Top

Published in:

Open Access 01-01-2021 | Cutaneous Squamous Cell Carcinoma | Original Article

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

Authors: 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2021

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.

Graphic abstract

Available only for authorised users

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 (2017) Characterization of the anti-PD-1 antibody REGN2810 and its antitumor activity in human PD-1 knock-in mice. Mol Cancer Ther 16(5):861–870. https://doi.org/10.1158/1535-7163.MCT-16-0665CrossRefPubMed

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 (2018) PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 379(4):341–351. https://doi.org/10.1056/NEJMoa1805131CrossRefPubMed

Davda J, Declerck P, Hu-Lieskovan S, Hickling TP, Jacobs IA, Chou J, Salek-Ardakani S, Kraynov E (2019) Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer 7(1):105. https://doi.org/10.1186/s40425-019-0586-0CrossRefPubMedPubMedCentral

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 (2020) 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 26(5):1025–1033. https://doi.org/10.1158/1078-0432.CCR-19-2609CrossRefPubMed

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). https://doi.org/10.1200/JCO.2019.37.8_suppl.116

Lomas A, Leonardi-Bee J, Bath-Hextall F (2012) A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol 166(5):1069–1080. https://doi.org/10.1111/j.1365-2133.2012.10830.xCrossRefPubMed

Rogers HW, Weinstock MA, Feldman SR, Coldiron BM (2015) Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol 151(10):1081–1086. https://doi.org/10.1001/jamadermatol.2015.1187CrossRefPubMed

Ishihara K, Saida T, Otsuka F, Yamazaki N (2008) Statistical profiles of malignant melanoma and other skin cancers in Japan: 2007 update. Int J Clin Oncol 13(1):33–41CrossRef

Nishi M (2016) Epidemiology of skin cancer in Japan. Journal of Tumor 4(2):369–373CrossRef

10.

Karia PS, Han J (2012) 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 68(6):957–966. https://doi.org/10.1016/j.jaad.2012.11.037CrossRef

11.

Weinberg AS, Ogle CA, Shim EK (2007) Metastatic cutaneous squamous cell carcinoma: an update. Dermatol Surg 33(8):885–899PubMed

12.

Schmults CD (2016) High-risk cutaneous squamous cell carcinoma: a practical guide for patient management. Springer, BerlinCrossRef

13.

European Medicines Agency (2019) LIBTAYO^® EPAR. https://www.ema.europa.eu/en/medicines/human/EPAR/libtayo. Accessed 22 May 2020

14.

Regeneron Pharmaceuticals, Inc. (2018) LIBTAYO^® [cemiplimab-rwlc] injection full US prescribing information. Regeneron Pharmaceuticals, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761097s000lbl.pdf. Accessed 22 May 2020

15.

Umebayashi Y, Akama T, Manabe M (2012) Most cases of cutaneous squamous cell carcinoma in Japan are classified as “high risk” according to the Japanese guideline. J Dermatol 39(9):812–814. https://doi.org/10.1111/j.1346-8138.2011.01419CrossRefPubMed

16.

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S (2016) Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774CrossRef

17.

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. https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 22 May 2020

18.

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.2008.10.026CrossRefPubMed

19.

Papadopoulos KP, Crittenden MR, Johnson ML, Lockhart AC, Moore KN, Falchook GS, Formenti S, Carvajal RD, Leidner RS, Naing A (2016) 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 34(suppl; abstr 3024)

20.

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. https://doi.org/10.1093/annonc/mdz255

21.

Rischin D, Gil-Martin M, González-Martín A, Brana I, Hou J, Cho D, Falchook G, Formenti S, Jabbour S, Moore K (2018) 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 29(suppl 8):viii342–viii343. https://doi.org/10.1093/annonc/mdy285CrossRef

22.

Hida T, Nishio M, Nogami N, Ohe Y, Nokihara H, Sakai H, Satouchi M, Nakagawa K, Takenoyama M, Isobe H (2017) Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer. Cancer Sci 108(5):1000–1006. https://doi.org/10.1111/cas.13225CrossRefPubMedPubMedCentral

23.

Shimizu T, Seto T, Hirai F, Takenoyama M, Nosaki K, Tsurutani J, Kaneda H, Iwasa T, Kawakami H, Noguchi K (2016) Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. Invest New Drugs 34(3):347–354. https://doi.org/10.1007/s10637-016-0347-6CrossRefPubMedPubMedCentral

24.

Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, Kawakami T, Takahashi T (2016) 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 34(5):596–603. https://doi.org/10.1007/s10637-016-0371-6CrossRefPubMedPubMedCentral

25.

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 (2020) Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 21:294–305. https://doi.org/10.1016/S1470-2045(19)30728-4CrossRefPubMed

26.

Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, Yoshida K, Iizuka J, Kobayashi H, Okumi M, Ishida H, Tanabe K (2019) Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol 37(6):355. https://doi.org/10.1016/j.urolonc.2019.03.003 (e321–355 e329)CrossRefPubMed

27.

Yamazaki N, Takenouchi T, Fujimoto M, Ihn H, Uchi H, Inozume T, Kiyohara Y, Uhara H, Nakagawa K, Furukawa H (2017) Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol 79(4):651–660CrossRef

28.

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. https://www.go-acop.org/assets/ACoP10/documents/ACoP10%20Combined%20Abstracts_2019.pdf

29.

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. https://doi.org/10.1093/annonc/mdz253

30.

Feng Y, Wang X, Bajaj G, Agrawal S, Bello A, Lestini B, Finckenstein FG, Park J-S, Roy A (2017) Nivolumab exposure-response analyses of efficacy and safety in previously treated squamous or nonsquamous non-small cell lung cancer. Clin Cancer Res 23(18):5394–5405CrossRef

31.

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 (2015) 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. https://doi.org/10.1158/1078-0432.CCR-14-2607CrossRefPubMed

32.

Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y (2017) Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometr Syst Pharmacol 6(1):58–66. https://doi.org/10.1002/psp4.12143CrossRef

33.

Ahamadi M, Freshwater T, Prohn M, Li CH, De Alwis DP, De Greef R, Elassaiss-Schaap J, Kondic A, Stone JA (2017) Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometr Syst Pharmacol 6(1):49–57. https://doi.org/10.1002/psp4.12139CrossRef

34.

Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grünwald V, Kähler KC, Loquai C, Reinmuth N, Steins M (2016) Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 45:7–18CrossRef

35.

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). https://doi.org/10.1200/JCO.2019.37.15_suppl.6015

36.

Yamamoto N, Nokihara H, Yamada Y, Shibata T, Tamura Y, Seki Y, Honda K, Tanabe Y, Wakui H, Tamura T (2017) Phase I study of nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest New Drug 35(2):207–216CrossRef

37.

Yamazaki N, Kiyohara Y, Uhara H, Uehara J, Fujimoto M, Takenouchi T, Otsuka M, Uchi H, Ihn H, Minami H (2017) Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: a phase II study. Cancer Sci 108(6):1223–1230. https://doi.org/10.1111/cas.13241CrossRefPubMedPubMedCentral

Title: Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies
Authors: 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
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Cutaneous Squamous Cell Carcinoma
Pharmacokinetics
Cutaneous Squamous Cell Carcinoma
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04161-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

Graphic abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

An investigation into possible interactions among four vascular epidermal growth factor receptor-tyrosine kinase inhibitors with gefitinib

MiniPDX-guided postoperative anticancer treatment can effectively prolong the survival of patients with hepatocellular carcinoma

Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: learnings from a survey of FDA-approved drugs

Artemisinin-type drugs for the treatment of hematological malignancies

Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer