Abstract
Introduction: Autologous stem cell transplant (ASCT) is widely accepted as the standard consolidation therapy for primary CNS lymphoma (PCNSL) in first remission, with whole brain radiation therapy (WBRT) used in selected cases. However, older and frail patients with PCNSL often cannot tolerate ASCT or WBRT due to increased risk of treatment-related toxicities, such as infections and neurocognitive impairment. Without consolidation, survival outcomes are poor, with a median progression free survival (PFS) ranging from 10 to 20 months. Therefore, novel therapeutic approaches are needed for older PCNSL patients. Nivolumab, an anti-PD1 antibody, has demonstrated promising activity in relapsed or refractory PCNSL, and we hypothesized that adding nivolumab in the frontline setting would be safe and improve survival in older PCNSL patients who are ineligible for ASCT or WBRT.
Methods: In this multicenter phase 1/1B study (NCT 04022980), patients aged ≥ 65 with previously untreated PCNSL received up to 6 cycles of nivolumab consolidation after receiving at least 3 cycles of high-dose methotrexate (HD-MTX)-containing induction chemotherapy. Patients with systemic lymphoma or known ocular involvement were excluded. Stage 1 aimed to evaluate the safety of nivolumab consolidation following HD-MTX-containing induction chemotherapy. A 3+3 design was used for the safety run-in, enrolling 6 patients on nivolumab at the FDA-approved single-agent dose and monitoring for dose-limiting toxicities (DLTs) during Cycle 1. Stage 2 assessed the efficacy of nivolumab consolidation based on 2-year PFS. Neurological function was evaluated at baseline and throughout the study follow-up using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Kaplan-Meier methods were used to estimate overall survival (OS) and PFS, with both time-to-event endpoints calculated from the initiation of nivolumab consolidation therapy.
Results: Fourteen patients were enrolled across four U.S. sites between April 2020 and December 2022. The median age was 72 years (range 65-79), 71% were female, and 36% had an ECOG score of 2-3 at enrollment. Induction chemotherapy regimens included 36% R-MPV (rituximab, methotrexate, procarbazine, and vincristine), 21% MRT (methotrexate, rituximab, and temozolomide), 21% MR (methotrexate and rituximab), and 7% MATRix (methotrexate, cytarabine, thiotepa, and rituximab). Following induction chemotherapy, 64% achieved a complete response (CR), 29% achieved a partial response (PR), and 7% had a stable disease (SD). Patients received a median of 6 nivolumab cycles (range 1 – 6). No DLTs occurred during Cycle 1 of nivolumab in Stage 1. The most common grade ≥ 3 adverse events (AEs) were neutropenia (14%) and fatigue (7%). One patient developed grade 4 Stevens-Johnson syndrome, leading to treatment discontinuation after Cycle 1. Among those receiving ≥ 1 cycle of nivolumab consolidation, the overall response rate was 86%, with a CR rate of 79%. Three patients improved from PR or SD post-induction to CR after nivolumab consolidation. At a median follow-up duration of 33 months, median OS and PFS were not reached. The 2-year OS and PFS rates were 79% and 63%, respectively. All deaths (3/3) were due to disease progression. Two patients were found to have active lymphoma during or immediately after Cycle 1 and were subsequently discontinued from the trial. In one case, intraocular involvement was diagnosed during Cycle 1, likely undetected at screening due to its occult presentation. Eleven patients completed all planned cycles of nivolumab consolidation, and 73% remain in remission at the last follow-up.
Conclusion: This study demonstrates favorable safety and clinical outcomes with nivolumab consolidation in older PCNSL patients unsuitable for ASCT or WBRT. No DLTs were observed during the safety run-in phase, and there were no unexpected toxicities associated with nivolumab, although one early discontinuation occurred due to Stevens-Johnson syndrome, a rare but known AE of nivolumab. Overall, the absence of DLTs and encouraging survival outcomes support further investigation. Ongoing analyses aim to identify predictive biomarkers, including 9p24.1 and 6p21.3 amplifications, that may correlate with response to nivolumab in PCNSL. Additionally, NANO assessments are being analyzed to measure neurological changes in this population.
