Enitociclib (VIP152/formerly BAY1251152) Is a Selective and Active CDK9 Inhibitor : Preliminary Safety and Early Signs of Efficacy in Patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

Background: Enitociclib is a potent and selective CDK9 inhibitor demonstrating improved selectivity and target modulation, which may be effective in controlling hematologic cancers. We have previously reported safety and efficacy data on enitociclib in 12 patients (pts) with B- cell lymphoma; including 2/7 pts with double-hit diffuse large B-cell lymphoma (DH-DLBCL) in complete metabolic remissions (CR) for ~5.5 and ~4.0 years, of which 3.7 and 2.3 years were on treatment, respectively (Diamond Clin Can Res 2022) and 5 pts including 4 high-grade B-cell lymphoma (HGBL) and 1 CLL (Frigault EHA 2022).

Aims: We aim to demonstrate the clinical utility of a selective CDK9 inhibitor for treatment of a wide range of B-cell malignancies. Also, we evaluated whether enitociclib inhibits antibody production in a rat model. The COVID-19 pandemic has highlighted the liabilities of anti-CD20 antibodies and BTK inhibitors regarding vaccine efficacy; therefore, a drug that does not inhibit antibody production could be valuable addition to the armamentarium of treatments for B-cell malignancies.

Methods: Enitociclib is currently being evaluated in two phase 1 trials in pts with solid tumors and aggressive NHL (VNC-152-101/NCT02635672) and in pts with CLL/Richter syndrome (RS) (VNC-152-102/NCT04978779). Pts in VNC-152-101 are receiving 30 mg once weekly, while the pts in VNC-152-102 are receiving 10 mg for the first week and 15 mg thereafter, as this study has a dose-escalation component. Herein, we show safety and preliminary efficacy data for 5 newly enrolled pts; DH-DLBCL [1], RS [1], transformed follicular lymphoma (tFL) [1], Burkitt lymphoma [1] and mantle cell lymphoma [1]. Pharmacokinetic and pharmacodynamic (PD) parameters and ctDNA dynamics of these pts will be presented. The PD effect of enitociclib in whole blood of 7 DH-DLBCL pts (Diamond Clin Can Res 2022) was evaluated by RNAseq. A rat study evaluating the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) of enitociclib was performed to determine the impact on vaccine efficacy.

Results: A pooled safety analysis of the 5 newly enrolled pts together with the previously reported 12 pts (n=17) is reported. Demographics of the 17- pt cohort are described: (15 men/2 women), median age 68 years (range 21-84), median prior therapy 3.5 (n=16; range 1-10) were enrolled across both trials. Five pts (29%) were refractory to their last therapy; median time on enitociclib was 3.1 weeks (range 1.1-194). In pts with B-cell malignancies (n=17), enitociclib demonstrates mostly Grade (Gr) 1 and 2 gastrointestinal adverse events (AEs) as well as Gr 1 to 3 fatigue and pyrexia. Hematologic AEs are anemia (12% Gr 2, 18% Gr 3), neutropenia/neutrophil count decrease (18% Gr 2, 6% Gr 3, 12% Gr 4) managed with G-CSF support, and platelet count decrease (6% each Gr 1, 2, 3 and 12% Gr 4). The results from the TDAR study demonstrate that anti-KLH IgG production is not impaired with enitociclib dosing (0.33 and 1.25 mg/kg).

Enitociclib provides robust and reproducible downregulation of MYC (90.3% [SD=6.9] and 93% [SD=2.4]) and MYCL (89.7% [SD=2.8] and 88.0% [SD=2.9]) after the first and third dose, respectively. Furthermore, transformation/transcription domain- associated protein WDR5 (Thomas PNAS 2014) is downregulated reproducibly by enitociclib treatment, at first and third dose (61.1% [SD=9.4] and 60.4 [SD=10.5]), respectively. Transcriptional changes observed in DH-DLBCL pts will be interrogated in the newly enrolled pts. Preliminary efficacy signals from the 5 newly enrolled pts include 1 stable disease (SD), 2 radiologic disease progression, and 2 on study and who have not yet had first tumor assessment. The pt with SD is a tFL pt who is still on study being treated with enitociclib and had a 16% reduction in tumor burden at the end of cycle 2, which is an observation consistent with the 2 previously reported DH-DLBCL pts who achieved SD at cycle 2 and deeper responses (CR) at cycle 8.

