Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors

  • Research
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (Cmax). The overall response rate (ORR) was 11.4% (n = 4) and disease control rate (DCR) was 34.3% (n = 12). Consistent with that observed in other envafolimab Phase 1 trials and approved PD-1/PD-L1 inhibitors, the safety profile of SC envafolimab in Japanese patients with advanced solid tumors was well tolerated with efficacy comparable to IV administered treatments. Pharmacokinetics data and preliminary anti-tumor response support dose regimens with longer dosing intervals (Q2W or Q4W). As such, envafolimab offers patients a more convenient treatment option than currently available intravenously administered PD-1/PD-L1 inhibitors.

ClinicalTrials.gov identifier

NCT03248843(August 14, 2017).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA (2019) Humanistic and economic impact of subcutaneous versus intravenous administration of oncology biologics. Future Oncol 15(28):3267–3281. https://doi.org/10.2217/fon-2019-0368 (Epub 2019 Aug 9 PMID: 31394933)

    Article  CAS  PubMed  Google Scholar 

  2. Davies A, Merli F, Mihaljević B, Mercadal S, Siritanaratkul N, Solal-Céligny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D (2017) Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol 4(6):e272–e282. https://doi.org/10.1016/S2352-3026(17)30078-9 (Epub 2017 May 2 PMID: 28476440)

    Article  PubMed  Google Scholar 

  3. Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C (2012) Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13(9):869–878. https://doi.org/10.1016/S1470-2045(12)70329-7 (Epub 2012 Aug 9 PMID: 22884505)

    Article  CAS  PubMed  Google Scholar 

  4. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12(5):431-40. https://doi.org/10.1016/S1470-2045(11)70081-X. Epub 2011 Apr 18. Erratum in: Lancet Oncol. 2011 Jun;12(6):522. PMID: 21507715

  5. Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Goldschmidt H (2015) Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica 100(7):964–969. https://doi.org/10.3324/haematol.2015.124347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M (2017) Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica 102(11):1913–1922. https://doi.org/10.3324/haematol.2017.173583. Epub 2017 Sep 21. PMID: 28935843; PMCID: PMC5664395

  7. Franken MG, Kanters TA, Coenen JL, de Jong P, Koene HR, Lugtenburg PJ, Jager A, Uyl-de Groot CA (2018) Potential cost savings owing to the route of administration of oncology drugs: a microcosting study of intravenous and subcutaneous administration of trastuzumab and rituximab in the Netherlands. Anticancer Drugs 29(8):791–801. https://doi.org/10.1097/CAD.0000000000000648 (PMID: 29846248)

    Article  CAS  PubMed  Google Scholar 

  8. Franken M, Kanters T, Coenen J, de Jong P, Jager A, Groot CU (2020) Hospital-based or home-based administration of oncology drugs? A micro-costing study comparing healthcare and societal costs of hospital-based and home-based subcutaneous administration of trastuzumab. Breast. 52:71–77. https://doi.org/10.1016/j.breast.2020.05.001. Epub 2020 May 16. PMID: 32447129; PMCID: PMC7487951

  9. Viola M, Sequeira J, Seiça R, Veiga F, Serra J, Santos AC, Ribeiro AJ (2018) Subcutaneous delivery of monoclonal antibodies: How do we get there? J Control Release 286:301–314. https://doi.org/10.1016/j.jconrel.2018.08.001 (Epub 2018 Aug 2 PMID: 30077735)

    Article  CAS  PubMed  Google Scholar 

  10. Zhang F, Wei H, Wang X, Bai Y, Wang P, Wu J, Jiang X, Wang Y, Cai H, Xu T, Zhou A (2017) Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade. Cell discovery 3:17004. https://doi.org/10.1038/celldisc.2017.4

    Article  PubMed  PubMed Central  Google Scholar 

  11. Envafolimab Injection (2021) Full prescribing information, 2021. NMPA, https://www.nmpa.gov.cn/datasearch/home-index.html

