Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma

Abstract

Exposure-response relationships were investigated to assess the risk/benefit of polatuzumab vedotin (pola) + bendamustine-rituximab (pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Analyses were conducted in pivotal study GO29365 (NCT02257567; BR/pola + BR/pola + BG [BG: bendamustine-obinutuzumab]; 1.8 mg/kg pola, every 3 weeks [Q3W], six cycles), and supportive studies DCS4968g (NCT01290549) and GO27834 (NCT01691898) (pola/pola + R/pola + G; 0.1–2.4 mg/kg pola Q3W; eight-cycle landmark), separately. Exposure was characterized as simulated cycle-6 AUC and C_max for antibody-conjugated mono-methyl auristatin E (acMMAE) and unconjugated MMAE. Supportive studies showed response rate and safety risk (grade ≥2 peripheral neuropathy; grade ≥3 anemia) increased with exposure, suggesting not to dose below 1.8 mg/kg (up to eight-cycle) for balancing safety and efficacy. Pivotal study with limited exposure range showed no exposure-safety relationship and slightly positive exposure (acMMAE)-efficacy relationship for overall survival. The exposure-response analyses and the observed risk/benefit characteristics in pivotal study supported pola (1.8 mg/kg) +BR Q3W for six cycles in R/R DLBCL patients.

Keywords:

• Polatuzumab vedotin
• relapsed/refractory
• diffuse large B-cell lymphoma
• pharmacokinetics
• exposure-response
• dose justification

Acknowledgments

We thank the study investigators and patients of the GO29365, DCS4968g, and GO27834 studies. Medical writing support, under the direction of the authors, was provided by Angela Rogers, PhD, from Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

Disclosures statement

All authors, except LG, are employees of Genentech, Inc. and stockholders of Roche. LG is a paid consultant for Roche and Genentech.

Data availability statement

Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Additional information

Funding

F. Hoffmann-La Roche Ltd. and Genentech, Inc. funded the GO29365, DCS4968g, and GO27834 studies.