Top

Published in:

Open Access 01-12-2019 | NSCLC | Original Article

Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting

Authors: Kari M. Morrissey, Mathilde Marchand, Hina Patel, Rong Zhang, Benjamin Wu, H. Phyllis Chan, Almut Mecke, Sandhya Girish, Jin Y. Jin, Helen R. Winter, René Bruno

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2019

Abstract

Purpose

To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.

Methods

ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.

Results

No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a C_max above and below the predicted C_max for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.

Conclusion

Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.

Available only for authorised users

Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10. https://doi.org/10.1016/j.immuni.2013.07.012 CrossRefPubMed

Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18(24):6580–6587. https://doi.org/10.1158/1078-0432.CCR-12-1362 CrossRefPubMed

Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. https://doi.org/10.1038/nature14011 CrossRefPubMedPubMedCentral

TECENTRIQ (atezolizumab) [package insert]. Genentech, Inc, South San Francisco, 2019

TECENTRIQ (atezolizumab) [summary of product characteristics]. Roche Registration Limited, Welwyn Garden City, 2019

Stroh M, Winter H, Marchand M, Claret L, Eppler S, Ruppel J, Abidoye O, Teng SL, Lin WT, Dayog S, Bruno R, Jin J, Girish S (2017) Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther 102(2):305–312. https://doi.org/10.1002/cpt.587 CrossRefPubMed

Deng R, Bumbaca D, Pastuskovas CV, Boswell CA, West D, Cowan KJ, Chiu H, McBride J, Johnson C, Xin Y, Koeppen H, Leabman M, Iyer S (2016) Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. MAbs 8(3):593–603. https://doi.org/10.1080/19420862.2015.1136043 CrossRefPubMedPubMedCentral

Bi Y, Liu J, Furmanski B, Zhao H, Yu J, Osgood C, Ward A, Keegan P, Booth BP, Rahman A, Wang Y (2019) Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective. Ann Oncol 30(4):644–651. https://doi.org/10.1093/annonc/mdz037 CrossRefPubMed

US Food and Drug Administration. (2019) Model-informed drug development pilot program. https://www.fda.gov/drugs/development-resources/model-informed-drug-development-pilot-program. Accessed 14 May 2019

10.

Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515(7528):558–562. https://doi.org/10.1038/nature13904 CrossRefPubMed

11.

Petrylak DP, Powles T, Bellmunt J, Braiteh F, Loriot Y, Morales-Barrera R, Burris HA, Kim JW, Ding B, Kaiser C, Fasso M, O’Hear C, Vogelzang NJ (2018) Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: long-term outcomes from a phase 1 study. JAMA Oncol 4(4):537–544. https://doi.org/10.1001/jamaoncol.2017.5440 CrossRefPubMedPubMedCentral

12.

Horn L, Gettinger SN, Gordon MS, Herbst RS, Gandhi L, Felip E, Sequist LV, Spigel DR, Antonia SJ, Balmanoukian A, Cassier PA, Liu B, Kowanetz M, O’Hear C, Fassò M, Grossman W, Sandler A, Soria JC (2018) Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. Eur J Cancer 101:201–209. https://doi.org/10.1016/j.ejca.2018.06.031 CrossRefPubMed

13.

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR, Group OAKS (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet (Lond, Engl) 389(10066):255–265CrossRef

14.

Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Flechon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A (2018) Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet (Lond, Engl) 391(10122):748–757CrossRef

15.

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 CrossRefPubMedPubMedCentral

16.

Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, Investigators IMT (2018) Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Eng J Med 379(22):2108–2121. https://doi.org/10.1056/NEJMoa1809615 CrossRef

17.

Yang J, Zhao H, Garnett C, Rahman A, Gobburu JV, Pierce W, Schechter G, Summers J, Keegan P, Booth B, Wang Y (2013) The combination of exposure–response and case–control analyses in regulatory decision making. J Clin Pharmacol 53(2):160–166. https://doi.org/10.1177/0091270012445206 CrossRefPubMed

18.

Wang J, Song P, Schrieber S, Liu Q, Xu Q, Blumenthal G, Amiri Kordestani L, Cortazar P, Ibrahim A, Justice R, Wang Y, Tang S, Booth B, Mehrotra N, Rahman A (2014) Exposure–response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer. Clin Pharmacol Ther 95(5):558–564. https://doi.org/10.1038/clpt.2014.24 CrossRefPubMed

19.

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 Pharmacometrics Syst Pharmacol 6(1):58–66. https://doi.org/10.1002/psp4.12143 CrossRefPubMed

20.

