Drug Evaluation

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma

Department of Oncology, Palacký University Medical School & Teaching Hospital, 77900 Olomouc, Czech Republic

Institute of Molecular & Translational Medicine, Palacký University Medical School Teaching Hospital, 77900 Olomouc, Czech Republic

Search for more papers by this author

Denisa Vitásková

Department of Oncology, Palacký University Medical School & Teaching Hospital, 77900 Olomouc, Czech Republic

Search for more papers by this author

Hana Študentová

*Author for correspondence: Tel.: +420 588 444 288;

E-mail Address: hana.studentova@fnol.cz

Department of Oncology, Palacký University Medical School & Teaching Hospital, 77900 Olomouc, Czech Republic

Search for more papers by this author

Published Online:5 Oct 2020https://doi.org/10.2217/fon-2020-0079

View article

Abstract

Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Yagoda A, Petrylak D, Thompson S. Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol. Clin. North Am. 20, 303–321 (1993).
Medline CASGoogle Scholar
2. Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353, 14–17 (1999).
MedlineGoogle Scholar
3. Pyrhonen S, Salminen E, Ruutu M et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J. Clin. Oncol. 17, 2859–2867 (1999).
Medline CASGoogle Scholar
4. Fyfe G, Fisher RI, Rosenberg SA et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. 13, 688–696 (1995).
Medline CASGoogle Scholar
5. McDermott DF, Regan MM, Clark JI et al. Randomized Phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 23, 133–141 (2005).
Medline CASGoogle Scholar
6. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J. Clin. Oncol. 17, 2530–2540 (1999).
Medline CASGoogle Scholar
7. Ko JJ, Xie WL, Kroeger N et al. International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 16(3), 293–300 (2015).
MedlineGoogle Scholar
8. Brugarolas J. Renal-cell carcinoma – molecular pathways and therapies. N. Engl. J. Med. 356(2), 185–187 (2007).
Medline CASGoogle Scholar
9. Escudier B, Bellmunt J, Negrier S et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J. Clin. Oncol. 28(13), 2144–2150 (2010).
Medline CASGoogle Scholar
10. Rini BI, Halabi S, Rosenberg JE et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J. Clin. Oncol. 28, 2137–2143 (2010).
Medline CASGoogle Scholar
11. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007). • Principal report of the trial that established sunitinib as the standard of care in metastatic renal cell carcinoma for more than a decade. Sunitinib monotherapy is the comparator arm in all Phase 3 trials of immune checkpoint inhibitor-based combination therapy.
Medline CASGoogle Scholar
12. Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized Phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).
Medline CASGoogle Scholar
13. Buchler T, Bortlicek Z, Poprach A et al. Outcomes for patients with metastatic renal cell carcinoma achieving a complete response on targeted therapy: a registry-based analysis. Eur. Urol. 70(3), 469–475 (2016).
MedlineGoogle Scholar
14. Buchler T, Poprach A, Bortlicek Z et al. Outcomes of patients with long-term treatment response to vascular endothelial growth factor-targeted therapy for metastatic renal cell cancer. Clin. Genitourin. Cancer 15(6), E1047–E1053 (2017).
MedlineGoogle Scholar
15. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
Medline CASGoogle Scholar
16. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled Phase III trial. Lancet 372, 449–456 (2008).
Medline CASGoogle Scholar
17. Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1814–1823 (2015).
Medline CASGoogle Scholar
18. Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1803–1813 (2015).
Medline CASGoogle Scholar
19. Motzer RJ, Nosov D, Eisen T et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a Phase III trial. J. Clin. Oncol. 31(30), 3791–3799 (2013).
Medline CASGoogle Scholar
20. Choueiri TK, Halabi S, Sanford BL et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J. Clin. Oncol. 35(6), 591–597 (2017).
Medline CASGoogle Scholar
21. Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind Phase III trial. Lancet 370, 2103–2111 (2007).
MedlineGoogle Scholar
22. Studentova H, Vitaskova D, Melichar B. Lenvatinib for the treatment of kidney cancer. Expert Rev. Anticancer Ther. 18(6), 511–518 (2018).
Medline CASGoogle Scholar
23. Buchler T, Klapka R, Melichar B et al. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma – data from the Czech registry. Ann. Oncol. 23, 395–401 (2012).
Medline CASGoogle Scholar
24. Huang H, Langenkamp E, Georganaki M et al. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kappa B-induced endothelial activation. FASEB J. 29(1), 227–238 (2015).
Medline CASGoogle Scholar
25. Alfaro C, Suarez N, Gonzalez A et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br. J. Cancer 100(7), 1111–1119 (2009).
Medline CASGoogle Scholar
26. 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. 2, 1096–1103 (1996).
Medline CASGoogle Scholar
27. McDermott DF, Huseni MA, Atkins MB 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. 24(12), 749–757 (2018).
Medline CASGoogle Scholar
28. Amin A, Plimack ER, Ernstoff MS et al. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunother Cancer 22(6), 109 (2018).
Google Scholar
29. Rini BI, Plimack ER, Stus V et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380(12), 1116–1127 (2019). •• Primary report of the KEYNOTE-426 trial that established the combination of pembrolizumab with axitinib.
Medline CASGoogle Scholar
30. Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380(12), 1103–1115 (2019). •• Primary report of efficacy of the combination of avelumab with axitinib, a competitor of the pembrolizumab plus axitinib combination.
Medline CASGoogle Scholar
31. Rini BI, Powles T, Atkins MB et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, Phase 3, randomised controlled trial. Lancet 393(10189), 2404–2415 (2019). •• Primary report of IMmotion151, a Phase 3 trial investigating the efficacy of the combination of atezolizumab with bevacizumab, a competitor of the pembrolizumab plus axitinib combination.
MedlineGoogle Scholar
32. Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378(14), 1277–1290 (2018). •• Primary report of the CheckMate 214 trial demonstrating efficacy of the combination of nivolumab with ipilimumab, the key competitor of the pembrolizumab plus axitinib combination.
Medline CASGoogle Scholar
33. Motzer R, Rini BI, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, Phase 3 trial. Lancet Oncol. 20(10), 1370–1385 (2019).
Medline CASGoogle Scholar
34. Dudani S, Graham J, Wells JC et al. First-line immuno-oncology combination therapies in metastatic renal-cell carcinoma: results from the International Metastatic Renal-Cell Carcinoma Database Consortium. Eur. Urol. 76(6), 861–867 (2019).
Medline CASGoogle Scholar
35. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
Medline CASGoogle Scholar
36. Ascierto PA, Ferrucci PF, Fisher R et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat. Med. 25(6), 941–946 (2019).
Medline CASGoogle Scholar
37. Sullivan RJ, Hamid O, Gonzalez R et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 25(6), 929–935 (2019).
Medline CASGoogle Scholar
38. Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 3584–3590 (2009).
Medline CASGoogle Scholar
39. Motzer RJ, Hutson TE, Glen H et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, Phase 2, open-label, multicentre trial. Lancet Oncol. 16(15), 1473–1482 (2015).
Medline CASGoogle Scholar
40. Atzpodien J, Kirchner H, Hanninen EL et al. Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer. Eur. J. Cancer 29A, S6–S8 (1993).
MedlineGoogle Scholar
41. Grunwald V, Powles T, Choueiri TK et al. Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. Future Oncol. 15(9), 929–941 (2019).
CASGoogle Scholar
42. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Medline CASGoogle Scholar
43. Melichar B, Freedman RS. Immunology of the peritoneal cavity: relevance for host-tumor relation. Int. J. Gynecol. Cancer 12, 3–17 (2002).
Medline CASGoogle Scholar
44. Melichar B, Nash MA, Lenzi R et al. Expression of costimulatory molecules CD80 and CD86 and their receptors CD28, CTLA-4 on malignant ascites CD3+ tumor infiltrating lymphocytes (TIL) from patients with ovarian and other types of peritoneal carcinomatosis. Clin. Exp. Immunol. 119, 19–27 (2000).
Medline CASGoogle Scholar
45. Melichar B, Jandik P, Krejsek J et al. Mitogen-induced lymphocyte proliferation and systemic immune activation in cancer patients. Tumori 82, 218–220 (1996).
Medline CASGoogle Scholar
46. Melichar B, Touskova M, Solichova D et al. CD4+ T-lymphocytopenia and systemic immune activation in patients with primary and secondary liver tumours. Scand. J. Clin. Lab. Invest. 61, 363–370 (2001).
Medline CASGoogle Scholar
47. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).
Medline CASGoogle Scholar
48. Motzer RJ, Rini BI, Bukowski RM et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295, 2516–2524 (2006).
Medline CASGoogle Scholar
49. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised Phase 3 trial. Lancet 378, 1931–1939 (2011).
Medline CASGoogle Scholar
50. Shah AY, Kotecha RR, Lemke EA et al. Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors. Eur. J. Cancer 114, 67–75 (2019).
Medline CASGoogle Scholar
51. Escudier B, Motzer RJ, Sharma P et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur. Urol. 72(3), 368–376 (2017).
Medline CASGoogle Scholar
52. Ott PA, Bang YJ, Piha-Paul SA et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol. 37(4), 318–327 (2019).
MedlineGoogle Scholar
53. Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375(19), 1823–1833 (2016).
Medline CASGoogle Scholar
54. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 272, 2521–2532 (2015).
Google Scholar
55. Patnaik A, Kang SP, Rasco D et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin. Cancer Res. 21(19), 4286–4293 (2015).
Medline CASGoogle Scholar
56. Chen Y, Tortorici MA, Garrett M et al. Clinical pharmacology of axitinib. Clin. Pharmacokinet. 52(9), 713–725 (2013).
Medline CASGoogle Scholar
57. Hutson TE, Lesovoy V, Al-Shukri S et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label Phase 3 trial. Lancet Oncol. 14(13), 1287–1294 (2013).
Medline CASGoogle Scholar
58. Atkins MB, Plimack ER, Puzanov I et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion Phase Ib trial. Lancet Oncol. 19(3), 405–415 (2018). • Phase Ib trial of the pembrolizumab plus axitinib combination.
Medline CASGoogle Scholar
59. McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2(5), 662–673 (2013).
Medline CASGoogle Scholar
60. Ahamadi M, Freshwater T, Prohn M et al. Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometrics Syst. Pharmacol. 6(1), 49–57 (2017).
Medline CASGoogle Scholar
61. Freshwater T, Kondic A, Ahamadi M et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J. Immunother. Cancer 5, 43 (2017).
MedlineGoogle Scholar
62. Wang DD, Zhang S, Zhao H et al. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J. Clin. Pharmacol. 49(9), 1012–1024 (2009).
Medline CASGoogle Scholar
63. Zientek MA, Goosen TC, Tseng E et al. In vitro kinetic characterization of axitinib metabolism. Drug Metab. Dispos. 44(1), 102–114 (2016).
Medline CASGoogle Scholar
64. Hu-Lowe DD, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res. 14(22), 7272–7283 (2008).
Medline CASGoogle Scholar
65. Inai T, Mancuso M, Hashizume H et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 165(1), 35–52 (2004).
Medline CASGoogle Scholar
66. Rugo HS, Herbst RS, Liu G et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J. Clin. Oncol. 23(24), 5474–5483 (2005).
Medline CASGoogle Scholar
67. Pithavala YK, Chen Y, Toh M et al. Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. Cancer Chemother. Pharmacol. 70(1), 103–112 (2012).
Medline CASGoogle Scholar
68. Tortorici MA, Toh M, Rahavendran SV et al. Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics. Invest. New Drugs 29(6), 1370–1380 (2011).
Medline CASGoogle Scholar
69. Chen Y, Rini BI, Motzer RJ et al. Effect of renal impairment on the pharmacokinetics and safety of axitinib. Target. Oncol. 11(2), 229–234 (2016).
MedlineGoogle Scholar
70. Kopecky J, Ticha A, Janeckova H, Melichar B. Hemodiafiltration and plasma levels of axitinib in a patient with metastatic renal clear cell carcinoma. Biomed. Pap. Olomouc 162(4), 335–339 (2018).
Google Scholar
71. Rini BI, Schiller JH, Fruehauf JP et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin. Cancer Res. 17(11), 3841–3849 (2011).
Medline CASGoogle Scholar
72. Rini BI, Melichar B, Ueda T et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind Phase 2 trial. Lancet Oncol. 14, 1233–1242 (2013).
Medline CASGoogle Scholar
73. Rini BI, Melichar B, Fishman MN et al. Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized Phase II study in metastatic renal cell carcinoma. Ann. Oncol. 26(7), 1372–1377 (2015).
