Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies

Shigehisa Kitano, Toshio Shimizu, Takafumi Koyama, Takahiro Ebata, Satoru Iwasa, Shunsuke Kondo, Akihiko Shimomura, Yutaka Fujiwara, Noboru Yamamoto, Anne Paccaly, Siyu Li, Petra Rietschel, Tasha Sims, Shigehisa Kitano, Toshio Shimizu, Takafumi Koyama, Takahiro Ebata, Satoru Iwasa, Shunsuke Kondo, Akihiko Shimomura, Yutaka Fujiwara, Noboru Yamamoto, Anne Paccaly, Siyu Li, Petra Rietschel, Tasha Sims

Abstract

Purpose: Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies.

Methods: Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Of 13 patients enrolled, median age was 62 years (range 33-75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD).

Conclusion: Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors.

Trial registration: NCT03233139 at ClinicalTrials.gov.

Keywords: Advanced tumors; Anti–PD-1; Cemiplimab; Immunotherapy; Japanese patients.

Conflict of interest statement

SK: Research grants from Regeneron Pharmaceutical, Inc. during the conduct of the study; personal lecture fees from Sanofi, Nippon Kayaku, Meiji Seika Pharma, Taiho, Celgene, and Sumitomo Dainippon Pharma; personal lecture and advisory board fees from AstraZeneca, Chugai, Pfizer, Boehringer Ingelheim, Novartis, Daiichi-Sankyo, MSD, Kyowa Hakko Kirin, Ono Pharmaceutical Co., Ltd., and Bristol-Myers Squibb; research grants and personal lecture and advisory board fees from Eisai; research grants from Astellas, Gilead Sciences, AMED (Japan Agency for Medical Research and Development), and JSPS (Japan Society for the Promotion of Science). TS: Institutional research expenses from Regeneron Pharmaceuticals, Inc. during the conduct of the study; institutional research expenses from Novartis, Eli Lilly, AbbVie, AstraZeneca, Eisai, Astellas, Chordia Therapeutics, Bristol-Myers Squibb, Daiichi-Sankyo, Milleniam-Takeda, PharmaMar, FivePrime, 3D-Medicine and Symbio-Pharma, advisory role personal fees from Milleniam-Takeda, personal lecture fees from Boehringer Ingelheim, Taiho Pharma, Chugai Pharmaceutical, Co., Ltd., Ono Pharmaceutical Co., Ltd., Ono Pharma Taiwan Co., Ltd., outside the submitted work. TK, TE, SI, SK, AS: No conflict of interest declared. YF: Research funding grants from Abbie, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Incyte, Merck Serono, MSD, and Novartis; advisory role personal fees from AstraZeneca, Bristol-Myers Squibb, Novartis, and Ono Pharmaceutical Co., Ltd., speaker’s bureau personal fees from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., and Taiho, all outside of the submitted work. NY: Research grants from Chugai, Taiho, Eisai, Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd. and Takeda; honoraria from Ono Pharmaceutical Co., Ltd., Chugai, AstraZeneca, Pfizer, Lilly, Bristol-Myers Squibb; and consulting fees from Eisai, Otsuka, Takeda, and Boehringer Ingelheim, outside the submitted work. AP, SL, PR, TS: Employee and shareholder of Regeneron Pharmaceuticals, Inc.

Figures

Fig. 1
Fig. 1
Study design. *Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by investigators in Part 1 and Part 2 Cohort B and by an independent central review committee in Part 2 Cohort A every 9 weeks in the first year, every 12 weeks in the second year, and every 8 weeks during the follow-up. IV intravenously, NSCLC non-small cell lung cancer, PD-L1 programmed cell death-ligand 1, PD-L1hi ≥ 50% PD-L1 expression in tumor cells, PD-L1lo < 50% PD-L1 expression in tumor cells, PK pharmacokinetics, Q3W every 3 weeks, Q6W every 6 weeks
Fig. 2
Fig. 2
Mean (± standard deviation) of cemiplimab concentration in serum by time. LLOQ lower limit of quantitation, Q3W every 3 weeks
Fig. 3
Fig. 3
Time to and duration of response in responding patients. Plot shows time to and duration of response in a four patients with confirmed partial response and b two patients with stable disease. Q3W every 3 weeks

