Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract

Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B‐cell lymphoma

“…The PK profile of these analytes was generally consistent with that seen for pola monotherapy in the previous Japanese phase 1 study, 17 and also consistent with the pharmacokinetics for non-Asian patients in an ethnic sensitivity analysis. 25 Based on these cross-study comparisons, bendamustine and rituximab do not appear to have a clinically significant impact on the pharmacokinetics of pola, and there were no clinically meaningful differences in pola pharmacokinetics based on Japanese ethnicity. The number of patients with available samples for PK analysis.…”

The molecular rationale for the combination of polatuzumab vedotin plus rituximab in diffuse large B‐cell lymphoma

“…To search for Pola‐refractory cells, we tested sensitivity to Pola and calculated the IC 50 value in a panel of 11 DLBCL cells, comprising eight germinal centre B‐cell‐like (GCB)‐DLBCL (DB, STR‐428, SU‐DHL‐5, SU‐DHL‐10, SU‐DHL‐4, NU‐DUL‐1, SU‐DHL‐8 and HT) and three activated B‐cell‐like (ABC)‐DLBCL (U‐2932, SU‐DHL‐2 and RC‐K8) (Figure 1A; Figure S1A). We used an IC 50 = 1 μg/ml as the cut‐off value, based on the clinical trough drug concentration levels in the GO29365 study, 14 and identified four cells showing refractoriness to Pola.…”

Ethnic sensitivity assessment: Polatuzumab vedotin pharmacokinetics in Asian and non‐Asian patients with previously untreated diffuse large B‐cell lymphoma in POLARIX

“…The current study contributes additional information to the ethnic sensitivity landscape in a number of ways. It includes data from a broader Asian patient population than in previous studies; Shi et al 1 . used data from Japanese and South Korean patients, whereas here, data from Chinese, Japanese, South Korean, and Taiwanese patients were used.…”

“…Drug efficacy and safety can potentially vary between patients of different ethnicities due to factors including bodyweight, genetic polymorphisms in key metabolic enzymes, and regional standard‐of‐care practices 1,9 . For example, between Asian and non‐Asian patients, such differences can necessitate dose adjustments across patient subpopulations 1 .…”

“…4 Drug efficacy and safety can potentially vary between patients of different ethnicities due to factors including bodyweight, genetic polymorphisms in key metabolic enzymes, and regional standard-of-care practices. 1,9 For example, between Asian and non-Asian patients, such differences can necessitate dose adjustments across patient subpopulations. 1 It is therefore important for clinical trial designs to consider ethnic diversity by ensuring that patients are recruited from different ethnicities and regions globally, to identify any significant covariates in drug exposure that may impact the dosing regimen.…”