Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study

Abstract

Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

Patients and methods: In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.

Results: Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1-14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9-16.1] and 2.7 (95% CI, 0.7-5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1-89.2) and 27.8% (95% CI, 10.1-48.9) for patients with CLL and NHL, respectively.

Conclusions: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Conflict of interest statement

Conflicts of Interest: DS has received research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, Mingsight, Arqule, Novartis, Verastem, Juno Therapeutics. She has received consulting fees from Pharmacyclics/Janssen, Karyopharm Therapeutics, Beigene, Innate, AstraZeneca, Abbvie, CSL Behring, Celegene, TG Therapeutics, and Innate Pharma. BH has received research funding from Roche, Miragen, Celgene and CRISPR Therapeutics. HS has received research funding from Epizyme, Seattle Genetics and Beigene. KR has received research funding from Genentech, AbbVie, Janssen, and Novartis, has consulted for Acerta Pharma, Genentech, AbbVie, Pharmacyclics, AstraZeneca, and Innate Pharma, and received travel funding from AstraZeneca. SB has received consulting fees from AstraZeneca and Beigene. She has received honoraria from AstraZeneca, OncLive, and Aptitude Health. SJ has received research funding from Kite, Novartis, Juno/BMS, and Caribou Biosciences. She has received consulting fees from Kite, Novartis, Juno/BMS, CRISPR Therapeutics, and Takeda. RL is on the medical advisory board for Vincera Pharmaceutical, Inc. JCB has received research funding from AstraZeneca, Gilead, Karyopharm, Celgene, Pharmacyclics/Abvie, Kartos, Telios, and Newave. He has consulted for Jannsen, Pharmacyclics, AstraZeneca, Novartis, Trillium, and Syndax. He is a founder and major stock owner in Vincera Pharmaceutical, Inc. JAW has received research funding from Karyopharm, Pharmacyclics, Janssen, and Schrodinger. She has received consulting fees from Abbvie, AstraZeneca, Beigene, Pharmacyclics, Janssen, Genentech, and Loxo. YH, AR, JSW, DC, CC, QF, SB, RV, HL have no relevant conflicts of interest to disclose.

©2022 American Association for Cancer Research.

Figures

Figure 1.. Treatment Duration and Best Response for Individual Patients By Disease Subtype

Swimmers plot. The length of the bar indicates the time on treatment. CLL=chronic lymphocytic leukemia, CR=complete response, CRi=complete response with incomplete count recovery, DLBCL=diffuse large B-cell lymphoma, MCL=mantle cell lymphoma, PD=progressive disease, PR=partial response, SD=stable disease

Figure 2.. Progression-Free (A) and Overall Survival (B) by Disease Subtype

(A) Progression-free survival for patients with chronic lymphocytic leukemia [median 8.9 (95%CI: 3.9–16.1) months] and non-Hodgkin lymphoma [median 2.7 (95%CI: 0.7–5.4) months]. (B) Estimated 2-year overall survival was 73.7% (95%CI:44.1–89.2%) and 27.8% (95%CI:10.1–48.9%) for CLL and NHL patients, respectively.