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

The antibody–drug conjugate (ADC) polatuzumab vedotin (pola; Polivy^®) was approved by the United States Food and Drug Administration in June 2019 for use in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in combination with bendamustine and rituximab (BR), for patients who have received two or more prior therapies [1]. DLBCL is the most common subtype of B-cell non-Hodgkin lymphoma (B-NHL) and, although often curable, approximately 40% of patients are refractory to, or will relapse after, standard front-line chemoimmunotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [2, 3]. For these patients, the standard of care remains autologous stem cell transplantation (ASCT) which also offers a curative approach. However, many DLBCL patients are ineligible for such therapy due to age, performance status, or comorbidities [4]. Unfortunately, the prognosis remains poor for patients with DLBCL who are not transplant eligible, do not respond to salvage therapy, or relapse after ASCT with a median overall survival (OS) of approximately 6 months [5, 6].

For many years, progress in identifying more effective therapies for patients with R/R DLBCL has been very limited. More recently, anti-CD19 chimeric antigen receptor T-cell therapies have become available but are associated with significant toxicity [7] and are only available at selected medical centers. As such, pola may help to address a long-standing unmet treatment need in these patients. Pola is an ADC comprising the potent cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) conjugated to an anti-CD79b monoclonal antibody via a protease-cleavable linker. MMAE is preferentially delivered to B cells expressing CD79b, which results in anti-cancer activity against B-cell malignancies [8]. Pola (1.8 mg/kg by an intravenous [IV] infusion every 3 weeks [Q3W]) was approved based on data from a randomized cohort of a phase 1b/2 study (GO29365 [NCT02257567]), in which pola in combination with BR (pola-BR) improved the outcomes of patients with R/R DLBCL compared with BR, and had a tolerable safety profile [9]. The study met its primary endpoint, with pola-BR inducing higher complete response rates at end of treatment compared with BR (40.0% vs. 17.5%; p = 0.026). Median progression-free survival (PFS) was significantly longer with pola-BR than with BR (9.5 vs. 3.7 months; stratified hazard ratio [HR] 0.36 [95% confidence interval (CI) 0.21–0.63]; p < 0.001); median OS was also improved (12.4 vs. 4.7 months; HR 0.42 [95% CI 0.24–0.75]; p = 0.002). Pola is currently being investigated in the front-line DLBCL setting in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP; with the cytotoxic component substituting for vincristine in the R-CHOP regimen [comparator arm]) in the ongoing phase 3 multicenter, randomized, double-blind placebo-controlled trial, POLARIX (NCT03274492) [10].

Ethnic diversity in drug efficacy and safety can lead to the need to adjust the recommended dose across different populations. Such ethnic differences are more applicable to small molecules rather than large molecules such as monoclonal antibodies (mAbs). For example, the approved starting dose for single-agent docetaxel is lower in Asian than in Western countries due to the higher rates of hematologic toxicity reported in Asian patients [11]. Similarly, for doxorubicin, higher hematologic toxicity was found in Chinese patients; Fan and colleagues [12] reported on a CBR3 variant where homozygous patients had a lower area under the concentration–time curve (AUC) ratio of a metabolite of doxorubicin, with these patients showing more hematologic toxicity but better tumor response [12]. This variant is found more commonly among Chinese patients than in Indian and Caucasian populations. A comprehensive review of the pharmacokinetics (PK) of approved therapeutic mAbs in Japan concluded that PK of mAbs is largely driven by body weight and antigen level, which supports body weight-based dosing of an ADC when body weight contributes significantly to the inter-subject variability of clearance [13]. This is supported by other studies in which ethnicity did not affect responses to rituximab-containing regimens in B-NHL [14, 15].

