Subscribe to RSS
DOI: 10.1055/a-1190-5681
Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure
Ansprechen eines fortgeschrittenen HCC auf Pembrolizumab und Lenvatinib Kombinationstherapie trotz Versagen der Monotherapie![](https://www.thieme-connect.de/media/zfg/202008/lookinside/thumbnails/zfg-0014_10-1055-a-1190-5681-1.jpg)
Abstract
In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.
Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.
As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.
Zusammenfassung
In den letzten Jahren wurden Immuncheckpointinhibitoren (ICIs) erfolgreich in die Krebstherapie eingeführt. Für einige Tumorentitäten sind diese Substanzen bereits unverzichtbarer Bestandteil der therapeutischen Optionen geworden. Beim fortgeschrittenen hepatozellulären Karzinom (aHCC) zeigte sich hingegen für die Monotherapie bisher keine statistisch signifikante Verbesserung des Patientenüberlebens.
Kürzlich wurde jedoch für die Kombination von Atezolizumab und Bevacizumab eine sehr gute Wirksamkeit gezeigt. Die Wirksamkeit einer Kombination von ICI- und VEGF-Hemmung, aber auch frühe Daten zu synergistischen Mechanismen der Substanzklassen wurden so weiter untermauert.
Da die TKI-Behandlung derzeit der Standard der aHCC-Behandlung ist und ICIs von der FDA zugelassen und in vielen anderen Regionen der Welt erhältlich sind, wurden trotz fehlender Zulassung in Europa zahlreiche Patienten mit einer Monotherapie dieser Medikamente behandelt. Es ist jedoch unklar, ob ein Nichtansprechen auf diese Substanzen in der Monotherapie Bedeutung für die Kombination hat. Wir berichten über eine erste Patientin, die trotz vorausgegangenen Nichtansprechens auf TKI- und ICI-Monotherapie sehr gut auf die Kombinationstherapie angesprochen hat.
Key words
PD-1 - tyrosine kinase inhibitor - lenvatinib - pembrolizumab - atezolizumab - bevacizumab - nivolumab - immunotherapy - liver cancer - HCCSchlüsselwörter
PD-1 - tyrosine kinase inhibitor - TKI - Lenvatinib - Pembrolizumab - Aatezolizumab - Bevacizumab - Nivolumab - Immuntherapie - Leberzellkarzinom - HCCPublication History
Received: 27 January 2020
Accepted: 23 May 2020
Article published online:
12 August 2020
© Georg Thieme Verlag KG
Stuttgart · New York
-
References
- 1 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163-1173
- 2 Bruix J, Qin S, Merle P. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389: 56-66
- 3 Kudo M. Cabozantinib for advanced hepatocellular carcinoma. Hepatobiliary Surg Nutr 2019; 8: 153-156
- 4 Zhu AX, Kang YK, Yen CJ. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 282-296
- 5 Wege H, Li J, Ittrich H. Treatment lines in hepatocellular carcinoma. Visc Med 2019; 35: 266-272
- 6 Finn RS, Ryoo BY, Merle P. et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clinical Oncol 2019; 37: 4004
- 7 BMS PR. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibbs-opdivo-nivolumab-receives-fda-approval-t
- 8 Roche PR. https://www.roche.com/media/releases/med-cor-2019-10-21.htm
- 9 Llovet J, Finn RS, Ikeda M. et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Ann Oncol 2019; 30: v253-v324
- 10 Alfarouk KO, Stock CM, Taylor S. et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 2015; 15: 71
- 11 Siravegna G, Mussolin B, Buscarino M. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015; 21: 795-801
- 12 Xu MJ, Feng M. Radiation therapy in HCC: what data exist and what data do we need to incorporate into guidelines?. Semin Liver Dis 2019; 39: 43-52
- 13 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69: 182-236
- 14 Gallicchio R, Nardelli A, Mainenti P. et al. Therapeutic strategies in HCC: radiation modalities. Biomed Res Int 2016; 2016: 1295329
- 15 Byun HK, Kim HJ, Im YR. et al. Dose escalation in radiotherapy for incomplete transarterial chemoembolization of hepatocellular carcinoma. Strahlenther Onkol 2019; 196: 132-141
- 16 Ngwa W, Irabor OC, Schoenfeld JD. et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018; 18: 313-322
- 17 Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 2018; 52: 117-124
- 18 Becht E, de Reynies A, Giraldo NA. et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res 2016; 22: 4057-4066
- 19 Gabrilovich DI, Chen HL, Girgis KR. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096-1103
- 20 Gabrilovich D, Ishida T, Oyama T. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92: 4150-4166
- 21 Oyama T, Ran S, Ishida T. et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998; 160: 1224-1232
- 22 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162-174
- 23 Huang Y, Yuan J, Righi E. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 2012; 109: 17561-17566
- 24 Kloepper J, Riedemann L, Amoozgar Z. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 2016; 113: 4476-4481
- 25 Peterson TE, Kirkpatrick ND, Huang Y. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci U S A 2016; 113: 4470-4475
- 26 Schmittnaegel M, Rigamonti N, Kadioglu E. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med 2017; 9: eaak9670
- 27 Matsui J, Yamamoto Y, Funahashi Y. et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008; 122: 664-671
- 28 Okamoto K, Kodama K, Takase K. et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett 2013; 340: 97-103
- 29 Makker V, Rasco D, Vogelzang NJ. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019; 20: 711-718
- 30 Taylor MH, Lee CH, Makker V. et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 2020; 38: 1154-1163