UMBRALISIB MONOTHERAPY DEMONSTRATES EFFICACY AND SAFETY IN PATIENTS WITH RELAPSED/REFRACTORY MARGINAL ZONE LYMPHOMA: A MULTICENTER, OPEN‐LABEL, REGISTRATION DIRECTED PHASE 2 STUDY (2019)

Introduction: Rituximab (RTX) alone or in combination with chemotherapy has substantially improved treatment outcomes for patients (pts) with marginal zone lymphoma (MZL), but relapse is common and not all pts are acceptable candidates for, or respond to, current salvage therapies. Umbralisib is a novel, next-generation PI3K-delta inhibitor with unique inhibition of casein kinase-1ε (CK1ε) and, compared to earlier generation PI3K-delta inhibitors, exhibits a differentiated tolerability profile with reduced rates of immune-mediated toxicity (Burris et al, 2018). This registration-directed study evaluates the efficacy and safety of umbralisib in pts with relapsed/refractory (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS ≤2, and had previously received ≥1 prior therapy including at least one CD20 monoclonal antibody (mAb)-containing regimen. All pts received umbralisib 800 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) according to 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. Results: Sixty-nine pts were enrolled; we report on the first 38 who are eligible for at least 6 months (mos) of follow-up as of the data cutoff date. Disease status for the 38 pts: extranodal (n=23), nodal (n=8), and splenic (n=7). Median age was 67 years (range, 34-81). Median number of prior systemic therapies was 2 (range, 1-5). Seven pts (18%) had received monotherapy RTX only, and 26 (68%) had received at least one CD20 mAb-containing chemoimmunotherapy. As of the cut-off date, the median follow-up was 9.6 mos. Per investigator assessment, ORR was 55% (4 CRs and 17 PRs), 29% of pts (n=11) had stable disease (SD) of which 6 of these SD pts remain on study with durations ranging from 7-12+ mos. The clinical benefit rate (CR+PR+SD) was 84%, and 91% of pts with at least 1 post-baseline assessment experienced tumor reductions. The median time to initial response was 2.7 mos, while the median DOR was not reached (95% CI: 8.4-not reached). The 12-month PFS was 71%. The most common (≥20%) adverse events (AE) of any grade included: diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). The most common Grade 3/4 events were neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). As of the cutoff date, 16 pts discontinued treatment (PD: 18%; AEs: 8%; pt decision: 8%; physician decision: 8%) and 58% continue treatment. Conclusions: PI3K-delta inhibition with single-agent umbralisib is active and well tolerated in pts with R/R MZL, achieving durable responses with chemotherapy-free therapy. Keywords: marginal zone lymphoma (MZL); non-Hodgkin lymphoma (NHL); PI3K/AKT/mTOR. Disclosures: Zinzani, P: Consultant Advisory Role: TG Therapeutics, Bayer, BMS, Merck, Gilead, SERVIER, Roche, Celltrion, Pfizer, Takeda, Verastem, Celgene; Honoraria: TG Therapeutics, BMS, Merck, Gilead, SERVIER, MSD, Roche, Celltrion, Pfizer, Verastem, Celgene, Janssen. Samaniego, F: Research Funding: ADC Therapeutics. Jurczak, W: Consultant Advisory Role: Sandoz Novartis, Janssen, European Medicines Agency, AstraZeneca, Acerta, Gilead; Research Funding: Pharmacyclics, MorphoSys, Merck, Nordic Nanovector, Janssen, Epizyme, Celgene, Beigene, Bayer, Afimed, Acerta, Gilead, Servier, Roche, TG Therapeutics. Lech-Maranda, E: Consultant Advisory Role: Roche, Jansen-Cilag, Novartis, BMS, Amgen. Patten, P: Consultant Advisory Role: Gilead; Honoraria: L Hoffman La Roche, Gilead, AbbVie Inc, Janssen; Research Funding: L Hoffman La Roche, Gilead. Derenzini, E: Research Funding: TG Therapeutics. Burke, J: Consultant Advisory Role: Gilead, Genentech, Celgene, Abbvie, Bayer, Seattle Genetics, Tempus Labs. Sharman, J: Consultant Advisory Role: Acerta, Pharmacyclics, Genentech, TG Therapeutics, AbbVie; Honoraria: Genentech; Research Funding: Acerta, Pharmacyclics, Pfizer, TG Therapeutics, AbbVie. Kolibaba, K: Consultant Advisory Role: Gilead; Honoraria: TG Therapeutics; Research Funding: Janssen. Gilead, Pharmacyclics, Celgene, Novartis, Seattle Genetics, TG Therapeutics, Acerta, Genentech, Cell Therapeutics. O'Connor, O: Research Funding: Celgene, ADC Therapeutics, Seattle Genetics. Miskin, H: Employment Leadership Position: TG Therapeutics. Sportelli, P: Employment Leadership Position: TG Therapeutics. Weiss, M: Employment Leadership Position: TG Therapeutics. Fowler, N: Consultant Advisory Role: Pharmacyclics, Janssen; Research Funding: Pharmacyclics, Janssen.