Preliminary results of retrospective analysis Atezolizumab and Bevacizumab in first-line therapy of advanced HCC

Introduction. HCC is a challenge for clinical oncology. 1-year mortality for advanced HCC accounts for 66% in the

Russian Federation. The results obtained in the combined Atezolizumab and Bevacizumab therapy in the advanced HCC cases are reported.

Objective. To assess efficacy and safety of anti-VEGF/PD-L1 Atezolizumab plus Bevacizumab therapy in 20 unresectable HCC patients.

Materials and methods. This analyses carried out in Blokhin National Cancer Research Centre included 20 patients with unresectable HCC treated with the first-line Atezolizumab (1200 mg) and Bevacizumab (15 mg/kg) once every 21 days, 11 patients participated into the global open-label phase 3 trial IMbrave150 23,24 (NCT03434379 / YO40245; Sponsor of study F. Hoffmann-La Roche, Ltd). The therapy was discontinued in cases of tumor progression or intolerant toxicity. The efficacy was evaluated according to RECICT 1.1 criteria. The results were analyzed and visualized on the basis of statistical calculations R 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics for quantitative variables are presented as mean (standard devia[1]tion) and median (lower and upper quartiles), for categorial variables as absolute number of observations (%). To compare quan[1]titative variables (AFP level) in progress Wilcoxon test was used. The differences were considered statistically significant with p < 0.05. Overall survival (OS) and progression-free survival (PFS) data were evaluated according to Kaplan-Meier methodology.

Results and discussion. Median follow up was 9.3 months (quartile 1–3: 6.0–14.4) for 20 patients. Median progression free sur[1]vival was 14.9 months (lower bound, 95% CI, 9.0 months, upper bound NA). 12–month progression-free survival rate from the fixed date of the initial therapy was 56.2% (95% CI: 34.4–91.8%). One-year survival for 20 patients from the fixed date of the initial therapy was 70.0% (95% CI: 49–100). Treatment resulted in objective response (partial regression) in 3 (15%) pts, stable disease in 13 (65.0%) and progression in 4 (20.0%), patients. 35% of patients experienced Gr 3–4 adverse events with Gr3–4 arterial hypertension was the most common one in 20%. In 1 case esophageal varices hemorrhage Gr3 took place.

Conclusion. Atezolizumab and Bevacizumab seems to be highly efficient in advanced HCC.

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. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi: 10.3322/caac.21442.

3. Kaprin A.D., Starinskiy V.V., Petrova G.V. (eds.). Malignant neoplasms in Russia in 2017 (morbidity and mortality). Moscow: P. Hertsen Moscow Oncology Research Institute - branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation; 2018. 250 p. (In Russ.) Available at: https://glavonco.ru/upload/pages/cancer-register/statistika_zabol_2017.pdf.

4. Imamura H., Matsuyama Y., Tanaka E., Ohkubo T., Hasegawa K., Miyagawa S. et al. Risk factors contributing to early and late phase intrahepatic recur rence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200–207. doi: 10.1016/s0168-8278(02)00360-4.

5. Boland P., Wu J. Systemic therapy for hepatocellular carcinoma: beyond sorafenib. Chin Clin Oncol. 2018;7(5):50. doi: 10.21037/cco.2018.10.10.

6. Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F. et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi: 10.1056/NEJMoa0708857.

7. Kudo M., Finn R.S., Qin S., Han K., Ikeda K., Piscaglia F. et al. Lenvatinib ver sus sorafenib in first-line treatment of patients with unresectable hepato cellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173. doi: 10.1016/S0140-6736(18)30207-1.

8. Yoong K.F., McNab G., Hübscher S.G., Adams D.H. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumorinfiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol. 1998;160(8):3978– 3988. Available at: https://pubmed.ncbi.nlm.nih.gov/9558106.

9. El-Khoueiry A.B., Sangro B., Yau T., Crocenzi T., Kudo M., Hsu C. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–2502. doi: 10.1016/S0140-6736(17)31046-2.

10. Yau T., Park J.W., Finn R.S., Cheng A., Mathurin P., Edeline J. et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30(5 Suppl.):851–934. Available at: https://oncologypro.esmo.org/meeting-resources/esmo 2019-congress/CheckMate-459-A-Randomized-Multi-Center-Phase-3- Study-of-Nivolumab-NIVO-vs-Sorafenib-SOR-as-First-Line-1L-Treatment in-Patients-pts-With-Advanced-Hepatocellular-Carcinoma-aHCC.

