Imbruvica Plus Drug Combo Shows Strong Responses in Newly Diagnosed PCNSL

Rituxan (rituximab) plus methotrexate, procarbazine and vincristine (R-MPV) plus Imbruvica (ibrutinib; R-MPV/i) induction therapy showed a high complete response rate (CR) rate and was shown to be tolerable in patients with newly diagnosed primary central nervous system (CNS) lymphoma (PCNSL), meeting the primary and key secondary end points of a phase 2 trial.

Data was presented at the 2025 SNO Annual Meeting.

At a median follow-up of 32.1 months, the overall response rate (ORR) was 100%, including a CR rate of 90% (27 patients) and an unconfirmed CR rate of 7% (2 patients), translating to an overall CR rate of 97% (29 patients). Additionally, the partial response rate was 3% (1 patient). No patients had refractory disease, and the median time to best response was 110 days.

The median progression-free survival (PFS) and overall survival (OS) were not reached. In total, four patients progressed with a median time to progression of 15.2 months. The two-year PFS rate was 84.2%, and the three-year PFS rate was 78.6%.

“The CR rate and the two-year PFS [rate] were much better than what you would expect, regardless of our consolidation measurement,” lead study author Dr. Christian Grommes, said in the presentation. “The question [you] might ask is: Is the addition of Imbruvica potentially modulating consolidation to a less aggressive approach?” Grommes is a neuro-oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

What is the rationale for investigating R-MPV plus Imbruvica in newly diagnosed PCNSL?

PCNSL is an aggressive form of non-Hodgkin lymphoma that develops in the CNS. Approximately 90% of cases of PCNSL present as diffuse large B-cell lymphoma. Recurrent B-cell receptor signaling axis mutations in genes like MYD88 and CD79B are common in this disease and can be targeted, according to Grommes.

Methotrexate (MTX)/R-MPV is a common induction regimen used to treat patients with newly diagnosed PCNSL. Grommes explained that previously, a prospective trial conducted at Memorial Sloan Kettering Cancer Center showed that induction therapy with R-MPV generated a 66% CR rate, a median PFS of 3.3 years, and a two-year PFS rate of 78% in this patient population. Additionally, the multicenter phase 2 NRG1114 trial demonstrated a CR rate of 76% and a two-year PFS rate of 54% with R-MPV plus cytarabine in this patient population.

Furthermore, a phase 2 trial showed a 74% ORR with Imbruvica monotherapy in patients with recurrent PCNSL.Collectively, these data supported the rationale for evaluating Imbruvica plus R-MPV in patients with newly diagnosed PCNSL.

“The idea that we had was to move…agents that are successful in the recurrent, refractory setting in reducing tumor size into the up-front [setting],” Grommes explained.

What was the safety profile of R-MPV/i in patients with PCNSL?

The most common any-grade side effects were decreased platelet counts (30 patients), lymphopenia (29 patients), anemia (28 patients), increased alanine aminotransferase (ALT) levels (28 patients), and increased aspartate aminotransferase (AST) levels (28 patients). The most common grade 3 (severe) side effects were lymphopenia (19 patients), anemia (16 patients), decreased white blood cell (WBC) counts (13 patients), decreased neutrophil counts (9 patients), increased ALT levels (9 patients), decreased platelet counts (4 patients), increased AST levels (3 patients), and increased creatine levels (1 patient).

No grade 5 (death) side effects were reported. Grade 4 (life-threatening) toxicities included neutropenia (4 patients), lymphopenia (3 patients), thrombocytopenia (3 patients), and decreased WBC counts (3 patients). Although Grommes noted that cardiotoxicity is a concern with the use of Imbruvica, in this trial, only two patients developed atrial fibrillation, and only one patient developed deep venous thrombosis. Investigators reported no major hemorrhage or Aspergillus/Pneumocystis infections.

“The combination of R-MPV plus Imbruvica is an excellent combination with excellent probability, especially no fungal infections, no major cardiac problems, and no hemorrhagic [side effects],” Grommes concluded.

What was the design of the phase 2 trial evaluating R-MPV/i in patients with newly diagnosed PCNSL?

This trial enrolled patients at least 18 years of age with newly diagnosed PCNSL who had an ECOG performance score of 2 or lower and normal end-organ function. Patients who had received 1 to 2 prior doses of methotrexate were allowed to enroll.

Patients were treated over four 28-day cycles with:

• Rituxan at 500 milligrams per square meter (mg/m²) on days 0+ to 14
• MTX on 3.5 g/m² on days 1+ to 15
• Vincristine at 1.4 mg/m² on days 1+ to 15 of cycles 1 and 2
• Procarbazine at 100 mg/m² on days 1 to 7 of each cycle
• Imbruvica at 560 mg on days 5 to 14 and 19 to 28 of each cycle

Consolidation treatment was determined by the investigators.

The primary end point was overall CR rate at end of induction. Secondary end points included safety and tolerability, PFS and OS.

References

1. “Imbruvica in combination with Rituxan, methotrexate, vincristine, and procarbazine for newly diagnosed primary CNS lymphoma” by Dr. Schaff, et al., presented at the 2025 SNO Annual Meeting.
2. “MTX-based chemotherapy combined with low-dose whole-brain radiotherapy improves progression-free survival for patients with newly diagnosed CNS lymphoma” by NRG Oncology, news release.
3. “A phase 2 study assessing long-term response to Imbruvica monotherapy in recurrent or refractory CNS lymphoma” by Dr. Grommes, et al., Clinical Cancer Research.

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