Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration

Polatuzumab vedotin (pola) is a CD79B-targeting antibody-drug conjugate with significant clinical activity in systemic diffuse large B-cell lymphoma. However, the ability of pola to penetrate the blood-brain barrier (BBB) and induce responses in central nervous system (CNS) lymphoma (CNSL) is unknown. Since other antibody-based therapies can partially penetrate the BBB to induce clinical responses in CNSL and other CNS malignancies, we hypothesized that pola would also partially penetrate the BBB, which could support its evaluation in future CNSL clinical trials. To test this hypothesis, we first evaluated the preclinical efficacy of pola in primary and secondary CNSL xenografts, where we observed that pola significantly decreased CNS tumor burden and prolonged survival in mice. To extend these findings, we compiled a clinical case series of 3 patients with CNSL treated with pola-based treatment. Here, on-treatment cerebrospinal fluid (CSF) samples revealed pola CSF drug concentrations exceeding its established 50% inhibitory concentration, with CSF drug levels being 0.56% to 1.31% of those in plasma. Interestingly, 2 of the 3 patients with CNSL achieved a complete response to pola-based treatment. In summary, these data indicate pola is effective against preclinical CNSL models and can partially penetrate the BBB in patients with CNSL, which together provide support for the evaluation of pola-based treatment in future clinical trials of primary and secondary CNSL.