References

    1. Burova E, Hermann A, Waite J, Potocky T, Lai VSH, Liu M, Allbritton O, Woodruff A, Wu Q, D'Orvilliers A, Garnova E, Rafique A, Poueymirou W, Martin J, Huang T, Skokos D, Kantrowitz J, Popke J, Mohrs M, MacDonald D, Ioffe E, Olson W, Lowy I, Murphy A, Thurston G. Characterization of the anti-PD-1 antibody REGN2810 and its antitumor activity in human PD-1 knock-in mice. Mol Cancer Ther. 2017;16(5):861–870. doi: 10.1158/1535-7163.MCT-16-0665.
    1. Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, Chung CH, Hernandez-Aya L, Lim AM, Chang ALS, Rabinowits G, Thai AA, Dunn LA, Hughes BGM, Khushalani NI, Modi B, Schadendorf D, Gao B, Seebach F, Li S, Li J, Mathias M, Booth J, Mohan K, Stankevich E, Babiker HM, Brana I, Gil-Martin M, Homsi J, Johnson ML, Moreno V, Niu J, Owonikoko TK, Papadopoulos KP, Yancopoulos GD, Lowy I, Fury MG. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–351. doi: 10.1056/NEJMoa1805131.
    1. Davda J, Declerck P, Hu-Lieskovan S, Hickling TP, Jacobs IA, Chou J, Salek-Ardakani S, Kraynov E. Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer. 2019;7(1):105. doi: 10.1186/s40425-019-0586-0.
    1. Papadopoulos KP, Johnson ML, Lockhart AC, Moore K, Falchook GS, Formenti SC, Naing A, Carvajal RD, Rosen LS, Weiss GJ, Leidner RS, Li J, Paccaly A, Feng M, Stankevich E, Lowy I, Fury MG, Crittenden MR. First-in-human study of cemiplimab alone or in combination with radiotherapy and/or low-dose cyclophosphamide in patients with advanced malignancies. Clin Cancer Res. 2020;26(5):1025–1033. doi: 10.1158/1078-0432.CCR-19-2609.
    1. Moreno Garcia V, Calvo E, Olmedo Garcia ME, Gil Martin M, Aljumaily R, Papadopoulos KP, Rosen LS, Rietschel P, Mohan KK, Li J (2019) Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, in patients with non-small cell lung cancer (NSCLC): interim data from phase 1 dose escalation and NSCLC expansion cohort. J Clin Oncol 37(suppl 8; abstr 116). 10.1200/JCO.2019.37.8_suppl.116
    1. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 2012;166(5):1069–1080. doi: 10.1111/j.1365-2133.2012.10830.x.
    1. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol. 2015;151(10):1081–1086. doi: 10.1001/jamadermatol.2015.1187.
    1. Ishihara K, Saida T, Otsuka F, Yamazaki N. Statistical profiles of malignant melanoma and other skin cancers in Japan: 2007 update. Int J Clin Oncol. 2008;13(1):33–41. doi: 10.1007/s10147-007-0751-1.
    1. Nishi M. Epidemiology of skin cancer in Japan. Journal of Tumor. 2016;4(2):369–373. doi: 10.17554/j.issn.1819-6187.2016.04.84.
    1. Karia PS, Han J. Schmults CD (2013) Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States. J Am Acad Dermatol. 2012;68(6):957–966. doi: 10.1016/j.jaad.2012.11.037.
    1. Weinberg AS, Ogle CA, Shim EK. Metastatic cutaneous squamous cell carcinoma: an update. Dermatol Surg. 2007;33(8):885–899.
    1. Schmults CD. High-risk cutaneous squamous cell carcinoma: a practical guide for patient management. Berlin: Springer; 2016.
    1. European Medicines Agency (2019) LIBTAYO® EPAR. . Accessed 22 May 2020
    1. Regeneron Pharmaceuticals, Inc. (2018) LIBTAYO® [cemiplimab-rwlc] injection full US prescribing information. Regeneron Pharmaceuticals, Inc. . Accessed 22 May 2020
    1. Umebayashi Y, Akama T, Manabe M. Most cases of cutaneous squamous cell carcinoma in Japan are classified as “high risk” according to the Japanese guideline. J Dermatol. 2012;39(9):812–814. doi: 10.1111/j.1346-8138.2011.01419.
    1. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. doi: 10.1056/NEJMoa1606774.
    1. US Department of Health Human Services (2016) Common terminology criteria for adverse events (CTCAE) version 4.03. 2010, USA: National Institutes of Health, National Cancer Institute. . Accessed 22 May 2020
    1. 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. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Papadopoulos KP, Crittenden MR, Johnson ML, Lockhart AC, Moore KN, Falchook GS, Formenti S, Carvajal RD, Leidner RS, Naing A. A first-in-human study of REGN2810, a monoclonal, fully human antibody to programmed death-1 (PD-1), in combination with immunomodulators including hypofractionated radiotherapy (hfRT) J Clin Oncol. 2017;34(15):3024.
    1. Rischin D, Lim AM, Schmults C, Khushalani NI, Hughes BG, Schadendorf D, Dunn L, Chang AL, Hauschild A, Ulrich C, Eigentler T, Migden MR, Pavlick AC, Geiger J, Stankevich E, Li S, Lowy I, Fury M, Guminski A (2019) Phase 2 study of 2 dosing regimens of cemiplimab, a human monoclonal anti–PD-1, in metastatic cutaneous squamous cell carcinoma (mCSCC). Ann Oncol 30(suppl_5):v533–v563. 10.1093/annonc/mdz255