ADCs contain an antibody, a linker, and a cytotoxic small molecule, and represent a special class of drugs when compared with the small or large molecules previously investigated in ethnic groups. Upon binding to the target CD79b, pola is internalized in the target cells, and unconjugated MMAE is then released by proteolytic cleavage of the linker [8, 16]. Unconjugated MMAE is expected to be mostly eliminated in feces via the biliary/fecal route, and urinary excretion is a minor elimination pathway. MMAE is mostly eliminated unchanged in feces and urine and is only partly metabolized [Genentech, Inc., data on file]. For the elimination portion that is metabolized, MMAE is mostly metabolized via cytochrome P450 3A4 (CYP3A4) [17]. Ethnic-related polymorphism in metabolism enzymes has been reported as a possible explanation for requiring different doses of small molecules in Asian patients; MMAE elimination will be evaluated in the current report in this context. Brentuximab vedotin, an ADC with the same linker and cytotoxic payload (MMAE) as pola, was evaluated in a population PK (popPK) model including 30 Asian patients (8% of a total of 380 patients with lymphomas), where body size, but not race, showed a strong effect on the clearance of MMAE; additionally, the conjugate drug clearance was not affected by race [18]. The exposures of pola related analytes (total antibody, acMMAE and unconjugated MMAE) increased proportionally over a pola dose range from 0.1 to 2.4 mg/kg [8]. The acMMAE terminal half-life is approximately 12 days (95% CI 8.1–19.5 days) at Cycle 6. The unconjugated MMAE terminal half-life is approximately 4 days after the first pola dose [1].

As pola has only recently been approved, there are limited data on how ethnic differences in patients with DLBCL may affect treatment outcomes with pola. PK, safety, and efficacy profiles in a global phase 1 dose-escalation study (DCS4968g; NCT01290549) in 34 patients with R/R B-NHL receiving pola alone or in combination with rituximab [8] have been compared with results from a phase 1 study conducted in seven Japanese patients with R/R B-NHL (JO29138; JAPICCTI‐142580), with preliminary results showing similar safety, PK, and efficacy [19].

In the US, pola is currently approved at the dose of 1.8 mg/kg Q3W, in combination with BR, for patients with R/R DLBCL who have received at least two prior therapies. The main objective of the current analysis was to conduct an ethnic sensitivity assessment of pola PK to systematically evaluate whether the PK of pola is similar in Asian and global populations, based on data from patients with B-NHL. The PK comparisons are discussed in the context of the exposure–response (efficacy/safety) relationship of pola in Asian and global populations. Here, we sought to determine whether any dose adjustment is required for Asian patients, both for the currently approved indication for pola in patients with R/R DLBCL and potentially for other B-NHL indications that may be approved in the future.

In this study, we conducted an ethnic sensitivity assessment of pola PK to evaluate whether the clinical recommended dose of pola in global populations is appropriate in Asian populations with B-NHL. Overall, our results indicate that there was minimal difference in pola exposure between Asian and non-Asian patients. The comparable acMMAE exposure between Asian (South Korean) patients and global patients in the phase 1b/2 GO29365 (NCT02257567) study, between Japanese patients and global patients in the phase 1 studies (JO29138 [JAPICCTI‐142580] and DCS4968g [NCT01290549]), as well as simulation evaluation by popPK model (including four studies) by race and region, suggest that a pola dose of 1.8 mg/kg Q3W would be expected to have similar PK (and, therefore, efficacy/safety) in Asian and non-Asian patients.

Exposure-efficacy analyses of pola [25] indicate that race or region are not significant covariates of this relationship, suggesting that exposure–response is likely to be similar in Asian and global patients. There were no statistically significant correlations between unconjugated MMAE exposure and multiple efficacy endpoints. However, there were significant correlations between acMMAE and efficacy endpoints, which indicated that acMMAE is the key driver for efficacy among the three analytes of acMMAE, total antibody, and unconjugated MMAE.

Similarly, exposure–response analyses of safety [25] suggested that the incidence of grade ≥ 2 peripheral neuropathy increased significantly with increasing acMMAE exposure and the incidence of grade ≥ 3 anemia increased significantly with increasing unconjugated MMAE exposure. Given that acMMAE exposure was comparable in the three PK analyses conducted in this manuscript, grade ≥ 2 peripheral neuropathy risk is expected to be similar in Asian and global patients.

For unconjugated MMAE, the current analyses identified numeric differences in the lower C_max and AUC_inf in Japanese patients compared with global patients. The prescribing information for pola states that “in mild hepatic impairment (aspartate aminotransferase or alanine aminotransferase > 1.0 to 2.5 × upper limit of normal [ULN] or total bilirubin > 1.0 to 1.5 × ULN), there was a 40% increase in unconjugated MMAE exposure, which was not deemed clinically significant” [26]. Based on the exposure-safety relationship for grade ≥ 3 anemia, although higher unconjugated MMAE exposure was correlated with a higher risk of this event, at a typical clinical exposure level a 40% AUC increase is associated with < 5% increase in incidence. Similarly, a 60% decrease in MMAE exposure is associated with < 5% decrease in grade ≥ 3 anemia. Consequently, the magnitude of the difference observed for unconjugated MMAE in Asian patients is unlikely to be clinically relevant to the safety of pola in Asian patients.