  12. Papadopoulos KP, Harb W, Peer CJ, Hua Q, Xu S, Lu H, Lu N, He Y, Xu T, Dong R, Gong J, Liu D (2021) First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors. Oncologist 26(9):e1514-e1525. https://doi.org/10.1002/onco.13817. Epub 2021 May 27. PMID: 33973293; PMCID: PMC8417852

  13. Li J, Deng Y, Zhang W, Zhou A-P, Guo W, Yang J, Yuan Y, Zhu L, Qin S, Xiang S, Lu H, Gong J, Xu T, Liu D, Shen L (2021) Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol 14:95. https://doi.org/10.1186/s13045-021-01095-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–54. https://doi.org/10.1056/NEJMoa1200690. Epub 2012 Jun 2. PMID: 22658127; PMCID: PMC3544539

  15. 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-14-2607 (Epub 2015 May 14 PMID: 25977344)

    Article  CAS  PubMed  Google Scholar 

  16. Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marté JL, Lepone LM, Donahue RN, Grenga I, Cuillerot JM, Neuteboom B, Heydebreck AV, Chin K, Schlom J, Gulley JL (2017) Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol 18(5):587–598. https://doi.org/10.1016/S1470-2045(17)30239-5. Epub 2017 Mar 31. PMID: 28373007; PMCID: PMC6387686

  17. TECENTRIQ®(atezolizumab). Full prescribing information. Genentech Oncology. 2021.; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761034s028lbl.pdf.

  18. KEYTRUDA® (pembrolizumab). Full prescribing information. Merck Sharp & Dohme Corp. 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125514s125lbl.pdf

  19. IMFINZIU® (durvalumab). Full prescribing information.AstraZeneca. 2021.; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761069s028lbl.pdf

  20. OPDIVO® (nivolumab). Full prescribing information. Bristol-Myers Squibb Company. 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/225554s112lbl.pdf.

  21. Shimizu T, Seto T, Hirai F, Takenoyama M, Nosaki K, Tsurutani J, Kaneda H, Iwasa T, Kawakami H, Noguchi K, Shimamoto T, Nakagawa 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/s10637-016-0347-6. Epub 2016 Mar 22. PMID: 27000274; PMCID: PMC4859860

  22. Fujiwara Y, Iguchi H, Yamamoto N, Hayama M, Nii M, Ueda S, Komuro K, Sugimoto M, Vlahovic G, Kozuki T (2019) Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors. Cancer Sci 110(5):1715–1723. https://doi.org/10.1111/cas.14003. Epub 2019 Apr 13. PMID: 30891877; PMCID: PMC6501043

  23. 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/s10637-016-0371-6. Epub 2016 Jul 1. PMID: 27363843; PMCID: PMC5007272

  24. 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 Drugs 35(2):207–216. https://doi.org/10.1007/s10637-016-0411-2. Epub 2016 Dec 8. PMID: 27928714; PMCID: PMC5352798

Download references

Acknowledgements

We thank the participating patients, their family members, and all researchers involved in this study.

Funding

This study was funded by 3D Medicines Co., Ltd, China.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, 1040045, Japan

    Toshio Shimizu, Noboru Yamamoto, Kan Yonemori, Takafumi Koyama & Shunsuke Kondo

  2. Department of Medical Oncology, St. Marianna University Hospital, Kawasaki, 2168511, Japan

    Takako Eguchi Nakajima, Yu Sunakawa, Naoki Izawa & Yoshiki Horie

  3. Department of Pulmonary Medicine and Medical Oncology, Graduate School of Medicine, Wakayama Medical University, Wakayama, 6418509, Japan

    Toshio Shimizu

  4. Department of Early Clinical Development, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan

    Takako Eguchi Nakajima

  5. 3D Medicines Co., Ltd, Sichuan, China

    Silong Xiang, Siying Xu, Lan Qin, John Gong & David Liu

Authors
  1. Toshio Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takako Eguchi Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noboru Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kan Yonemori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takafumi Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shunsuke Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Sunakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoki Izawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshiki Horie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Silong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Siying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. John Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were involved in acquisition, analysis, or interpretation of data and critical revision of the manuscript for important intellectual content. All authors gave final approval of the manuscript and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshio Shimizu.

