A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Christian Grommes, Subhiksha Nandakumar, Lauren R Schaff, Igor Gavrilovic, Thomas J Kaley, Craig P Nolan, Jacqueline Stone, Alissa A Thomas, Sarah S Tang, Julia Wolfe, Alexis Bozza, Venissala Wongchai, Allison Hyde, Emma Barrett, Elizabeth A Lynch, Juli T Madzsar, Andrew Lin, Anna F Piotrowski, Elena Pentsova, Jasmine H Francis, Vaios Hatzoglou, Nikolaus Schultz, Anne S Reiner, Katherine S Panageas, Lisa M DeAngelis, Ingo K Mellinghoff

TLDR

  • The study looked at how well ibrutinib worked in people with a type of cancer called CNS lymphoma that had come back or was resistant to other treatments. The study found that ibrutinib worked well in these patients and that certain genetic changes in the body may be associated with a long-term response to the treatment. The study also found that clearing a certain type of DNA from the body was associated with a complete and long-term response to the treatment. The study was registered with NCT02315326.

Abstract

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK). We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL). 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 PCNSLs, 15 SCNSLs). Patients received ibrutinib at 560mg or 840mg daily in the dose-escalation and 840mg daily in the expansion cohort. 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 (CSF) collected before and during ibrutinib therapy. Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. Median progression-free survival (PFS) for PCNSL was 4.5 months (95%CI: 2.8-9.2) with 1y-PFS at 23.7% (95%CI: 12.4%-45.1%). Median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. Median PFS in SCNSL was 5.3 months (95%CI: 1.3-14.5) with a median DOR 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 circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. 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. NCT02315326.

Overview

  • The study focused on the safety and antitumor activity of ibrutinib in patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL).
  • The methodology involved enrolling 26 additional patients into a dose-expansion cohort of the trial, with patients receiving ibrutinib at 560mg or 840mg daily. Tumor responses were assessed through DNA sequencing of available tumor biopsies and cerebrospinal fluid (CSF) collected before and during ibrutinib therapy. The primary objective was to evaluate the efficacy and safety of ibrutinib in r/r CNS lymphoma patients. The study had a median follow-up of 49.9 months for PCNSL patients and 62.1 months for SCNSL patients. The study was registered with NCT02315326.

Comparative Analysis & Findings

  • Tumor responses were observed in 74% of PCNSLs and 60% of SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months with a 1y-PFS at 23.7%. The median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months with a median DOR 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 circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response.

Implications and Future Directions

  • The study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up. The findings suggest that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL. Clearance of circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. Future research could focus on identifying additional biomarkers associated with response and developing combination therapies to improve outcomes in r/r CNS lymphoma patients. The study was registered with NCT02315326.
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