Exposure-response analysis of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy

Mita Kuchimanchi, Min Zhu, John D Clements, Sameer Doshi, Mita Kuchimanchi, Min Zhu, John D Clements, Sameer Doshi

Abstract

Aims: The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission [CR] and duration of overall survival [OS]) or adverse events (occurrence of cytokine release syndrome [CRS] and neurological events) were investigated in adult patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen.

Methods: Exposure, efficacy and safety data from adult patients (n = 646) with r/r ALL receiving stepwise (9 then 28 μg/day, 4-week cycle) continuous intravenous infusion (n = 537) of blinatumomab or SOC (n = 109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurological and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed.

Results: Blinatumomab steady-state concentration following 28 μg/day dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval: 1.073 [1.033-1.114]), and a longer duration of OS compared to SOC (hazard ratio and 95% confidence interval: 0.954 [0.936-0.973], P < .05) in multivariate analyses. The exposure-safety analyses indicated that blinatumomab steady-state concentration following the 9 or 28 μg/day dose was not associated with increased probability of CRS or neurological events, after accounting for blinatumomab treatment effect (P > .05).

Conclusions: Blinatumomab step-dosing regimen of 9/28 μg/day provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurological events in patients with r/r ALL.

Keywords: acute lymphoblastic leukaemia; blinatumomab; exposure-response analysis.

Conflict of interest statement

This study was funded by Amgen Inc. Amgen designed the study, and collected, analysed, and interpreted the data. All authors participated in the writing of the manuscript and agreed to the decision to submit the manuscript for publication. J.D.C. and S.D. are employees of and shareholders in Amgen Inc. M.K. and M.Z. were employees of Amgen and shareholders in Amgen Inc. when the analysis was conducted.

© 2019 Amgen. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
Kaplan–Meier survival curve across exposure quartiles in patients treated with blinatumomab. CssCategory is the category based on quartiles of Css. Black (CssCategory = 1), red (CssCategory = 2), blue (CssCategory = 3), and green (CssCategory = 4) lines represent, respectively, the overall survival Kaplan–Meier curves for the first (< 265.5 pg/mL), second (≥ 265.5 and < 501 pg/mL), third (≥ 501 and < 811.1 pg/mL) and fourth (≥ 811.1 pg/mL) exposure‐based quartiles for patients treated with blinatumomab. Css, steady‐state concentration; OS, overall survival. Numbers indicate the number of subjects at risk at times matching the tick values for the x‐axis

References

    1. Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46(1):64‐75.
    1. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944‐950.
    1. Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120(10):2032‐2041.
    1. Dinner S, Lee D, Liedtke M. Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia. Leuk Lymphoma. 2014;55(8):1715‐1724.
    1. Alexander SP, Kelly E, Marrion NV, et al. The Concise Guide to PHARMACOLOGY 2017/18: Overview. Br J Pharmacol. 2017;174(S1):S1‐S16.
    1. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific single‐chain antibody constructs on MHC class I‐negative tumor cells. Mol Immunol. 2006;43(6):763‐771.
    1. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B‐lineage acute lymphoblastic leukemia to continuous infusion of T cell‐engaging CD19/CD3‐bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226‐6233.
    1. Amgen, CA, USA . Blincyto® (blinatumomab) full US prescribing information. . Accessed December 5, 2018.
    1. Zhu M, Wu B, Brandl C, et al. Blinatumomab, a bispecific t‐cell engager (BiTE(®)) for CD‐19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin Pharmacokinet. 2016;55(10):1271‐1288.
    1. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B‐precursor acute lymphoblastic leukaemia: a multicentre, single‐arm, phase 2 study. Lancet Oncol. 2015;16(1):57‐66.
    1. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome‐positive B‐precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single‐arm, multicenter study. J Clin Oncol. 2017;35(16):1795‐1802.
    1. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836‐847.
    1. Zhu M, Kratzer A, Johnson J, et al. Blinatumomab pharmacodynamics and exposure‐response relationships in relapsed/refractory acute lymphoblastic leukemia. J Clin Pharmacol. 2018;58(2):168‐179.
    1. Amgen, CA, USA . A Phase 3, randomized, open label study investigating the efficacy of the BiTE(R) antibody blinatumomab versus standard of care chemotherapy in adult subjects with relapsed/refractory b‐precursor acute lymphoblastic leukemia (ALL) (TOWER Study). Protocol for. N Engl J Med. 2017;376:836‐847. . Accessed December 5, 2018
    1. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the anti‐CD19 bispecific T cell‐engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B‐precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134‐4140.
    1. Zhu M, Wu B, Brandl C, et al. Blinatumomab, a bispecific T‐cell engager (BiTE(®)) for CD‐19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin Pharmacokinet. 2016;55(10):1271‐1288.
    1. Harding SD, Sharman JL, Faccenda E, et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 2018;46(D1):D1091‐d1106.
    1. US FDA . Guidance for Industry; Exposure‐Response Relationships — Study Design, Data Analysis, and Regulatory Applications. April 2003. . Accessed December 5, 2018.
    1. Overgaard RV, Ingwersen SH, Tornøe CW. Establishing good practices for exposure‐response analysis of clinical endpoints in drug development. CPT Pharmacometrics Syst Pharmacol. 2015;4(10):565‐575.

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