D. Lu,1 J. Y. Jin,1 L. Gibiansky,2 P. Agarwal,1 R. Dere,1 C. Jones,1 C. Li,1 M. Wenger,1 Y. Chu,1 R. Kahn,1 A. Joshi,1 S. Girish1; 1Genentech, South San Francisco, CA, 2QuantPharm, North Potomac, MD
BACKGROUND: Polatuzumab vedotin, an anti-CD79b ADC, is studied in Phase I and II studies as a single-agent or in combination with rituximab for treating relapsed/refractory (R/R) B-cell lymphoma (BCL). Population pharmacokinetics (PK) and exposure-response (E-R) correlation of antibody-conjugated monomethyl auristatin E (acMMAE) were assessed.
METHODS: A population PK model was established with covariates explored, using data from 155 BCL patients. Correlations between exposure parameters and efficacy (objective response) or safety (peripheral neuropathy) were assessed by logistical regression.
RESULTS: A two-compartmental model with linear clearance dominating acMMAE elimination at steady state (>95% of total clearance) adequately described the acMMAE PK. Body weight, gender, baseline B-cell count and tumor burden were statistically significant covariates impacting clearance, but no further dose adjustment was justified for the current body weight based regimen. With increases in acMMAE exposure, the probability of objective response increased, suggesting a higher dose (2.4 mg/kg) is preferred over 1.8 mg/kg for anti-tumor activity. However, a trend of higher probability of peripheral neuropathy is also observed with higher exposure and longer treatment duration.
CONCLUSION: Conjugate (acMMAE) primarily exhibits linear PK in BCL patients. The 2.4 mg/kg q3w dose is supported for better anti-tumor activity. Dose reduction to manage peripheral neuropathy is also supported by the exposure-safety correlation. Phase III data will be used to re-assess/update the population PK and exposure-response.