The use of a new combination of avelumab + axitinib in patients with metastatic kidney cancer in the first line of treatment

Introduction. Simultaneous inhibition of programmed cell death-1 (PD-1)/PD-L1 immune checkpoint and VEGF/VEGFR signaling has a  synergistic antitumor effect in  preclinical models. This article presents the  results of  the  phase III study JAVELIn Renal 101 (NCT02684006), as well as the experience of using this combination in real clinical practice.

Materials and methods. In 2016, the JAVELIn Renal 101 randomized phase III trial (NCT02684006) was launched to compare the efficacy of avelumab and axitinib versus sunitinib in previously untreated patients with metastatic renal cell carcinoma (mRCC). The study included 886 patients randomized 1:1: avelumab + axitinib group (442 patients) and sunitinib group (444 patients). A total of 560 (63.2%) patients had PD-L1 positive tumor expression (PD-L1+): 270 in avelumab + axitinib group and 290 in sunitinib group.

Results and discussion. Median progression-free survival was 13.8 versus 7.2 months, respectively (RR for disease progression or death 0.61; 95% CI). In the general population median progression-free survival was 13.8 months versus 8.4 months, respectively (RR 0.69; 95% CI 0.56 to 0.84; p < 0.001). Among those with PD-L1-positive tumor status, the objective response rate was 55.2% in avelumab + axitinib group and 25.5% in the sunitinib group; the median follow-up period for overall survival was 11.6 months and 10.7 months; 37 vs 44 patients died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab + axitinib group and in 99.3% in the sunitinib group. Experience of using the combination of avelumab with axitinib in real practice was presented by British researchers in another study. The study included 44 patients with mRCC who had not previously received drug therapy. The mean follow-up period was 6.9 months (range 0.8–13.5 months). The mean age was 68 years (range 48–81). The obtained clinical data confirmed the results of the JAVELIn Renal 101 study with the high efficacy of avelumab + axitinib combination in patients with mRCC in the first line of drug therapy.

Conclusion. The avelumab + axitinib combination is effective in mRCC treatment regardless of ECOG, PD-L1 status and risk group. This combination shows objective rate and PFS increase both in general and PD-L1+ population. 

1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6): 394–424. doi: 10.3322/caac.21492.

2. Fisher R., Gore M., Larkin J. Current and future systemic treatments for renal cell carcinoma. Semin Cancer Bio. 2013;23(1):38–45. doi: 10.1016/j.semcancer.2012.06.004.

3. Choueiri T.K., Motzer R.J. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376(4):354–366. doi: 10.1056/NEJMra1601333.

4. Rini B.I., Escudier B., Tomczak P., Kaprin A., Szczylik C., Hutson T.E. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–1939. doi: 10.1016/S0140-6736(11)61613-9.

5. Motzer R.J., Escudier B., Tomczak P., Hutson T.E., Michaelson M.D., Negrier S. et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14(6):552–562. doi: 10.1016/S1470-2045(13)70093-7 .

6. Bracarda S., Bamias A., Casper J., Negrier S., Sella A., Staehler M. et al. Is Axitinib Still a Valid Option for mRCC in the Second- Line Setting? Prognostic Factor Analyses From the AXIS Trial. Clin Genitourin Cancer. 2019;17(3):e689–e703. doi: 10.1016/j.clgc.2019.03.017 .

7. Taneja S.S. Re: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. J Urol. 2012;188(2):412–413. doi: 10.1016/j.juro.2012.04.069.

8. Hutson T.E., Lesovoy V., Al- Shukri S., Stus V.P., Lipatov O.N., Bair A.H. et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol. 2013;14(13):1287–1294. doi: 10.1016/S1470-2045(13)70465-0.

9. Rini B.I., Melichar B., Ueda T., Grünwald V., Fishman M.N., Arranz J.A. et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomized double- blind phase 2 trial. Lancet Oncol. 2013;14(12):1233–1242. doi: 10.1016/S1470-2045(13)70464-9.

10. Roland C.L., Lynn K.D., Toombs J.E., Dineen S.P., Udugamasooriya D.G., Brekken R.A. Cytokine levels correlate with immune cell infiltration after anti- VEGF therapy in preclinical mouse models of breast cancer. PLoS ONE. 2009;4(11):e7669. doi: 10.1371/journal.pone.0007669.

