A Phase II Study Assessing Long-term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma

Abstract

Purpose: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL).

Patients and methods: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy.

Results: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses.

Conclusions: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

Figure 1:. Clinical trial population for PK and long-term follow up analysis

A) Cartoon highlighting the timing of tissue samples (tumor biopsy and cerebrospinal fluid (CSF) samples) collection. Archival tissue was collected from the time of initial diagnosis. Pre- (CSF1) and on-treatment (CSF2) CSF samples were collected from trial participants. B) Overview of the phase I/II study population and associated clinical and laboratory assessments.

Figure 2:. Clinical and imaging-based response to Ibrutinib

A) Best response to ibrutinib, assessed using International PCNSL Collaborative Group (IPCG) guidelines. Displayed is the change in target lesion diameter from baseline (%) by magnetic resonance imaging or clearance of cerebrospinal fluid; negative values indicate tumor shrinkage. Shown are subjects who underwent at least 15 days of drug treatment and one post-treatment evaluation. Dashed lines indicate +25%/−50% change. Black: progression of disease (PD); orange: stable disease (SD); blue: partial response (PR), and green: complete response (CR). Patients with Primary Central Nervous System Lymphoma (PCNSL) are grouped on the left; those with Secondary Central Nervous System Lymphoma (SCNSL) on the right. B) PCNSL/C) (SCNSL) Kaplan-Meier curve showing progression-free survival (PFS) and overall survival (OS).

Figure 3:. Ibrutinib Concentrations in the CSF and plasma.

A) CSF concentrations in patients dosed at 530 mg (n=3) and 840 mg (n=27) in ng/mL and nM concentrations. B) Correlation of plasma and CSF ibrutinib concentrations (patients doses with 560 mg are highlighted in blue).

Figure 4:. Changes in CSF ctDAN during Ibrutinib therapy

A) Matched pre- (CSF1) and on-treatment (CSF2) CSF samples were used from 11 PCNSL and 3 SCNSL patients. Displayed is the presence (blue) vs. absence (white) of mutations in matched pre- (CSF1) and on-treatment (CSF2) CSF samples in individual patients. Those archiving a complete response on imaging are highlighted in green. B) Displayed are the number of circulating tumor DNA (ctDNA) mutations identified in the pre-treatment (CSF1) sample compared to the on-treatment (CSF2) sample in the same patient after 4 weeks of ibrutinib therapy. Patients are grouped into those with a complete response (CR; green) on imaging and those that did not achieve a complete response (No CR; black).

Figure 5:. Genomic correlates of Long-term ibrutinib response in pretreatment tumor biopsies

. A) Archival PCNSL tumor samples collected at the initial diagnosis from trial participants (n=25) were used to identify genomic alterations. Displayed is an oncoprint containing mutations identified in at least 10% of archival tumors. B) Frequency of mutations observed in a large MSK population compared to the study population are displayed. C) PCNSL patients are sorted based on progression-free survival (PFS). Displayed are the subtype, overall response to ibrutinib monotherapy and depth of response. The median PFS of ibrutinib in PCNSL is highlighted as dashed line. D) Cartoon of the TBL1XR1 gene with location of identified mutations. E) Kaplan-Meier curves showing progression-free survival in patients with PCNSL based on TBL1XR1, CARD11, MYD88, and CD79B mutation status.