.02.010.

23. McDermott D. F., Huseni M. A., Atkins M. B., Motzer R. J. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018 Jun;24 (6):749-757. doi: 10.1038/s41591-018-0053-3.

24. Rini B. I., Motzer R. J., Powles T., McDermott D. F. et al. Atezolizumab plus Bevacizumab Versus Sunitinib for Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Features: A Prespecified Subgroup Analysis of the IMmotion151 Clinical Trial. Eur Urol. 2021 May;79 (5):659-662. doi: 10.1016/j. eururo. 2020.06.021.

25. Courcier J., Dalban C., Laguerre B., Ladoire S. et al. Primary Renal Tumour Response in Patients Treated with Nivo-lumab for Metastatic Renal Cell Carcinoma: Results from the GETUG-AFU 26 NIVOREN Trial. Eur Urol. 2021 Jun 5: S0302-2838 (21) 00389-4. doi: 10.1016/j. eururo. 2021.05.020.