11. Kaufman H.L., Russell J., Hamid O., Bhatia S., Terheyden P., D’Angelo S.P. et al. Avelumab in patients with chemotherapy- refractory metastatic Merkel cell carcinoma: a multicentre, single- group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374–1385. doi: 10.1016/S14702045(16)30364-3.

12. Gulley J.L., Rajan A., Spigel D.R., Iannotti N., Chandler J., Wong D.J.L. et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIn Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol. 2017;18(5):599– 610. doi: 10.1016/S1470-2045(17)30240-1.

13. Heery C.R., O’Sullivan- Coyne G., Madan R.A., Cordes L., Rajan A., Rauckhorst M. et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIn Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587–598. doi: 10.1016/ S1470-2045(17)30239-5.

14. Patel M.R., Ellerton J., Infante J.R., Agrawal M., Gordon M., Aljumaily R. et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIn Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51–64. doi: 10.1016/ S1470-2045(17)30900-2.

15. Vaishampayan U., Schöffski P., Ravaud A., Borel C., Peguero J., Chaves J. et al. Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIn Solid Tumor trial. J Immunother Cancer. 2019;7(1):275. doi: 10.1186/s40425-019-0746-2.

16. Powles T., Park S.H., Voog E., Caserta C., Valderrama B.P., Gurney H. et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218–1230. doi: 10.1056/ NEJMoa2002788.

17. Hamilton G., Rath B. Avelumab: combining immune checkpoint inhibition and antibody- dependent cytotoxicity. Expert Opin Biol Ther. 2017;17(4):515–523. doi: 10.1080/14712598.2017.1294156.

18. Larroquette M., Gross- Goupil M., Daste A., Robert G., Ravaud A., Domblides C. Which place for avelumab in the management of urothelial carcinoma? Expert Opin Biol Ther. 2019;19(9):863–870. doi: 10.1080/14712 598.2019.1637412.

19. Yasuda S., Sho M., Yamato I., Yoshiji H., Wakatsuki K., Nishiwada S. et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172(3):500–506. doi: 10.1111/cei.12069.

20. Brahmer J.R., Tykodi S.S., Chow L.Q., Hwu W.J., Topalian S.L., Hwu P. et al. Safety and activity of anti- PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. doi: 10.1056/NEJMoa1200694.

21. Choueiri T.K., Larkin J., Oya M., Thistlethwaite F., Martignoni M., Nathan P. et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIn Renal 100): an openlabel, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451–460. doi: 10.1016/S1470-2045(18)30107-4.

22. Motzer R.J., Penkov K., Haanen J., Rini B., Albiges L., Campbell M.T. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–1115. doi: 10.1056/NEJMoa1816047 .

23. Motzer R.J., Robbins P.B., Powles T., Albiges L., Haanen J.B., Larkin J. et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIn Renal 101 trial. Nat Med. 2020;26(11):1733–1741. doi: 10.1038/s41591-020-1044-8.

24. Schwartz L.H., Litière S., de Vries E., Ford R., Gwyther S., Mandrekar S. et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016;62:132–137. doi: 10.1016/j.ejca.2016.03.081.

25. Chalian H., Töre H.G., Horowitz J.M., Salem R., Miller F.H., Yaghmai V. Radiologic assessment of response to therapy: comparison of RECIST Versions 1.1 and 1.0. Radiographics. 2011;31(7):2093–2105. doi: 10.1148/ rg.317115050.

26. Choueiri T.K., Motzer R.J., Rini B.I., Haanen J., Campbell M.T., Venugopal B. 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;31(8):1030–1039. doi: 10.1016/j.annonc.2020.04.010.

27. Huang B., Tian L., Talukder E., Rothenberg M., Kim D.H., Wei L.J. Evaluating treatment effect based on duration of response for a comparative oncology study. JAMA Oncol. 2018;4(6):874–876. doi: 10.1001/jamaoncol.2018.0275.

28. Allison J., Charnley N., Stevenson R., Waddell T., Pillai M.R. Axitinib and avelumab (AA) as first-line treatment of metastatic renal cell carcinoma (mRCC): A realworld outcome review in the Northwest of England, United Kingdom. J Clin Oncol. 2021;39(6S):294. Available at: https://10.1200/JC O.2021.39.6_suppl.294.