Results of the primary end-point of the LOC-R01: A randomized phase II Study of lenalidomide and ibrutinib in association with rituximab-methotrexate procarbazine vincristin (R-MPV) as a targeted induction treatment for patients aged 18 to 65 with a newly diagnosed primary central nervous system lymphoma (PCNSL)

Abstract

Abstract BACKGROUND With standard high-dose methotrexate (HDMTX) and cytarabine (HDAraC)-based inductions, half of the patients achieved complete response (CR). Improvement of the CR rate to induction is crucial to allow consolidation with high dose therapy followed by autologous stem cell transplantation (HD+ASCT) in eligible patients. The objective of the LOC-R01 study was to evaluate efficacy of the standard R-MPV first-line induction therapy combined with either lenalidomide or ibrutinib as a targeted induction therapy in newly diagnosed PCNSL. Recommended doses of ibrutinib and lenalidomide in combination with R-MPV were previously determined in the phase Ib part of the study (Alcantara et al. 2024). METHODS Immunocompetent patients (18 to 65 years of age) with untreated PCNSL were randomly assigned to receive 4 cycles of R-MPV with lenalidomide (15 mg/day, D1-D21) or ibrutinib 560 mg daily (D3-14 and D17-28). Randomization was stratified by centers and Karnofsky index (KI) (> 60 or < 60) in a non-comparative prospective phase II trial (NCT04446962). Responders received two cycles of HDAraC followed by HD thiotepa-busulfan and ASCT. Responses were assessed according to the IPCG criteria after MRI central review. Patients were included in the efficacy population if they received at least one dose of lenalidomide or ibrutinib. The primary end-point was the CR rate at the end of the induction phase (A'Hern design: P0 = 45%; P1 = 65%, alpha = 8%; beta = 9%). Forty-four assessable patients per arm with at least 25 CR/CRu were required to conclude that the treatment is effective. Patients without response assessment in any of the 3 CNS compartment (brain, CSF, eyes) at the end of induction were considered as non-responders. RESULTS Between March 2022 and August 2024, 92 patients from 20 centers were randomized in Lenalidomide (n = 45) or Ibrutinib (n = 47) arm. Primary endpoint was evaluated on 89 patients with 44 patients in the lenalidomide arm (median age = 57; range, 30 to 64; n= 8 with KI< 60), and 45 patients in the ibrutinib arm (median age = 58; range, 20 to 65; n=11 with KI < 60). Lenalidomide was suspended in five patients during induction because of cutaneous toxicity (n=3), cholangitis (n=1) and psychiatric disorder (n=1). One other patient in the lenalidomide arm was withdrawn from the trial after developing a Steven Johnson syndrome at cycle 1. Ibrutinib was suspended in 4 patients during induction because of subdural hematoma (n=2), hepatic cytolysis (n=1), and one patient refusal. The addition of Ibrutinib or lenalidomide did not affect the dose intensity of methotrexate. At the end of the induction, in the lenalidomide arm, 38 patients (86 %) were in CR/CRu, 2 in PR (4%), 2 patients (4%) had progressive disease (PD) and two patients were not evaluable for response. In the ibrutinib arm, 37 patients (82%) were in CR/CRu, 5 patients in PR (11%) and 3 patients in PD (7%). Thirty-three (75%) and 39 (87%) patients proceeded to ASCT in the lenalidomide and ibrutinib arm, respectively. With a median follow-up of 20 months, 18 months-PFS and OS were 72% (95%, 59-88%), 87% (95%,76-98%) and 82% (95%,-71-94%), 88% (95%, 78-98%) in the lenalidomide and ibrutinib arm respectively. The safety profiles were consistent with those observed with R-MPV regimen and targeted therapies confirming the results of the phase IB. An exploratory analysis of the lymphoid subpopulations, stratified according to CMV status at baseline, was performed in each arm at baseline and end of induction. Both treatments modulate T cell subsets. In the ibrutinib arm, a decrease in the CD4+ and an increase in the activation markers PD-1 and ICOS were observed, whereas a significant increase of the Treg cells were observed in the lenalidomide arm. CONCLUSION Both arms met the predetermined threshold of efficacy with 86% and 82% of CR/CRu rates in the lenalidomide and ibrutinib arm, respectively. R-MPV plus a BTK-inhibitor or an immunomodulatory drug constitutes an interesting first-line induction for PCNSL patients up to 65 years. Correlation of patient, disease and lymphoid subpopulations characteristics with response in each treatment arm will be explored to guide the choice of the targeted therapy. Ancillary studies regarding the prognostic impact of baseline and end of induction levels of cytokines in the CSF, ctDNA in plasma/CSF and radiomic features, as biomarkers of response, are planned.