Interim analysis of a Phase I/II study of tafasitamab with lenalidomide in patients with relapsed central nervous system lymphoma

Abstract Introduction The development of novel, effective and well-tolerated biological strategies to treat primary and secondary CNS lymphoma (CNSL) is a significant priority. We are evaluating tafasitamab, a humanized anti-CD19 monoclonal antibody, as a novel therapeutic for relapsed/refractory (R/R) PCNSL and SCNSL. We hypothesize that tafasitamab may have unique activity given enhanced ADCC as well as potential CNS penetration via perturbation of CD19 expressed on mural cells, a component of the blood-brain barrier. We reported that the tafasitamab/lenalidomide combination induced brain parenchymal regressions in two consecutive cases of relapsed PCNSL and SCNSL, each with disease refractory to methotrexate, lenalidomide and rituximab. (Rauschecker et al., Br J Haematol 2023). One of these responses has been durable, exceeding 3.5 years. Methods This single-arm, open-label, multicenter Phase I/II study (NCT05351593) was designed to assess the safety and preliminary efficacy of tafasitamab plus lenalidomide in R/R PCNSL/SCNSL. The study applies 3+3 dose escalation rules to identify the recommended phase 2 dose (RP2D), analyzing lenalidomide doses of 10mg, 15mg and 20 mg plus standard dose intravenous tafasitamab (12 mg/kg). After the RP2D is identified, the Phase II portion of the study will begin. The primary objective of the Phase II expansion is to evaluate the clinical benefit rate (stable disease or better) via Simon's minimax two-stage design. Results Thus far nine patients (8 PCNSL, 1 SCNSL, all large B-cell lymphoma) have been treated on protocol (4 male/5 female; median age 66, range 59-75). The cohort was exposed to a median of three prior lines of therapy (range 1-6) and four had prior IMiD exposure. Among the 7 PCNSL pts with baseline lymphoma mutational data available, 6 had high risk aberrations, as identified by Geng et al., Blood Advances 2025. The combination of tafasitamab plus lenalidomide has been well-tolerated with only one grade 3 adverse event related to study drugs (febrile neutropenia associated with urinary tract infection) and no evidence of neurotoxicity. The activity of tafasitamab plus lenalidomide has been confirmed thus far in R/R PCNSL/SCNSL, at both 10 mg and 20 mg dose levels, with median of 24 days to best response, and in each compartment within the neuroaxis, resulting in 3 CRs, 4 PRs and one SD. The study drug combination has shown efficacy in three patients whose tumors had progressed on lenalidomide. One patient on study treated with tafasitamab plus lenalidomide at the 10 mg dose level experienced rapid clearance of leptomeningeal lymphoma (confirmed by flow-cytometry and cytology) and partial regression of a brain parenchymal lesion, disease previously refractory to lenalidomide dosed at 15mg/d, intravenous rituximab and high-dose methotrexate. The second patient, with disease refractory to methotrexate, temozolomide, rituximab, etoposide plus cytarabine, ASCT (Thiotepa/BCNU) and lenalidomide, had near complete resolution of a 2.5 cm enhancing cerebellar mass within one month of tafasitamab plus lenalidomide, 15 mg/day. The third patient, treated with tafasitamab plus lenalidomide at 15 mg/day on study, experienced stable disease lasting 6.5 months on study. The durations of complete response in brain parenchyma have thus far exceeded 6 months in two patients, with the longest response, 8 months, exceeding by > 2-fold the response duration in this patient to up-front high-dose methotrexate, temozolomide, and intravenous rituximab. Three patients currently receive tafasitamab/lenalidomide on study. Serial ELISA measurements of IL-10 in CSF were associated with response and resistance. Declines in IL-10 correlated with both clinical responses and radiographic stable disease, whereas increases in IL-10 signaled impending radiographic progression. Conclusions These phase I trial data support the activity and safety of tafasitamab plus lenalidomide in heavily pre-treated, high-risk, R/R PCNSL/SCNSL, including in tumors that had progressed on lenalidomide and rituximab. These preliminary results may indicate an enhanced efficacy and/or synergy of the tafasitamab/lenalidomide combination in the CNSL tumor microenvironment. The combination has been well-tolerated at lenalidomide 10 and 15 mg dose levels and accrual continues at the lenalidomide 20 mg dose level with the aim of determining the RP2D. Supported by the Leukemia and Lymphoma Society.