CYP3A4 polymorphism is not expected to impact the exposure of unconjugated MMAE in such a way that would affect the safety of pola. The activity of CYP3A4 can vary by a factor of 10 and 100 between individuals [27]. Causes of variations in CYP3A4 activity are largely non-genetic, according to the Dutch Pharmacogenetics Working Group guideline on polymorphism of CYP3A4 [27]. There is a low prevalence of CYP3A4 poor metabolizer genotypes (< 1.1%), with an overall lack of clinical evidence for quantitative association with increased plasma exposure [26]. This is further supported by the absence of CYP3A4 in the Clinical Pharmacogenomics Implementation Consortium guidelines [28]. Furthermore, given that unconjugated MMAE is both metabolized and excreted unchanged into bile [Genentech Inc., data on file], the impact of poor metabolizer genotypes on exposure is expected to be lower for pola than for drugs that are exclusively eliminated via CYP3A metabolism. Overall, the risk for a marked increase in MMAE exposure in poor metabolizers is considered low, based on the absence of clear data indicating a clinically relevant effect and the alternative non-CYP mediated pathway for elimination.

Only a small magnitude of difference was observed in the PK parameters by race and region in the popPK model (using data from a total of 460 patients with B-NHL), which were not considered relevant to pola treatment outcomes. The popPK model identified bodyweight as the most important covariate influencing PK parameters, providing support for body weight-based dosing [24]. Bodyweight correlated with race and region. Both acMMAE and unconjugated MMAE exposures were influenced by body weight to a similar extent. For acMMAE, among all the statistically significant covariates, body weight was the most important covariate which explained 41.6% and 52.0% of the inter-individual variance (IIV) for CL_INF and V₁, compared with the base model. For unconjugated MMAE, among the statistically significant covariates, body weight was the most important covariate and explained 35.7% and 44.1% of the IIV for CL_INF and V₁, compared with the base model. All covariates together explained the majority of the IIV (54.8% and 70.3% of CL_INF and V₁) [24]. The pCC-based simulation is based on individual patient body weights, thus has incorporated the potential impact of lower body weight in Asian patients or Asia regions on PK exposures compared with other groups. Therefore, the pCC approach provided a realistic assessment of exposures in Asian patients or patients from Asia, in comparison with the other groups.

Previously published studies have found no impact of Asian ethnicity on clinical outcomes in DLBCL patients receiving pola or standard chemoimmunotherapy. For example, Hatake and colleagues [19] reported no substantial differences in antitumor response to pola monotherapy in Asian versus global or non-Asian populations when data from the Japanese JO29138 (JAPICCTI‐142580) and global DCS4968g (NCT01290549) studies were analyzed. Another study comparing PFS and OS in global and Asian patients with DLBCL following treatment with R-CHOP reported no marked differences in treatment outcomes [14]. As far as we are aware, there are no reports of clinically meaningful differences in treatment outcomes in Asian versus global patients treated with CHOP. Interestingly, Asian ethnicity has also been reported to have no effect on the PK of another ADC, trastuzumab emtansine, in patients with HER2-positive breast cancer, suggesting that treatment outcomes in these patients would be similar to those of non-Asian populations [29].

This study shows that PK data for Asian (South Korean) patients were similar to those in non-Asian patients in a phase 1b/2 pola-BR cohort of patients with R/R DLBCL, with the overlapping distribution of exposure from a Japanese phase 1 study and global phase 1 study of pola monotherapy in B-NHL. In addition, the popPK model analyses found no clinically meaningful differences in acMMAE and unconjugated MMAE exposures after pola dosing in Asian versus global populations with B-NHL, when analyzed by both race and region. The small magnitude of difference in PK observed is not considered to be clinically relevant, supported by exposure–response relationships of efficacy and safety. Overall, our data indicate that no adjustment of the clinically recommended pola dose of 1.8 mg/kg Q3W in Asian patients is warranted in the currently approved R/R DLBCL indication, or in other B-NHL indications that could potentially be approved in the future. This dosing schedule is being utilized in an ongoing phase 2 study of pola-BR in Japanese patients with R/R DLBCL (JO40762).