Researchers at The University of Texas MD Anderson Cancer Center have reported promising results from a single-arm phase 2 trial evaluating the combination of ibrutinib (Imbruvica) and nivolumab (Opdivo) in patients with relapsed or refractory central nervous system (CNS) lymphoma.
The study, published in Blood Advances, demonstrated significant clinical activity with an objective response rate (ORR) of 77.8% (14 of 18 patients) and a complete response (CR) rate of 50% (9 of 18 patients). These findings suggest a potential new treatment approach for a patient population with limited therapeutic options.
Impressive Response Rates Across Patient Subgroups
The trial enrolled 18 patients across two cohorts. Cohort A received ibrutinib monotherapy for one 28-day cycle before adding nivolumab, while Cohort B received the combination from the beginning of treatment. Notably, Cohort A showed superior outcomes with an ORR of 90% and CR rate of 60%, compared to 62.5% and 12.5%, respectively, in Cohort B (P = .008).
"The combination of ibrutinib and nivolumab for the treatment of relapsed/refractory CNS lymphoma showed a high ORR of 77.8%, and responses were durable for more than 2 years without further treatment in 17% of patients," stated primary investigator Dai Chihara, MD, PhD, an associate professor in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center.
The study included patients with both primary CNS lymphoma (89%) and secondary CNS lymphoma (11%). Interestingly, patients without germinal center B-cell (GCB) lymphoma showed a higher ORR (91% vs 50%) but similar CR rates (45% vs 50%) compared to those with GCB disease.
Survival Outcomes and Durability of Response
At a median follow-up of 31 months, the median progression-free survival (PFS) was 6.5 months and median overall survival (OS) was 21.0 months. The 1-year PFS and OS rates were 42% and 63%, respectively.
Particularly encouraging was the finding that three patients with primary CNS lymphoma experienced remissions lasting more than two years without additional treatment. This suggests the potential for durable responses with this combination therapy in a subset of patients.
Treatment Regimen and Patient Characteristics
Patients in Cohort A received 560 mg of oral ibrutinib daily for one 28-day cycle followed by the addition of 240 mg intravenous nivolumab administered biweekly. Cohort B received both medications from the start of treatment. Patients achieving partial response or better after six treatment cycles continued therapy for up to two years or until disease progression or unacceptable toxicity.
The study population had a median age of 63 years (range 43-88), with only 22% being male. Most patients were heavily pretreated, with a median of two prior therapy lines. More than half (55%) had disease refractory to previous treatments, and some had undergone prior transplantation (17%) or CAR T-cell therapy (11%).
Safety Profile and Tolerability
The combination therapy demonstrated a manageable safety profile. While all patients experienced treatment-related adverse effects, 50% had at least one grade 3 or 4 event. No grade 5 toxicities occurred.
The most common adverse events included fatigue (50%), nausea (33%), and mucositis (28%). Grade 3-4 adverse events included neutropenia and oral mucositis (two cases each), as well as single instances of pneumonitis, arthritis, and maculopapular rash.
Two patients discontinued nivolumab due to arthritis and rash flare-ups. Notably, no atrial fibrillation or bleeding events—known complications of ibrutinib—were observed in this trial.
Challenges and Future Directions
Despite the promising results, Dr. Chihara noted that the trial was closed early due to slow recruitment, highlighting the challenges of conducting clinical research in rare diseases like CNS lymphoma.
"The trial was unfortunately closed because of slow recruitment, showing the significant challenge of clinical investigation in CNS lymphoma and accentuating the unmet need of biology-driven, well-designed studies that maximize the sample size of small patient numbers," Dr. Chihara explained.
The researchers suggested that future trials should incorporate newer technologies such as circulating tumor DNA analysis to overcome sample collection challenges and better characterize CNS lymphoma, potentially leading to improved understanding of response and resistance mechanisms.
This study represents an important step forward in addressing the significant unmet need for effective treatments for patients with relapsed or refractory CNS lymphoma, a condition that has historically been difficult to treat with limited therapeutic options.
