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P089 (0137) POPULATION PHARMACOKINETIC (POPPK) MODELING AND EXPOSURE-RESPONSE (ER) ASSESSMENT OF BRENTUXIMAB VEDOTIN EFFICACY AND SAFETY IN PATIENTS WITH ADVANCED CLASSICAL HODGKIN LYMPHOMA (CHL) FROM THE PHASE 3 ECHELON-1 STUDY

doi: 10.1097/01.HS9.0000547932.32447.7a
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Ajit Suri1, Diane R. Mould2, Gregory Song1, Graham Collins3, Chris Endres4, Jesus Gomez-Navarro1, Karthik Venkatakrishnan1

1 Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 2 Projections Research Inc., Phoenixville, PA, USA, 3 Oxford Cancer and Haematology Centre, Oxford University Hospital, Oxford, UK, 4 Seattle Genetics Inc., Seattle Genetics, Inc., Bothell, WA, USA

Background: Frontline brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), given in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved outcomes vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for patients (pts) with advanced cHL (modified progression-free survival [mPFS] hazard ratio 0.77 [95% confidence interval 0.60–0.98]; p = 0.04, corresponding to a 23% risk reduction). We report POPPK and ER modeling for the relationships between drug exposure and efficacy and safety endpoints for ADC and its cytotoxic payload (MMAE) using data from ECHELON-1 pts who received A+AVD.

Methods: A+AVD pts received brentuximab vedotin as a 30-min intravenous infusion at 1.2 mg/kg every 2 weeks (Q2W). POPPK were evaluated for 661 pts (using NONMEM version 7.3), including 59 pts with intensive PK sampling. Qualified final POPPK models were used to derive pt-level ADC and MMAE exposure metrics for use in ER analyses of data from 662 pts. Logistic regression or Cox proportional hazard models were used to evaluate relationships between ADC and/or MMAE area under curve (AUC)/time and primary efficacy (mPFS) and safety endpoints (grade [G] ≥2 peripheral neuropathy [PN], G≥4 neutropenia [N; ± granulocyte colony-stimulating factor {G-CSF} primary prophylaxis {PP}], febrile neutropenia [FN; ± G-CSF PP] and G≥3 treatment-emergent adverse events [TEAEs; ± G-CSF PP]).

Results: ADC PK were described by a linear 3-compartment model with zero-order input and first-order elimination. MMAE PK were described by a 2-compartment model with first-order elimination and release of MMAE from ADC and via ADC target binding. There were no clinically meaningful changes in simulated ADC AUC for body surface area or albumin. ADC AUC/time was not a significant predictor of mPFS. ADC AUC/time was predictive of G≥2 PN and FN, but not of G≥4 N or G≥3 TEAEs. MMAE AUC/time was predictive of G≥4 N, FN and G≥3 TEAE, but not G≥2 PN. Covariate analyses concluded that G-CSF PP protected against N, FN, and G≥3 TEAEs. ER analyses supported the protocol-specified ADC dose reductions for treatment-related AEs.

Conclusions: Brentuximab vedotin offers consistent benefit across the range of exposures in ECHELON-1. ER analyses support the recommended starting dose (1.2 mg/kg Q2W) and risk reduction of PN and N by G-CSF PP, and support management of treatment-related AEs by dose reductions per ECHELON-1.

Copyright © 2018 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.