Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma

Abstract

Purpose: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.

Patients and methods: In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.

Results: The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.

Conclusion: Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.

Trial registration: ClinicalTrials.gov NCT02793583.

Conflict of interest statement

Nathan H. FowlerEmployment: BostongeneConsulting or Advisory Role: Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene, NovartisResearch Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, AbbVie, BeiGene Felipe SamaniegoConsulting or Advisory Role: Astex Pharmaceuticals, ADC Therapeutics, Imbrium Therapeutics Wojciech JurczakResearch Funding: TG Therapeutics Nilanjan GhoshConsulting or Advisory Role: Seattle Genetics, TG Therapeutics, AstraZeneca, Verastem, Pharmacyclics/Janssen, Karyopharm Therapeutics, Genmab, Bristol-Myers Squibb, Gilead Sciences, Adaptive Biotechnologies, Beigene, AbbVie, IncyteSpeakers' Bureau: AbbVie, Janssen Oncology, Kite/Gilead Sciences, Seattle Genetics, AstraZeneca, Bristol-Myers Squibb, Celgene, Pharmacyclics/Janssen, EpizymeResearch Funding: Pharmacyclics, TG Therapeutics, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb/Celgene, Gilead Sciences Enrico DerenziniConsulting or Advisory Role: AstraZenecaResearch Funding: TG-Therapeutics, ADC Therapeutics James A. ReevesResearch Funding: Sarah Cannon Research Institute, Eli Lilly, Tesaro, TG Therapeutics, Genentech, Celgene, Merck, Bristol-Myers Squibb, Boston Biomedical Inc, AstraZeneca, NovoCure, Calithera Biosciences, Novartis, Guardant Health, Acerta Pharma, Rhizen Pharmaceuticals, Takeda, Onconova Therapeutics, Sanofi, CTI Biopharma, Eisai, Janssen Chan Y. CheahHonoraria: Roche/Genentech, Janssen-Cilag, TG Therapeutics, Loxo/Lilly, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Ascentage Pharma, MDSConsulting or Advisory Role: Janssen-Cilag, Roche/Genentech, TG Therapeutics, Loxo/Lilly, Gilead Sciences, AstraZeneca, Bristol-Myers Squibb, Ascentage Pharma, MDSSpeakers' Bureau: Janssen-CilagResearch Funding: Roche, Celgene, AbbVieTravel, Accommodations, Expenses: Roche Tycel PhillipsHonoraria: Seattle Genetics, Incyte, Pharmacyclics, Bayer, Gilead Sciences, GenentechConsulting or Advisory Role: Seattle Genetics, Pharmacyclics, Incyte, Genentech, Bayer, Gilead Sciences, Curis, Kite/Gilead, Celgene, GenmabResearch Funding: AbbVie, Pharmacyclics/Janssen, Bayer Ewa Lech-MarandaConsulting or Advisory Role: Roche, Amgen, AbbVie, Astellas Pharma, Novartis, Janssen-Cilag, Sanofi/Aventis, Takeda, Gilead Sciences Bruce D. ChesonConsulting or Advisory Role: TG Therapeutics, AbbVie, Pharmacyclics/Janssen, Morphosys, Celgene, Karyopharm Therapeutics, Epizyme, Gilead Sciences, SymBio Pharmaceuticals, Parexel, Merck, Glaxo Smith Kline, Beigene, Kite, Reddy Biosimilar, Bayer, CelgeneResearch Funding: TG Therapeutics, Trillium Therapeutics, Seattle Genetics, Bristol-Myers Squibb, Gilead Sciences, Pharmacyclics, AbbVie, AstraZenecaTravel, Accommodations, Expenses: SymBio Pharmaceuticals Paolo F. CaimiConsulting or Advisory Role: Genentech, Seattle Genetics, TG Therapeutics, Kite Pharma, ADC Therapeutics, Bayer, Amgen, Verastem, EpizymeSpeakers' Bureau: CelgeneResearch Funding: Genentech, ADC Therapeutics Lori A. LeslieConsulting or Advisory Role: Kite/Gilead, TG Therapeutics, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZenecaSpeakers' Bureau: Kite Pharma, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZeneca, Epizyme, Karyopharm Julio C. ChavezConsulting or Advisory Role: Kite/Gilead, Novartis, Karyopharm Therapeutics, MorphoSys, TeneoBio, AbbVie, JanssenSpeakers' Bureau: AstraZeneca, BeiGene, MorphoSys, EpizymeResearch Funding: Merck Gustavo FonsecaHonoraria: Amgen, CelgeneConsulting or Advisory Role: Amgen, Celgene, Bayer, Abvie/Pharmacyclics, Dava Oncology, KaryopharmSpeakers' Bureau: Amgen, CelgeneResearch Funding: Celgene, Amgen, TG Therapeutics, Verastem OncologyTravel, Accommodations, Expenses: Amgen, Celgene Sunil BabuStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol-Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite Pharma, Janssen OncologySpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol-Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, AbbVie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Daniel J. HodsonResearch Funding: Gilead Sciences John M. BurkeConsulting or Advisory Role: Genentech/Roche, AbbVie, Seattle Genetics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem, MorphoSys, Kura Oncology, Epizyme, BeiGene, Kymera, NovartisSpeakers' Bureau: Seattle Genetics, Beigene Jeff P. SharmanLeadership: US OncologyConsulting or Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, Beigene, PfizerResearch Funding: Pharmacyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda John M. PagelConsulting or Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, BeiGene, Loxo Hari P. MiskinEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Peter SportelliEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Owen A. O'ConnorEmployment: TG TherapeuticsLeadership: TG TherapeuticsBoard Appointments, Stock, and Other Ownership Interests: TG Therapeutics, Kymera, Myeloid Therapeutics, NomoCan PharmaceuticalsHonoraria: MundipharmaConsulting or Advisory Role: Mundipharma Research, Astex PharmaceuticalsResearch Funding: Merck, Celgene/Bristol-Myers Squibb, Seagen, Mundipharma, Astex Pharmaceuticals, ADC Therapeutics Michael S. WeissEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Pier Luigi ZinzaniConsulting or Advisory Role: Sanofi, Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko Kirin, TG Therapeutics, TakedaSpeakers' Bureau: Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko KirinNo other potential conflicts of interest were reported.

Figures

FIG 1.

Response in index lesion size by independent review committee assessment (intent-to-treat population). The best percentage change in the sum of the product of the longest perpendicular dimensions (SPD) during umbralisib treatment, according to assessment by an independent review committee, is shown for patients with MZL, FL, or SLL. Data are shown only for those patients with at least one postbaseline radiographic assessment (N = 198). The majority of patients (86.4%) (with an available scan at data cutoff) showed a decrease in SPD (58 of 64 patients with MZL [90.6%], 96 of 115 patients with FL [83.5%], and 17 of 19 patients with SLL [89.5%]) as assessed by change from baseline. Data cutoff: July 24, 2020. FL, follicular lymphoma; MZL, marginal zone lymphoma; SLL, small lymphocytic lymphoma; SPD, sum of products of perpendicular diameters.

FIG 2.

Kaplan-Meier curves for DOR and PFS by independent review committee assessment (ITT population). Kaplan-Meier curves are shown for the secondary end points of the DOR and PFS (respectively) among patients with MZL (A and D), FL (B and E), and SLL (C and F), who were treated with umbralisib (ITT population). The end points were assessed by an independent review committee. Data Cutoff: July 13, 2020. DOR, duration of response; FL, follicular lymphoma; ITT, intent-to-treat; MZL, marginal zone lymphoma; NE, not estimable; NR, not reached; PFS, progression-free survival; SLL, small lymphocytic lymphoma.