Polatuzumab Vedotin and R-CHP Appropriate for Untreated DLBCL

The combination of polatuzumabvedotinand rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) as a first-line treatment for diffuse large B-cell lymphoma (DLBCL) was found to be appropriate, according to a study that considered population pharmacokinetics (PKs)and exposure-response (ER)analyses published in CPT: Pharmacokinetics & Systems Pharmacology.

Standard care for patients with previously untreated DLBCL has revolved around rituximab plus cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (R-CHOP). Despite the positives of this treatment, 30% to 40% of patients thatrelapse or become refractory to treatment.

Polatuzumabvedotin, anantibody-drug conjugate that consists of a humanized anti-CD79b immunoglobulin G1 monoclonal antibodyand delivers the cytotoxic payload monomethyl auristatin E (MMAE), has been approved in multiple countries outside of the US for patients with previously untreated DLBCL.

Polatuzumabvedotin is approved in multiple countries outside of the US for patients with previously untreated DLBCL | Image Credit: alessandrobiascioli - stock.adobe.com

The POLARIX study evaluated polatuzumabvedotin in combination with R-CHP and found significantly improved progression-free survival compared withR-CHOP in patients with DLBCL (HR, 0.73; 95% CI: 0.57-0.95; P = .02), the investigators wrote.

To further investigate the impact of polatuzumabvedotin dose selection and R-CHP regimen, population PK and exposure-response analyses were performed. The investigators discussed the important role these analyses have in providing support for dosing decisions and in the approval process for oncology drugs.

There were 429 patients included in the current analysis, pooled from the 435 safety-evaluable patients with previously untreated DLBCL who received Pola-R-CHP in the POLARIX study.The population PKs analysis showed there were no clinically meaningful relationships between cycle 6 antibody-conjugated MMAE/unconjugated MMAE area under the concentration-time curve or maximum concentration, and patient and disease characteristics such as sex, weight, ethnicity, region, and others, according to the investigators.

Importantly, the investigators found that repeated dosing of polatuzumabvedotin did not lead to an accumulation of antibody-conjugated MMAE. Furthermore, the choice of nominal vs an actual polatuzumabvedotin dose as an exposure metric had a lesser chance of confounding the interpretation of ER relationships with a high dose intensity of polatuzumabvedotin in POLARIX.

Consistent with previous ER analyses in patients with relapsed/refractory DLBCL, changes in unconjugated MMAE exposures did not lead to any clinically meaningful increase in the likelihood of adverse events of special interest (AESI), the investigators found. Additionally, despite increased AEs being observedwith increased exposure to treatment, there was still a favorable benefit-risk profile.

Patients who weighed more than 100 kg had higher exposure than those who weighed less than 100 kg because of weight-based dosing, although the investigators cautioned that these differences are not expected to have a clinically relevant impact on safety based on the exposure-safety analysis.

Those with moderate hepatic impairment had moderately higher exposure to unconjugated MMAE exposures, according to the investigators. At the same time, a logistic regression of unconjugated MMAE exposures centered around the probability of AESIs implied that this higher exposure will not lead to a meaningful increase in the incidence of AESI.

The ER analysis suggested that at a polatuzumabvedotin dose of 1.8 mg/kg every 3 weeks, lower exposure could be associated with lower efficacy. Higher exposure of polatuzumabvedotin was associated with decreased dose intensities of polatuzumabvedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone, although the investigators did not consider this clinically relevant.

Some limitations of the analyses noted by the investigators were the small sample sizes for some of the covariates used and data that werelimited to a single dosing of polatuzumabvedotin at 1.8 mg/kg every 3 weeks, which could cause confounding of ER results and limit the range of exposure that is included in the analyses.

“The starting dose of polatuzumabvedotin 1.8 mg/kg Q3W is appropriate for patients with DLBCL based on the covariates investigated, which are representative characteristics of the wider DLBCL patient population,” the investigators concluded.

Reference

Deng R, Gibiansky L, Lu T, et al. Population pharmacokinetics and exposure–response analyses of polatuzumabvedotin in patients with previously untreated DLBCL from the POLARIX study. CPT Pharmacometrics Syst Pharmacol. Published online April 15, 2024. doi:10.1002/psp4.13141