TG‐1701, A SELECTIVE BRUTON TYROSINE KINASE (BTK) INHIBITOR, AS MONOTHERAPY AND IN COMBINATION WITH UBLITUXIMAB AND UMBRALISIB (U2) IN PATIENTS WITH B‐CELL MALIGNANCIES (2021)

Introduction: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the “U2” combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ε inhibitor umbralisib) and BTK inhibition are highly active in treatment-naïve (TN) and relapsed/refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Herein we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Patients (pts) with R/R CLL, MCL and Waldenström's (WM) were enrolled in an ongoing Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded. All pts were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Results: As of 03 February 2021, 123 pts were treated with TG-1701 as follows: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1 - 10). All pts were BTKi-naïve. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3 - 28.6+) in DE and 8.5 mos (1.4 -15.6+) in disease-specific cohorts. Best change from baseline in tumor burden in pts in the 1701+U2 combination arm is presented in the figure below. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy. Recruitment to this study (NCT03671590) continues. EA – previously submitted to EHA 2021. The research was funded by: TG Therapeutics Inc. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies, Combination Therapies Conflicts of interests pertinent to the abstract C. Y. Cheah Employment or leadership position: None Consultant or advisory role: Janssen-Cilag, Roche/Genentech, TG Therapeutics, Loxo/Lilly, Gilead Sciences, AstraZeneca, Bristol-Myers Squibb, Ascentage Pharma, MDS Stock ownership: None Honoraria: Roche/Genentech, Janssen-Cilag, TG Therapeutics, Loxo/Lilly, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Ascentage Pharma, MDS Research funding: Roche, Celgene, AbbVie Other remuneration: Travel, Accommodations, Expenses: Roche W. Jurczak Employment or leadership position: None Consultant or advisory role: MEI Pharma, Debiopharm, Loxo, Takeda, AstraZeneca, BeiGene Stock ownership: None Honoraria: None Research funding: GlaxoSmithKline You Acerta Pharma You AstraZeneca You Nordic Nanovector You Incyte You DebiopGenentech, Janssen, Loxo, MEI Pharma, MorphoSys, Takeda, TG Therapeutics, BeiGene Educational grants: None Other remuneration: None T. Wróbel Employment or leadership position: None Consultant or advisory role: Roche/Genentech, Abbvie, Takeda, Novartis, Janssen-Cilag, Amgen Stock ownership: None Honoraria: Celgene, Roche, Gilead Sciences, Amgen, Janssen-Cilag Research funding: Roche Educational grants: None Other remuneration: None J. Walewski Employment or leadership position: None Consultant or advisory role: Roche, Abbvie, Takeda/Millennium, Gilead Sciences, Novartis Stock ownership: None Honoraria: Roche, Abbvie, Servier, Amgen, Takeda/Millennium, Gilead Sciences, Novartis Research funding: None Educational grants: Roche Other remuneration: None S. Cheung Employment or leadership position: None Consultant or advisory role: Novartis Stock ownership: None Honoraria: None Research funding: None Educational grants: None Other remuneration: None K. L. Lewis Employment or leadership position: None Consultant or advisory role: Roche Stock ownership: None Honoraria: Janssen, Novartis Research funding: None Educational grants: Janssen, Novartis Other remuneration: None M. Długosz-Danecka Employment or leadership position: None Consultant or advisory role: Servier, Abbvie Stock ownership: None Honoraria: None Research funding: None Educational grants: None Other remuneration: Speakers' Bureau: Janssen, Servier, Roche, Takeda. K. Giannopoulos Employment or leadership position: None Consultant or advisory role: Abbvie, Bristol-Myers Squibb/Celgene, Sanofi, Takeda, Amgen Stock ownership: None Honoraria: Janssen, Bristol-Myers Squibb/Celgene, Sanofi, Takeda, Amgen. Research funding: TG Therapeutics, Abbvie, Bristol-Myers Squibb/Celgene, Sanofi, Takeda, Amgen. Educational grants: None Other remuneration: None H. P. Miskin Employment or leadership position: TG Therapeutics Consultant or advisory role: None Stock ownership: TG Therapeutics Honoraria: None Research funding: None Educational grants: TG Therapeutics Other remuneration: None J.-P. Tang Employment or leadership position: TG Therapeutics Consultant or advisory role: None Stock ownership: TG Therapeutics, Roche, Alexion Pharmaceuticals Honoraria: None Research funding: None Educational grants: None Other remuneration: None E. Normant Employment or leadership position: TG Therapeutics Consultant or advisory role: None Stock ownership: TG Therapeutics, Surface Oncology Honoraria: None Research funding: None Educational grants: None Other remuneration: None O. A. O'Connor Employment or leadership position: TG TherapeuticsTG, Kymera, NomoCan Consultant or advisory role: Kymera, Celgene, Mundipharma, SERVIER Stock ownership: TG Therapeutics, Kymera. Honoraria: Kymera, Celgene, Astex Pharmaceuticals Research funding: Celgene, Astex Pharmaceuticals, Merck Educational grants: None Other remuneration: None A. D. Ricart Employment or leadership position: TG Therapeutics Consultant or advisory role: None Stock ownership: Pfizer, Merck, TG Therapeutics, Seattle Genetics, Collegium, Immunomedics, Stemline Therapeutics Honoraria: None Research funding: None Educational grants: None Other remuneration: None C. S. Tam Employment or leadership position: None Consultant or advisory role: Janssen, Loxo, Roche, BeiGene, Abbvie Stock ownership: None Honoraria: Janssen-Cilag, Abbvie, Novartis, Beigene, Pharmacyclics Research funding: Janssen-Cilag, Abbvie Educational grants: None Other remuneration: None