    1. Rischin D, Gil-Martin M, González-Martín A, Brana I, Hou J, Cho D, Falchook G, Formenti S, Jabbour S, Moore K. 958P Cemiplimab, a human PD-1 monoclonal antibody, in patients (pts) with recurrent or metastatic cervical cancer: interim data from phase I cohorts. Ann Oncol. 2018;29(8):285. doi: 10.1093/annonc/mdy285.
    1. Hida T, Nishio M, Nogami N, Ohe Y, Nokihara H, Sakai H, Satouchi M, Nakagawa K, Takenoyama M, Isobe H. Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer. Cancer Sci. 2017;108(5):1000–1006. doi: 10.1111/cas.13225.
    1. Shimizu T, Seto T, Hirai F, Takenoyama M, Nosaki K, Tsurutani J, Kaneda H, Iwasa T, Kawakami H, Noguchi K. Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. Invest New Drugs. 2016;34(3):347–354. doi: 10.1007/s10637-016-0347-6.
    1. Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, Kawakami T, Takahashi T. Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest New Drugs. 2016;34(5):596–603. doi: 10.1007/s10637-016-0371-6.
    1. Migden MR, Khushalani NI, Chang ALS, Lewis KD, Schmults CD, Hernandez-Aya L, Meier F, Schadendorf D, Guminski A, Hauschild A, Wong DJ, Daniels GA, Berking C, Jankovic V, Stankevich E, Booth J, Li S, Weinreich DM, Yancopoulos GD, Lowy I, Fury MG, Rischin D. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020;21:294–305. doi: 10.1016/S1470-2045(19)30728-4.
    1. Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, Yoshida K, Iizuka J, Kobayashi H, Okumi M, Ishida H, Tanabe K. Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol. 2019;37(6):355. doi: 10.1016/j.urolonc.2019.03.003.
    1. Yamazaki N, Takenouchi T, Fujimoto M, Ihn H, Uchi H, Inozume T, Kiyohara Y, Uhara H, Nakagawa K, Furukawa H. Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041) Cancer Chemother Pharmacol. 2017;79(4):651–660. doi: 10.1007/s00280-016-3237-x.
    1. Yang F, Paccaly AJ, Rippley R, Davis J, DiCioccio A (2019) Selection of fixed dose 350 mg every 3 weeks (Q3W) cemiplimab (Anti–PD-1) in patients with advanced malignancies based on population pharmacokinetics (PopPK) modelling. ACoP10, Orlando FL, ISSN:2688-3953, Vol 1, S-004.
    1. Paccaly A, Migden M, Papadopoulos K, Yang F, Davis J, Rippley R, Lowy I, Fury M, Stankevich E, Rischin D (2019) Pharmacokinetic (PK) analysis of weight-based and fixed dose cemiplimab in patients (pts) with advanced malignancies. Ann Oncol 30(suppl_5):v475–v532. 10.1093/annonc/mdz253
    1. Feng Y, Wang X, Bajaj G, Agrawal S, Bello A, Lestini B, Finckenstein FG, Park J-S, Roy A. Nivolumab exposure-response analyses of efficacy and safety in previously treated squamous or nonsquamous non-small cell lung cancer. Clin Cancer Res. 2017;23(18):5394–5405. doi: 10.1158/1078-0432.CCR-16-2842.
    1. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286–4293. doi: 10.1158/1078-0432.CCR-14-2607.
    1. Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometr Syst Pharmacol. 2017;6(1):58–66. doi: 10.1002/psp4.12143.
    1. Ahamadi M, Freshwater T, Prohn M, Li CH, De Alwis DP, De Greef R, Elassaiss-Schaap J, Kondic A, Stone JA. Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometr Syst Pharmacol. 2017;6(1):49–57. doi: 10.1002/psp4.12139.
    1. Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grünwald V, Kähler KC, Loquai C, Reinmuth N, Steins M. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev. 2016;45:7–18. doi: 10.1016/j.ctrv.2016.02.003.
    1. Migden M, Khushalani N, Chang A, Rischin D, Schmults C, Hernandez-Aya L, Meier F, Schadendorf D, Guminski A, Hauschild A, Wong D, Daniels G, Berking C, Jankovic V, Stankevich E, Booth J, Li S, Lowy I, Fury M, Lewis K (2019) Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients with locally advanced cutaneous squamous cell carcinoma (P6015). J Clin Oncol 37(suppl; abstr 6015). 10.1200/JCO.2019.37.15_suppl.6015
    1. Yamamoto N, Nokihara H, Yamada Y, Shibata T, Tamura Y, Seki Y, Honda K, Tanabe Y, Wakui H, Tamura T. Phase I study of nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drug. 2017;35(2):207–216. doi: 10.1007/s10637-016-0411-2.
    1. Yamazaki N, Kiyohara Y, Uhara H, Uehara J, Fujimoto M, Takenouchi T, Otsuka M, Uchi H, Ihn H, Minami H. Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: a phase II study. Cancer Sci. 2017;108(6):1223–1230. doi: 10.1111/cas.13241.

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