Long-term results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia

Given the fundamental importance of the B-cell receptor (BCR) pathway in chronic lymphocytic leukemia (CLL) pathophysiology,¹ we investigated dual BCR blockade in treating relapsed or refractory (R/R) disease. We hypothesized that combining the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, which is highly effective in R/R CLL,^{2, 3} with the next-generation oral phosphoinositide-3-kinase-delta isoform inhibitor (PI3Kδi) umbralisib would be an effective, well-tolerated, and convenient therapeutic approach that could lead to more durable remissions than historical results with ibrutinib alone. Unlike the approved PI3Kis idelalisib and duvelisib, umbralisib also targets casein-kinase-1-epsilon,⁴ which may spare regulatory T cell functioning through downregulation of WNT signaling,⁵ and thereby lead to less immune-mediated toxicity. A large integrated safety analysis across four early-phase umbralisib monotherapy studies demonstrated favorable long-term tolerability.⁶ Our initial results of this combination indeed found the combination achieved a high overall response rate (ORR; 90%) with a promising 2-year progression-free-survival (PFS) rate of 90%.⁷ Here, we report long-term results with a median follow-up for survivors of just under 5 years.

The design of this multicenter, investigator-sponsored trial (NCT02268851) has been described previously.⁷ Of note, the study also included patients with R/R mantle cell lymphoma (MCL), but here we report only on long-term follow-up for the patients with CLL, as nearly all of the patients with MCL had either progressed or died soon after the data cut for the prior publication. Briefly, key inclusion criteria were R/R CLL with progression after ≥1 prior therapy, indication for treatment per iwCLL guidelines,⁸ and ECOG performance status ≤2. Key exclusion criteria were allogeneic transplantation within 12 months, active graft versus host disease, or central nervous system involvement. Patients received daily oral dosing of ibrutinib 420 mg and umbralisib at 3 dose levels. Study treatment was continued until progressive disease (PD) or unacceptable toxicity. Toxicity was by CTCAE 4.0 and iwCLL hematologic criteria, and response was by iwCLL criteria. Median duration on treatment was estimated by reverse Kaplan-Meier method. PFS and overall survival (OS) were estimated by Kaplan–Meier method. Statistical analyses used R version 4.3.1 (R Foundation for Statistical Computing).

Twenty-one patients with CLL were enrolled; median age was 67 years (range 48–85) with full characteristics previously described.⁷ Patients had a median of 1 prior line of therapy (range 1–6), with 43% of patients having received ≥2 lines. Two patients had prior BTKi exposure (both treated with ibrutinib for <6 months and without disease progression), 11/19 (58%) patients evaluated had unmutated IGHV, and 7/21 (33%) patients had TP53-aberrant disease (presence of del(17p) and/or TP53-mutation). At data cutoff (September 20, 2022), median follow-up among survivors was 57.6 months (range 8.3–86.7). Six patients were still on therapy (five patients remained on both drugs; one patient on umbralisib only), and 15 patients had discontinued treatment: five due to patient/physician decision, four due to unacceptable toxicity (n = 1 arthralgias, n = 1 elevated lipase and amylase, n = 2 general intolerance), and two each due to PD, death, and intercurrent illness (n = 1 fatal lung infection [COVID-19 pneumonia], n = 1 myelodysplastic syndrome [MDS]).

The recommended phase 2 dose was umbralisib 800 mg daily when given with standard dose ibrutinib. The median duration of umbralisib and ibrutinib treatment was 48.2 and 41.8 months, respectively. The safety profile remained similar to that previously reported. Table 1 lists all toxicities (any grade) that occurred in ≥20% of patients. Hypertension and atrial fibrillation occurred in 29% of patients (5% Grade 3/4) and 19% of patients (10% Grade 3/4), respectively. One major bleeding complication occurred (Grade 3 hematoma). Grade 4 events included 1 case each of sepsis, lipase elevation, hypophosphatemia, and MDS. Grade 5 events included one lung infection and one sudden death after 5 months on study, presumed to be cardiac in nature.

The best ORR was 95% (CR in 33%), and responses were durable (Figure 1), with a 5-year PFS of 59% (95% confidence interval [CI]: 39%–89%) and median PFS of 83 months (95% CI: 55–not reached). The 5-year OS was 75% (95% CI: 56%–100%). In the 11 patients with unmutated IGHV status, both the 5-year PFS and OS were 80% (95% CI: 58%–100%). In the seven patients with TP53-aberrant disease, both the 3-year PFS and OS were 71% (95% CI: 45%–100%); all had discontinued therapy by 5 years: five patients without PD but due to other medical issues (nonfatal aspergillus brain abscess that developed 2 months into study treatment, severe anxiety, treatment for squamous cell carcinoma, MDS, election for hospice), one patient with PD, and one sudden death.