11. Morse M.A., Sun W., Kim R., He A.R., Abada P.B., Mynderse M., Finn R.S. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019;25(3):912–920. doi: 10.1158/1078-0432.CCR-18-1254.

12. Zhu A.X., Duda D.G., Sahani D.V., Jain R.K. HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol. 2011;8(5):292–301. doi: 10.1038/nrclinonc.2011.30.

13. Motz G.T., Santoro S.P., Wang L.-P., Garrabrant T., Lastra R.R., Hagemann I.S. et al. Tumor endothelium FasL establishes a selective immune barrier promot ing tolerance in tumors. Nat Med. 2014;20(6):607–615. doi: 10.1038/nm.3541.

14. Wallin J.J., Bendell J.C., Funke R., Sznol M., Korski K., Jones S. et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624. doi: 10.1038/ncomms12624.

15. Hegde P.S., Wallin J.J., Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52(Pt. 2):117–124. doi: 10.1016/j.semcancer.2017.12.002.

16. Chen D.S., Hurwitz H. Combinations of bevacizumab with cancer immuno therapy. Cancer J. 2018;24(4):193–204. doi: 10.1097/ PPO.0000000000000327.

17. Herbst R.S., Soria J.-C., Kowanetz M., Fine G.D., Hamid O., Gordon M.S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567. doi: 10.1038/nature14011.

18. Finn R.S., Bentley G., Britten C.D., Amado R., Busuttil R.W. Targeting vascu lar endothelial growth factor with the monoclonal antibody bevacizumab inhibits human hepatocellular carcinoma cells growing in an orthotopic mouse model. Liver Int. 2009;29(2):284–290. doi: 10.1111/j.1478-3231.2008.01762.x.

19. Boige V., Malka D., Bourredjem A., Dromain C., Baey C., Jacques N. et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist. 2012;17(8):1063–1072. doi: 10.1634/theoncologist.2011-0465.

20. Siegel A.B., Cohen E.I., Ocean A., Lehrer D., Goldenberg A., Knox J.J. et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26(18):2992– 2998. doi: 10.1200/JCO.2007.15.9947.

21. Thomas M.B., Garrett-Mayer E., Anis M., Anderton K., Bentz T., Edward A. et al. A randomized phase II open-label multi-institution study of the combi nation of bevacizumab and erlotinib compared to sorafenib in the first line treatment of patients with advanced hepatocellular carcinoma. Oncology. 2018;94(6):329–339. doi: 10.1159/000485384.

22. Lee M.S., Ryoo B-Y., Hsu C.-H., Numata K., Stein S., Verret W. et al. Atezolizumab with or without bevacizumab in unresectable hepatocellu lar carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 2020;21(6):808–820. doi: 10.1016/S1470-2045(20)30156-X.

23. Finn R.S., Qin S., Ikeda M., Qin S., Ikeda M., Galle P. et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi: 10.1056/NEJMoa1915745.

24. Finn R.S., Qin S., Ikeda M., Galle P.R., Ducreux M., Kim T.-Y. et al. IMbrave150: updated overall survival data from a global, randomized, open-label Phase III study of atezolizumab + bevacizumab vs sorafenib in patients with unresectable hepatocellular carcinoma. In: Gastrointestinal Cancers Symposium. January 15–17, 2021. Available at: https://bit.ly/3m2WYcl.

25. Marrero J.A., Kulik L.M., Sirlin C.B., Zhu A.X., Finn R.S., Abecassis M.M. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–750. doi: 10.1002/hep.29913.

26. Ikeda M., Zhu A.X., Qin S., Kim T.-Y., Lim H.Y., Kudo M. et al. 1008P IMbrave150: management of adverse events of special interest (AESIs) for atezolizumab (atezo) and bevacizumab (bev) in unresectable HCC. European Society for Medical Oncology (ESMO). Ann Oncol. 2020;31(4 Suppl.):698–699. doi: 10.1016/j.annonc.2020.08.1124.

27. Lu L.C., Hsu C., Shao Y.Y., Chao Y., Yen C.J., Shih I.L. et al. Differential organ specific tumor response to immune checkpoint inhibitors in hepatocellular carcinoma. Liver Cancer. 2019;8(6):480–490. doi: 10.1159/000501275.

28. Kim H.S., Hong J.Y., Cheon J., Kim I., Kim C.G., Kang B. et al. Different organ-spe cific response to nivolumab to determine the survival outcome of patients with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(15S):4584. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4584.