Conclusions: Enitociclib has a favorable safety profile with evidence of clinical activity in DH-DLBCL and perhaps, with longer follow up, in other B-cell malignancies. Also, we show that enitociclib downregulates the MYC transcriptional program and is unlikely to abrogate vaccine efficacy, an important feature given the current COVID-19 pandemic.

Shadman:Atara Biotherapeutic: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; MEI Pharma: Consultancy; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Epi Lilly: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; TG Therapeutics: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Sound Biologics: Consultancy; AstraZeneca: Consultancy, Research Funding; Fate Therapeutics: Consultancy; Adaptimmune: Consultancy; Mustang Bio: Consultancy, Research Funding; Merck: Consultancy; Regeneron: Consultancy; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Celgene, a BMS Company: Research Funding; Gilead: Research Funding; Sunesis: Research Funding; Genmab: Research Funding. Mato:PER: Honoraria; DTRM Biopharma: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria; Medscape: Honoraria; Genmab: Honoraria, Research Funding; Acerta: Research Funding; BeiGene: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; Nurix: Research Funding; LOXO: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Octopharma: Honoraria, Research Funding; Pfizer: Research Funding; Curio: Honoraria; Dava: Honoraria; PerView: Honoraria. Batlevi:Dava Oncology: Other: Provision of Services; ADC Therapeutics: Other: Provision of Services; Bristol-Myers Squibb: Other: Ownership / Equity Interests; Provision of Services; Autolus: Research Funding; Bayer: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Roche/Genentech: Research Funding; Xynomic: Research Funding; GLG Pharma: Consultancy; Juno/Celgene: Consultancy; Kite Pharma: Consultancy; Life Sciences: Consultancy; Seattle Genetics: Consultancy. Flinn:Novartis: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; ArQule: Research Funding; Xencor: Consultancy; Unum Therapeutics: Research Funding; Acerta Pharma: Research Funding; Infinity Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals: Research Funding; Merck: Research Funding; Forma Therapeutics: Research Funding; Genmab: Consultancy; Celgene: Research Funding; Loxo@Lilly: Research Funding; Forty Seven: Research Funding; InnoCare Pharma: Consultancy, Research Funding; Hutchison MediPharma: Consultancy; Epizyme: Research Funding; City of Hope National Medical Center: Research Funding; Bristol Myers Squibb: Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Trillium Therapeutics: Research Funding; Takeda: Consultancy; Roche: Consultancy, Research Funding; Biopath: Research Funding; Tessa Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Century Therapeutics: Consultancy; CTI Biopharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Curis: Research Funding; Agios: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; CALIBR: Research Funding; CALGB: Research Funding; Servier Pharmaceuticals: Consultancy; Secura Bio: Consultancy; Myeloid Therapeutics: Research Funding; Seattle Genetics: Research Funding; Millenium Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Research Funding; Fate Therapeutics: Research Funding; TCR2 Therapeutics: Research Funding; 2seventy bio: Research Funding; Triphase Research & Development Corp: Research Funding. Byrd:Vincerx Pharma: Current equity holder in publicly-traded company; Xencor, Inc: Research Funding; Syndax: Consultancy; Novartis: Consultancy, Honoraria; AstraZeneca: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Kura Oncology, Inc: Consultancy; Pharmacyclics LLC: Honoraria, Research Funding; TG Therapeutics: Honoraria. Frigault:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company; Astra Zeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Clemens:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company. Huang:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company. Izumi:Astra Zeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company. Wong:Vincerx Pharma: Consultancy; Genentech: Consultancy; Denali: Consultancy; Chinook: Consultancy; Crescenta: Consultancy; Barer Institute: Consultancy; Enliven: Consultancy; Exelixis: Consultancy; Surrozen: Consultancy; Cleave: Consultancy. Breed:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company; Astra Zeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Amgen: Current equity holder in publicly-traded company. Garban:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company; ImmunityBio, Inc.: Ended employment in the past 24 months, Patents & Royalties. Johnson:Janssen: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company. Stelte-Ludwig:Bayer: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma GmbH: Current Employment, Current equity holder in publicly-traded company. Mithal:Vincerx Pharma: Current Employment. Birkett:Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company; PearlRiver Bio: Ended employment in the past 24 months; Centessa Pharmaceutical: Current equity holder in publicly-traded company; TeloNostiX: Current equity holder in publicly-traded company, Other: non-paid appointment. Hamdy:Astra Zeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma: Current Employment, Current equity holder in publicly-traded company. Rogers:AstraZeneca: Consultancy, Other: Travel Funding; Beigene: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy; Novartis: Research Funding; Janssen: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding.