A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors
Tóm tắt
Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W.
ClinicalTrials.gov
ID:
NCT02718911
(Registration Date: May 3, 2011).
Tài liệu tham khảo
Yin Z, Bai L, Li W, Zeng T, Tian H, Cui J (2019) Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy. J Exp Clin Cancer Res 38(1):403. https://doi.org/10.1186/s13046-019-1409-3
Thommen DS, Schumacher TN (2018) T cell dysfunction in Cancer. Cancer Cell 33(4):547–562. https://doi.org/10.1016/j.ccell.2018.03.012
Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39(1):98–106. https://doi.org/10.1097/COC.0000000000000239
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Marquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD (2019) Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med 381(16):1535–1546. https://doi.org/10.1056/NEJMoa1910836
Gonzalez-Martin A, Sanchez-Lorenzo L (2019) Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: still promising? Cancer 125(Suppl 24):4616–4622. https://doi.org/10.1002/cncr.32520
Papadopoulos KP, Gluck L, Martin LP, Olszanski AJ, Tolcher AW, Ngarmchamnanrith G, Rasmussen E, Amore BM, Nagorsen D, Hill JS, Stephenson J Jr (2017) First-in-human study of AMG 820, a monoclonal anti-Colony-stimulating factor 1 receptor antibody, in patients with advanced solid tumors. Clin Cancer Res 23(19):5703–5710. https://doi.org/10.1158/1078-0432.CCR-16-3261
Cassetta L, Kitamura T (2018) Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front Cell Dev Biol 6:38. https://doi.org/10.3389/fcell.2018.00038
Saung MT, Muth S, Ding D, Thomas DL 2nd, Blair AB, Tsujikawa T, Coussens L, Jaffee EM, Zheng L (2018) Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. J Immunother Cancer 6(1):118. https://doi.org/10.1186/s40425-018-0435-6
Holmgaard RB, Zamarin D, Lesokhin A, Merghoub T, Wolchok JD (2016) Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine 6:50–58. https://doi.org/10.1016/j.ebiom.2016.02.024
Li M, Li M, Yang Y, Liu Y, Xie H, Yu Q, Tian L, Tang X, Ren K, Li J, Zhang Z, He Q (2020) Remodeling tumor immune microenvironment via targeted blockade of PI3K-gamma and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy. J Control Release 321:23–35. https://doi.org/10.1016/j.jconrel.2020.02.011
Peng X, Hou P, Chen Y, Dai Y, Ji Y, Shen Y, Su Y, Liu B, Wang Y, Sun D, Jiang Y, Zha C, Xie Z, Ding J, Geng M, Ai J (2019) Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models. J Exp Clin Cancer Res 38(1):372. https://doi.org/10.1186/s13046-019-1357-y
Boulakirba S, Pfeifer A, Mhaidly R, Obba S, Goulard M, Schmitt T, Chaintreuil P, Calleja A, Furstoss N, Orange F, Lacas-Gervais S, Boyer L, Marchetti S, Verhoeyen E, Luciano F, Robert G, Auberger P, Jacquel A (2018) IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential. Sci Rep 8(1):256. https://doi.org/10.1038/s41598-017-18433-4
IMC CS4. Adis Insight. 2011. Available on https://adisinsight.springer.com/drugs/800034411. Accesssed 16 March 2020
Autio KA, Klebanoff CK, Schaer D, Kauh JS, Slovin SF, Blinder VS, Comen EA, Danila DC, Hoffman DMJ, Kang S, McAndrew P, Modi S, Morris MJ, Rathkopf DE, Sanford RA, Tate SC, Yu D, McArthur HL (2019) Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC). J Clin Oncol 37(15_suppl):2548–2548. https://doi.org/10.1200/JCO.2019.37.15_suppl.2548
Holmgaard RB, Brachfeld A, Gasmi B, Jones DR, Mattar M, Doman T, Murphy M, Schaer D, Wolchok JD, Merghoub T (2016) Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy. Oncoimmunology 5(7):e1151595. https://doi.org/10.1080/2162402X.2016.1151595
Hamanishi J, Mandai M, Konishi I (2016) Immune checkpoint inhibition in ovarian cancer. Int Immunol 28(7):339–348. https://doi.org/10.1093/intimm/dxw020
Santini FC, Hellmann MD (2018) PD-1/PD-L1 Axis in lung Cancer. Cancer J 24(1):15–19. https://doi.org/10.1097/PPO.0000000000000300
Peters S, Kerr KM, Stahel R (2018) PD-1 blockade in advanced NSCLC: a focus on pembrolizumab. Cancer Treat Rev 62:39–49. https://doi.org/10.1016/j.ctrv.2017.10.002
Doo DW, Norian LA, Arend RC (2019) Checkpoint inhibitors in ovarian cancer: a review of preclinical data. Gynecol Oncol Rep 29:48–54. https://doi.org/10.1016/j.gore.2019.06.003
U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Available on https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf. Accesssed 16 March 2020
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026
Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D (2017) Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 5(1):53. https://doi.org/10.1186/s40425-017-0257-y
von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S, Aquino R, Kotoulek S, de Boer CJ, Engert A (2015) An open-label, multicenter, phase I/II study of JNJ-40346527, a CSF-1R inhibitor, in patients with relapsed or refractory Hodgkin lymphoma. Clin Cancer Res 21(8):1843–1850. https://doi.org/10.1158/1078-0432.CCR-14-1845
Gomez-Roca CA, Italiano A, Le Tourneau C, Cassier PA, Toulmonde M, D'Angelo SP, Campone M, Weber KL, Loirat D, Cannarile MA, Jegg AM, Ries C, Christen R, Meneses-Lorente G, Jacob W, Klaman I, Ooi CH, Watson C, Wonde K, Reis B, Michielin F, Ruttinger D, Delord JP, Blay JY (2019) Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages. Ann Oncol 30(8):1381–1392. https://doi.org/10.1093/annonc/mdz163
Wesolowski R, Sharma N, Reebel L, Rodal MB, Peck A, West BL, Marimuthu A, Severson P, Karlin DA, Dowlati A, Le MH, Coussens LM, Rugo HS (2019) Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther Adv Med Oncol 11:1758835919854238. https://doi.org/10.1177/1758835919854238
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, Lu D, Zhang Y, Joshi A, Dresser MJ (2012) A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet 51(2):119–135. https://doi.org/10.2165/11596370-000000000-00000
Pradel LP, Ooi CH, Romagnoli S, Cannarile MA, Sade H, Ruttinger D, Ries CH (2016) Macrophage susceptibility to Emactuzumab (RG7155) treatment. Mol Cancer Ther 15(12):3077–3086. https://doi.org/10.1158/1535-7163.MCT-16-0157
Cassier PA, Garin G, Eberst L, Delord J-P, Chabaud S, Terret C, Montane L, Bidaux A-S, Laurent S, Jaubert L, Ferlay C, Bernardin M, Tabone-Eglinger S, Gilles-Afchain L, Menetrier-Caux C, Caux C, Treilleux I, Pérol D, Gomez-Roca CA (2019) MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). J Clin Oncol 37(15_suppl):2579–2579. https://doi.org/10.1200/JCO.2019.37.15_suppl.2579
Dowlati A, Rugo HS, Harvey RD, Kudchadkar RR, Carvajal RD, Manji GA, Hamid O, Klempner SJ, Tang S, Yu D, Kauh JS, Schaer DA, Tate SC, Wesolowski R (2017) A phase I study of LY3022855, a colony stimulating factor-1 receptor (CSF-1R) inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol 35(15_suppl):2523–2523. https://doi.org/10.1200/JCO.2017.35.15_suppl.2523
Baverel PG, Dubois VFS, Jin CY, Zheng Y, Song X, Jin X, Mukhopadhyay P, Gupta A, Dennis PA, Ben Y, Vicini P, Roskos L, Narwal R (2018) Population pharmacokinetics of Durvalumab in Cancer patients and association with longitudinal biomarkers of disease status. Clin Pharmacol Ther 103(4):631–642. https://doi.org/10.1002/cpt.982
Ryman JT, Meibohm B (2017) Pharmacokinetics of monoclonal antibodies. CPT Pharmacometrics Syst Pharmacol 6(9):576–588. https://doi.org/10.1002/psp4.12224
Pognan F, Couttet P, Demin I, Jaitner B, Pang Y, Roubenoff R, Sutter E, Timsit Y, Valentin MA, Vogel B, Woerly G, Wolf A, Schramm U (2019) Colony-stimulating Factor-1 antibody Lacnotuzumab in a phase 1 healthy volunteer study and mechanistic investigation of safety outcomes. J Pharmacol Exp Ther 369(3):428–442. https://doi.org/10.1124/jpet.118.254128