Ethics declarations

Competing interests

Dr. Toshio Shimizu (TS) received research grants from 3D Medicine related to the submitted work; and research grants from Novartis, Eli Lilly, Loxo Oncology, Daiichi-Sankyo, AbbVie, Bristol-Myers Squibb, Eisai, AstraZeneca, Pfizer, Takeda Oncology, Incyte, Chordia Therapeutics, Symbio Pharmaceuticals, PharmaMar, Astellas; and advisory role fees from AbbVie, Daiichi-Sankyo, Takeda Oncology, Chordia Therapeutics; and personal fees (speakers) from Eli Lilly, Chugai Pharmaceutical Co., Taiho, Boehringer Ingelheim, MSD outside the submitted work. Dr. Noboru Yamamoto (NY) received research grants from Astellas, AstraZeneca, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi; and advisory role fees from Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai; and personal fees (speakers) from AstraZeneca, Eli Lilly, ONO, Chugai, Sysmex, Daiichi-Sankyo, Eisai outside the submitted work. Dr. Kan Yonemori (KY) received research grants from MSD, Daiichi-Sankyo, Astrazeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe; and advisory role fees from Novartis, Eisai, AstraZeneca, Chugai, Takeda, Genmab, OncXerna; and personal fees from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma outside the submitted work. Dr. Shunsuke Kondo (SK) received research grants from Takeda, AstraZeneca, Abbie, Eli Lilly, MSD, Boehringer Ingelheim, Chugai, Eisai, Incyte, Pfizer; and personal fees from Chugai, Incyte, Takeda, Chugai, Termo, and Eisai outside the submitted work. Dr. Takafumi Koyama (TK) received research grants from Novartis, Daiichi-Sankyo, Eli Lilly, PACT Pharma; and personal fees from Chugai and Sysmex outside the submitted work. Dr. NAKAJIMA reports grants and personal fees from Sumitomo Dainippon Pharma Co., personal fees from Boehringer Ingelheim , personal fees from Bristol-Myers Squibb, grants and personal fees from Ono Pharmaceutical Co., grants and personal fees from Taiho Pharmaceutical Co., personal fees from Amgen, grants and personal fees from Takeda Pharmaceutical Co., grants and personal fees from Chugai Pharmaceutical Co., grants and personal fees from Sanofi K.K., personal fees from Novartis Japan, grants and personal fees from Nippon Kayaku Co., grants and personal fees from MSD K.K., grants and personal fees from Eli Lilly Japan K.K., personal fees from Bayer Yakuhin, personal fees from Pfizer Japan Inc., personal fees from Daiichi Sankyo Co., personal fees from Yakult Honsha Co., personal fees from Nipro Co, personal fees from Merck Serono Co., grants from PAREXEL, grants from JCRO, grants from SHIONOGI & CO., LTD., personal fees from AstraZeneca, personal fees from IQVIA, personal fees from GlaxoSmithKline, outside the submitted work; Yu Sunakawa; Research funding and honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda, Eli Lilly Japan, and Sanofi Honoraria from Bristol-Myers Squibb Japan, Merck Biopharma, Ono Pharmaceutical, Bayer Yakuhin, MSD, Daiichi Sankyo, Sysmex and Guardant Health Naoki Izawa: Honoraria from Taiho Pharmaceutical, Takeda, Eli Lilly Japan, and Bristol-Myers Squibb Japan Yoshiki Horie: No. COI Silong Xiang, Siying Xu, Lan Qin, John Gong, and David Liu are employees of and own stock in 3D Medicines Co., Ltd. JG and DL have leadership roles at 3D Medicines Co., Ltd.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 326 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shimizu, T., Nakajima, T.E., Yamamoto, N. et al. Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors. Invest New Drugs 40, 1021–1031 (2022). https://doi.org/10.1007/s10637-022-01287-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-022-01287-7

Keywords

Search

Navigation