Background:

Central Nervous System (CNS) lymphoma is a distinct entity of large B-cell lymphoma (LBCL) with a unique genomic profile with similarities to the activated B-cell (ABC) subtype, which may offer potential targets for therapy. These aberrancies commonly include MYD88 mutations, which enhances sensitivity to Bruton's tyrosine kinase (BTK) inhibitors, and translocation or copy number alterations of 9p24, which may associate with sensitivity with programmed death (PD)-targeted therapies. Expression of PD-L1 is common in CNS lymphoma and tumor infiltrating lymphocytes, and the majority of CNS lymphomas have a copy gain of 9p24.1. This suggests an attenuated immune response against CNS lymphoma. Ibrutinib in combination with nivolumab has shown safety and clinical activity in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia in a phase 1/2 trial, and therefore we hypothesized that this combination may be active in CNS lymphoma.

Methods:

We conducted an investigator-initiated, open label, single center, phase 2 clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Adult patients were eligible if they had CNS lymphoma (primary or secondary) refractory to or relapsed after at least 1 prior CNS directed therapy, with adequate organ and bone marrow function, without prior ibrutinib or PD1 inhibitor therapy, and did not require persistent high dose steroids. The trial had two sequentially enrolled cohorts: Cohort A included ibrutinib 560mg oral daily for one cycle (28-days per cycle), followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B included ibrutinib and nivolumab during the first cycle. Patients with a partial response or greater after 6 cycles of combined ibrutinib and nivolumab could continue therapy for up to 2 years or until progression of disease or unacceptable toxicity occurs. The primary objective was to determine the best overall response rate (ORR) of ibrutinib and nivolumab. Secondary objectives included the ORR of ibrutinib as a lead in prior to the combination, best complete response (CR) rate, landmark survival outcomes, and the safety of the combination. The trial planned to enroll 20 patients in both cohort A and B, but closed early due to slow accrual, due in part to the COVID19 pandemic.

Results:

The trial accrued 18 patients from February 2019 to June 2022, with all patients evaluable for response. The median age was 63 years (range 43-88), 33% were >70 years, and 78% were female. 89% had primary CNS lymphoma, 50% had non-GCB, 22% had GCB, and 28% were unable to be classified due to missing components of the Hans algorithm. The median number of prior lines of therapy was 2 (range, 1-4), 55% had refractory disease, 17% had prior stem cell transplant, and 11% had prior CAR T-cell therapy. 10 patients were enrolled to Cohort A (ibrutinib lead in), and 8 patients were enrolled to Cohort B (initial combination therapy). Adverse events included 50% with fatigue, 33% with nausea, and 28% with mucositis.

For both cohorts, the best ORR was 77.8% (95% CI: 52~94%) and the best CR rate was 50% (95% CI: 26-74%). In cohort A, the ORR of ibrutinib as a lead in after 1 cycle was 90% (95% CI: 55.5-99.7%), and the CR rate was 60%. In GCB patients (n = 4), the ORR and CR rates were 25%. In non-GCB patients (n =9), the ORR and CR rates were 100% and 56%, respectively. With a median follow up time of 34.6 months, the median overall survival (OS) was 25.4 months (95% CI 12.5-NR), and the OS rate at 12 months was 70%. The median progression free survival (PFS) was 6.6 months (95% CI: 2.9 - NR), and the PFS rate at 18 months was 47%. 4 patients withdrew from protocol therapy in CR, including 2 who proceeded to stem cell transplant consolidation, and 2 who stopped due to fatigue. 3 patients withdrew from protocol therapy in PR, 2 due to mucositis and 1 due to arthralgias. 1 patient died of COVID19 infection with a CR after 4 cycles of therapy.

Conclusion:

Ibrutinib and Nivolumab resulted in significant clinical activity in patients with refractory/relapsed CNS lymphoma. Our trial is limited by small patient numbers but suggests the potential for targeted therapy combinations in future larger clinical studies.

Westin:Abbvie: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; SeaGen: Consultancy; Nurix: Consultancy; Novartis: Consultancy, Research Funding; MonteRosa: Consultancy; Calithera: Research Funding; Kymera: Research Funding. Iyer:Pfizer: Research Funding; Acrotech: Consultancy, Research Funding; Ono: Research Funding; Merck: Research Funding; CRISPR: Consultancy, Research Funding; American Society of Hematology: Speakers Bureau; Innate: Research Funding; CuraBio: Speakers Bureau; Seagen: Consultancy, Research Funding; Yingli: Consultancy, Research Funding; Legend: Research Funding; Drenbio: Research Funding; Astra Zeneca: Research Funding; Salarius: Consultancy; American Society of Transplant and Cellular Therapy: Speakers Bureau. Neelapu:Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Merck: Consultancy, Other: Advisory Board Member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; Incyte: Consultancy, Other: Advisory board member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Bluebird Bio: Consultancy, Other: Advisory board member; Fosun Kite: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Caribou: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Janssen: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Orna Therapeutics: Consultancy, Other: Advisory board member; Takeda: Consultancy, Other: Advisory board member; Synthekine: Consultancy, Other: Advisory board member; Carsgen: Consultancy; Precision Biosciences: Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property). Strati:Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astrazeneca Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Hutchinson MedoPharma: Consultancy; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Genentech: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:Gilead Sciences/Kite Pharma: Honoraria, Research Funding; AstraZeneca: Honoraria; Regeneron: Honoraria; Genentech, Inc., Genmab, Gilead/Kite, Janssen, Merck, Novartis, Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; DeNovo: Honoraria; Caribou Biosciences: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria. Vega:Allogene: Research Funding; Geron: Research Funding. Flowers:Abbvie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Beigene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech Roche: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Pharmacyclics Jansen: Consultancy; SeaGen: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Jannsen Pharmaceuticals: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroghs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; CPRIT Scholar in Cancer Research: Research Funding.

Use of ibrutinib and nivolumab in CNS lymphoma

This content is only available as a PDF.
2023
Sign in via your Institution