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Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of non-Hodgkin lymphoma with poor prognosis. Salvage chemotherapy for relapsed or refractory (R/R) PCNSL has limited efficacy and is often associated with significant toxicity. Lenalidomide-rituximab and BTK inhibitors have shown activity in R/R PCNSL. Poseltinib is a potent and selective BTK-TEC dual inhibitor with high CNS penetration profile. To this end, we conducted a phase II trial to evaluate the efficacy of a chemotherapy-free salvage regimen comprising rituximab, lenalidomide, and poseltinib (R2P) in patients with R/R PCNSL. Methods This is an investigator-initiated, open-label, single-arm, multi-center phase II trial started in December 2022 at four university-affiliated hospitals in South Korea (NCT06737250). This regimen consists of 9 cycles: 6 induction cycles (R2P) followed by 3 consolidation cycles (lenalidomide, poseltinib), with each cycle lasting 28 days. Rituximab (375 mg/m2 intravenously) was administered on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2–6. Lenalidomide (15 mg daily) and poseltinib (40mg twice daily) were administered orally from day 1 to day 21 of each cycle for a total of 9 cycles. Based on the favorable safety profile in the safety cohort, the poseltinib dose was increased to 60 mg twice daily per a protocol amendment in February 2024. Primary endpoints were complete response (CR) and overall response rate (ORR); secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Next-generation sequencing (NGS) was performed on pre-treatment Formalin-fixed paraffin-embedded tumor samples using the SureSelect Cancer CGP assay (Agilent). Results Overall, 10 patients were enrolled from April 2023 to May 2024. The trial was terminated early to initiate a sponsor-initiated study of poseltinib with an optimized dosing regimen (NCT06737250). The median age was 70 years (range, 53–75), and four were male. The median number of prior chemotherapy lines was 2 (range, 1–3). All patients received methotrexate-based chemotherapy as first-line treatment. Nine patients received poseltinib 40 mg twice daily, while the last enrolled patient received 60 mg twice daily. One patient on 40 mg withdrew consent before completing cycle 1 without disease progression and was lost to follow-up; thus, efficacy was assessed in the remaining 9 patients. Based on the best response, three patients achieved a CR (33.3%), and two achieved a partial response (PR) (22.2%), resulting in an ORR of 55.6% (95% confidence interval [CI], 21.2–86.3). Four patients were confirmed to have progressive disease (PD) after cycle 3. Among the two patients who achieved a PR after cycle 3, one withdrew consent after completing cycle 5 without evidence of PD, while the other developed PD after cycle 5. Among the 3 CR patients, one maintained CR, completed treatment up to cycle 9, and remained in CR at the time of analysis. Another patient progressed after cycle 6. The remaining patient discontinued treatment after cycle 7 due to withdrawal of consent but has continued follow-up and remains in CR. For responders, the median DoR was 3.5 months (95% CI, 2.0–not reached). During a median follow-up of 20.1 months, 6 patients experienced PD, and 3 patients died due to disease progression. The median PFS was 5.6 months, with 6-month and 12-month PFS rates of 41.7% (95% CI, 18.5–94.0) and 27.8% (95% CI, 8.9–86.9), respectively. The median OS was not reached, with 6-month and 12-month OS rates of 76.2% (95% CI, 52.1–100.0) and 61.0% (95% CI, 34.1–100.0), respectively. NGS was conducted in 4 out of the 10 patients (2 CR, 1 PR, and 1 PD). The most frequently identified mutations were in PIM1 (4/4, 100%), followed by CD79B (3/4, 75%). Missense mutations in CD79B were identified in all three responders but were absent in the non-responder. The MYD88 L265P mutation was identified in two patients—one who achieved a best response of CR, and the other who exhibited PD. A patient who achieved CR with concurrent CD79B missense and MYD88 L265P mutations has maintained CR for over 20 months at the time of analysis. Conclusions Poseltinib in combination with lenalidomide and rituximab may represent a promising therapeutic approach for patients with R/R PCNSL. Further studies with larger cohorts and integrated genomic analysis are warranted.