Medline CASGoogle Scholar
74. Rixe O, Bukowski RM, Michaelson MD et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a Phase II study. Lancet Oncol. 8(11), 975–984 (2007).
MedlineGoogle Scholar
75. Rini BI, Tomita Y, Melichar B et al. Overall survival analysis from a randomized Phase II study of axitinib with or without dose titration in first-line metastatic renal cell carcinoma. Clin. Genitourin. Cancer 14(6), 499–503 (2016).
MedlineGoogle Scholar
76. Tykodi SS, Donskov F, Lee JL et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J. Clin. Oncol. 37(15), v381–v382 (2019).
Google Scholar
77. Lee JL, Ziobro M, Gafanov R et al. KEYNOTE-427 cohort B: first-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (NCC-RCC). J. Clin. Oncol. 37(15), 4569 (2019).
Google Scholar
78. Tzogani K, Skibeli V, Westgaard I et al. The European Medicines Agency approval of axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Oncologist 20(2), 196–201 (2015).
Medline CASGoogle Scholar
79. DeVito T, Saleh N. FDA approves two new indications and dosage form for pembrolizumab. Oncology (Williston Park) 33(5), 186 (2019).
MedlineGoogle Scholar
80. Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369(2), 134–144 (2013).
Medline CASGoogle Scholar
81. Melichar B. Laboratory medicine and medical oncology: the tale of two Cinderellas. Clin. Chem. Lab. Med. 51, 99–112 (2013).
Medline CASGoogle Scholar
82. Iacovelli R, Nole F, Verri E et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target. Oncol. 11(2), 143–148 (2016).
MedlineGoogle Scholar
83. Choueiri TK, Figueroa DJ, Fay AP et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin. Cancer Res. 21(5), 1071–1077 (2015).
Medline CASGoogle Scholar
84. Pradere JP, Dapito DH, Schwabe RF. The yin and yang of Toll-like receptors in cancer. Oncogene 33(27), 3485–3495 (2014).
Medline CASGoogle Scholar
85. Melichar B, Gregor J, Solichova D et al. Increased urinary neopterin in acute myocardial infarction. Clin. Chem. 40, 338–339 (1994).
Medline CASGoogle Scholar
86. Solichova D, Melichar B, Blaha V et al. Biochemical profile and survival in nonagenarians. Clin. Biochem. 34, 563–569 (2001).
Medline CASGoogle Scholar
87. Melichar B, Solichova D, Melicharova K et al. Urinary neopterin in patients with advanced colorectal carcinoma. Int. J. Biol. Markers 21, 190–198 (2006).
Medline CASGoogle Scholar
88. Melichar B, Solichová D, Freedman RS. Neopterin as an indicator of immune activation and prognosis in patients with gynecological malignancies. Int. J. Gynecol. Cancer 16, 240–252 (2006).
Medline CASGoogle Scholar
89. Melichar B, Solichova D, Svobodova I, Melicharova K. Neopterin in renal cell carcinoma: inhalational administration of interleukin-2 is not accompanied by a rise of urinary neopterin. Luminescence 20, 311–314 (2005).
Medline CASGoogle Scholar
90. Krcmova LK, Cervinkova B, Solichova D et al. Fast and sensitive HPLC method for the determination of neopterin, kynurenine and tryptophan in amniotic fluid, malignant effusions and wound exudates. Bioanalysis 7(21), 2751–2762 (2015).
Medline CASGoogle Scholar
91. Friberg M, Jennings R, Alsarraj M et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101(2), 151–155 (2002).
Medline CASGoogle Scholar
92. Li HX, Bullock K, Gurjao C et al. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nature Comm. 10, 4346 (2019).
MedlineGoogle Scholar

Vol. 17, No. 3

Metrics

Downloaded 298 times

History

Received 3 February 2020

Accepted 26 August 2020

Published online 5 October 2020

Published in print January 2021

Information

Keywords

Financial & competing interests disclosure

B Melichar receives honoraria for speeches and has an advisory role with Roche, Pfizer, BMS, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E. Lilly and Pierre Farbre. Funding was received from Grantová Agentura České Republiky 17-16614S and 18-12204S. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Company review disclosure

In addition to the peer-review process, with the authors’ consent, the manufacturer of the product discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made by the authors at their discretion and based on scientific or editorial merit only. The authors maintained full control over the manuscript, including content, wording and conclusions.

PDF download