We report long-term results from the first clinical trial in CLL demonstrating successful dual BCR pathway inhibition via a BTKi and PI3Kδi. With a median follow-up of nearly 5 years, we found that the combination of ibrutinib and umbralisib can provide durable clinical benefit in R/R CLL. The 5-year PFS of 59% is favorable in light of historical results with ibrutinib or PI3Ki monotherapy. For example, in the PCYC-1103 study, the 5-year PFS of ibrutinib monotherapy in R/R CLL was 44%,² and in the phase 3 RESONATE trial, the median PFS was just under 4 years.³ In a phase 2 study of umbralisib monotherapy in CLL patients intolerant to either BTK or other PI3Kδ inhibitors, median PFS was 23.5 months.⁹

Although we observed typical ibrutinib-related cardiovascular toxicities, the incidence of immune-mediated toxicities was low, with no late events seen with longer follow-up. Our data provide further evidence that combining a BTKi and PI3Ki over a prolonged treatment period is feasible. Time-limited treatment approaches aim to preserve efficacy while minimizing toxicity, and our initial experience with this trial provided the foundation for the triplet combination of ibrutinib, umbralisib, and ublituximab with MRD-guided treatment duration, which demonstrated promising initial results.¹⁰ We also led a study of acalabrutinib, umbralisib, and ublituximab with a planned maximum of two years of therapy regardless of MRD, which has had encouraging results.¹¹

A major limitation of our report is that umbralisib is no longer in clinical development and it is therefore unlikely that additional studies with this agent will be performed in CLL. Nonetheless, our data establish a proof of principle that this approach of dual BCR pathway blockade can achieve sustained efficacy and could inform the design of future studies. Such studies could leverage either a more selective covalent BTKi such as acalabrutinib or zanubrutinib, which have both been demonstrated in randomized studies to have improved safety profiles compared to ibrutinib (and in the case of zanubrutinib also an efficacy advantage), or the noncovalent BTKi pirtobrutinib, which is also highly active with excellent tolerability.¹² Furthermore, BTKi may affect differentiation of Th17 cells, which have been shown to contribute to PI3Ki toxicity,¹³ and thus the BTKi/PI3Ki combination may be particularly poised for more tolerable toxicity, as suggested by our study. Alternative combination partners for BTKi within the BCR pathway that could be explored include downstream proteins such as protein kinase C beta.¹⁴ Since the initial design of this study, BTKis are now a frontline standard-of-care, and thus there is also opportunity to explore dual BCR pathway inhibition as initial therapy.

Overall, we confirmed with long-term follow-up that dual BCR pathway blockade in R/R CLL can provide durable efficacy with an acceptable safety profile. Our results may inform the design of future studies utilizing better-tolerated agents targeting this same pathway, with a goal of developing new BTKi-based doublet regimens that can provide durable benefit with the convenience of an all-oral regimen that does not require intensive laboratory monitoring to safely initiate therapy.

Matthew S. Davids was the regulatory Sponsor and Principal Investigator of the study. Matthew S. Davids, Jennifer R. Brown, Hari Miskin, and Peter Sportelli designed the study. Christine E. Ryan, Jon E. Arnason, Adam M. Boruchov, Caron A. Jacobson, David C. Fisher, Jennifer R. Brown, Matthew S. Davids treated patients and/or collected data. Yue Ren and Svitlana Tyekucheva performed data analysis. Christine E. Ryan and Matthew S. Davids wrote the manuscript. All authors reviewed the manuscript and gave final approval for publication.

Christine E. Ryan has received honoraria from Research to Practice, Curio Science, and AstraZeneca and has received institutional research funding from Genentech. Hari Miskin is an employee of TG Therapeutics. Peter Sportelli is an employee of TG Therapeutics. Jennifer R. Brown has served as a consultant for Abbvie, Acerta/Astra-Zeneca, Alloplex Biotherapeutics, BeiGene, Bristol-Myers Squibb, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc., iOnctura, Kite Pharma, Loxo/Lilly, Merck, Numab Therapeutics, Pfizer, Pharmacyclics; received research funding from BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics; and serves on the Data Safety Monitoring Board for Grifols Therapeutics. Matthew S. Davids has received consulting fees from AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Genmab, Janssen, Merck, MEI Pharma, Mingsight Pharmaceuticals, Nuvalent, Secura Bio, Takeda, and TG Therapeutics; has received institutional research funding from Ascentage Pharma, MEI Pharma, Novartis, and Surface Oncology and receives royalties from Up-To-Date. Yue Ren, Svitlana Tyekucheva, Jon E. Arnason, Adam M. Boruchov, Caron A. Jacobson, and David C. Fisher declare no relevant disclosures.

This study was approved by the appropriate Institutional Review Boards and conducted by the Declaration of Helsinki. All patients provided informed written consent. This clinical trial is registered at clinicaltrials.gov: NCT02268851.

The study was supported by TG Therapeutics, with additional support from the Blood Cancer Research Partnership from a Therapy Accelerator Program (TAP) grant from the Leukemia and Lymphoma Society (LLS). MSD was a Clinical Scholar of the LLS and receives support from a National Institutes of Health R01 award (R01CA266298). CER acknowledges support from the CLL Society through a Young Investigator Award, as well as from the Lymphoma Research through their Scientific Research Mentorship Program and a Career Development Award.