Li H, Yu J, Liu C, Liu J, Subramaniam S, Zhao H, Blumenthal GM, Turner DC, Li C, Ahamadi M, de Greef R, Chatterjee M, Kondic AG, Stone JA, Booth BP, Keegan P, Rahman A, Wang Y (2017) Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J Pharmacokinet Pharmacodyn 44(5):403–414. https://doi.org/10.1007/s10928-017-9528-y CrossRefPubMed

21.

Liu C, Yu J, Li H, Liu J, Xu Y, Song P, Liu Q, Zhao H, Xu J, Maher VE, Booth BP, Kim G, Rahman A, Wang Y (2017) Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther 101(5):657–666. https://doi.org/10.1002/cpt.656 CrossRefPubMed

22.

Wang Y, Booth B, Rahman A, Kim G, Huang SM, Zineh I (2017) Toward greater insights on pharmacokinetics and exposure–response relationships for therapeutic biologics in oncology drug development. Clin Pharmacol Ther 101(5):582–584. https://doi.org/10.1002/cpt.628 CrossRefPubMed

23.

Bruno R, Mercier F, Claret L (2014) Evaluation of tumor size response metrics to predict survival in oncology clinical trials. Clin Pharmacol Ther 95(4):386–393. https://doi.org/10.1038/clpt.2014.4 CrossRefPubMed

24.

Claret L, Jin JY, Ferte C, Winter H, Girish S, Stroh M, He P, Ballinger M, Sandler A, Joshi A, Rittmeyer A, Gandara D, Soria JC, Bruno R (2018) A model of overall survival predicts treatment outcomes with atezolizumab versus chemotherapy in non-small cell lung cancer based on early tumor kinetics. Clin Cancer Res 24(14):3292–3298. https://doi.org/10.1158/1078-0432.CCR-17-3662 CrossRefPubMed

25.

Bruno R, Claret L, Wu B, Jin JY, Winter H, Cui N, Derleth CL, Shen X, Girish S, Rosenberg JE, Powles T (2018) A tumor growth rate/overall survival model for atezolizumab as an early predictor of OS in patients with first or second line metastatic urothelial carcinoma. J Clin Oncol 36(5_Suppl):62. https://doi.org/10.1200/jco.2018.36.5_suppl.62 CrossRef

26.

Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2011) NONMEM user’s guides. (1989–2011). Icon Development Solutions, Ellicott City, MD

27.

Center for drug evaluation and research. BLA (2016) 761034 clinical pharmacology review—atezolizumab. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761034Orig1s000ClinPharmR.pdf. Accessed 14 May 2019

28.

Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, Olson A, Bao W, Rutgeerts P (2004) Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2(7):542–553CrossRefPubMed

29.

Shankar G, Pendley C, Stein KE (2007) A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol 25(5):555–561. https://doi.org/10.1038/nbt1303 CrossRefPubMed

30.

KEYTRUDA (pembrolizumab) [summary of product characteristics.]. Merck Sharp & Dohme B.V., Haarlem, The Netherlands, 2019

31.

OPDIVO (nivolumab) [package insert]. Bristol-Meyers Squibb Company, Princeton, NJ, 2018

32.

Lala M, Li M, Sinha V, de Alwis D, Chartash E, Jain L (2018) A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure–response (E–R) evaluation using modeling and simulation. J Clin Oncol 36(15):3062CrossRef

33.

Zhao X, Suryawanshi S, Hruska M, Feng Y, Wang X, Shen J, Vezina HE, McHenry MB, Waxman IM, Achanta A, Bello A, Roy A, Agrawal S (2017) Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol 28(8):2002–2008. https://doi.org/10.1093/annonc/mdx235 CrossRefPubMedPubMedCentral

34.

Freshwater T, Kondic A, Ahamadi M, Li CH, de Greef R, de Alwis D, Stone JA (2017) Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 5:43. https://doi.org/10.1186/s40425-017-0242-5 CrossRefPubMedPubMedCentral

Title: Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting
Authors: Kari M. Morrissey
Mathilde Marchand
Hina Patel
Rong Zhang
Benjamin Wu
H. Phyllis Chan
Almut Mecke
Sandhya Girish
Jin Y. Jin
Helen R. Winter
René Bruno
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Pharmacokinetics
NSCLC
Urothelial Cancer
Urothelial Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03954-8

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2019

A reliable method to determine which candidate chemotherapeutic drugs effectively inhibit tumor growth in patient-derived xenografts (PDX) in single mouse trials

Dasatinib attenuates overexpression of Src signaling induced by the combination treatment of veliparib plus carboplatin in triple-negative breast cancer

Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs

JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies

A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer