Umbralisib Shows Early Promise for Patients with Marginal Zone Lymphoma
ATLANTA — The investigational therapeutic umbralisib, which targets the molecule PI3K- delta, was well tolerated and highly active in patients with relapsed/refractory marginal zone lymphoma, according to early results from the UNITY-NHL phase II clinical trial, which were presented at the AACR Annual Meeting 2019, March 29–April 3.
As of October 20, 2018, 55 percent of patients who had at least six months of follow-up had a partial or complete response following umbralisib treatment. The median duration of response had not been reached. Updated data will be presented at the meeting, according to Nathan H. Fowler, MD, associate professor of medicine and director of clinical research in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston.
In January 2019, the U.S. Food and Drug Administration (FDA) granted umbralisib breakthrough therapy designation for the treatment of adults with marginal zone lymphoma who have received at least one anti-CD20 treatment. Breakthrough therapy designation is an FDA strategy to expedite assessment of therapeutics for life-threatening diseases such as cancer.
“Marginal zone lymphoma is an uncommon, slow-growing type of non-Hodgkin lymphoma,” said Fowler. “Rituximab, either alone or in combination with chemotherapy, has improved outcomes for patients, but in most cases the disease eventually relapses, and these individuals have limited treatment options.
“Umbralisib is a small-molecule inhibitor that targets PI3K-delta, which is a component of a signaling pathway that has a key role in promoting the survival and expansion of many types of cells, and has also been shown to uniquely inhibit CK1 epsilon,” continued Fowler. “Our exciting results suggest that this oral targeted therapeutic has significant activity against relapsed/refractory marginal zone lymphoma and offers hope for patients.”
As of October 20, 2018, 69 patients with relapsed/refractory marginal zone lymphoma had been enrolled on the trial and received 800 milligrams of umbralisib orally once daily until disease progression or unacceptable toxicity. At that time, 38 patients had at least six months of follow- up.
Among the 38 patients, the median follow-up time was 9.6 months. Four had a complete response and 17 had a partial response, as assessed by the investigators, for an overall response rate of 55 percent. An additional 11 patients had stable disease, for a clinical benefit rate
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(complete response, partial response, and stable disease) of 84 percent. Progression-free survival at 12 months was 71 percent.
The most common adverse event of any grade was diarrhea, which affected 45 percent of the 38 patients. Nausea, fatigue, headache, cough, and decreased appetite affected between 20 percent and 30 percent of patients. The most common grade 3/4 adverse events were neutropenia, febrile neutropenia, and diarrhea, which affected 8 percent, 5 percent, and 5 percent of the 38 patients, respectively. No events of colitis or pneumonitis had been reported.
“All the adverse events we have seen in the trial are to be expected with this class of drugs,” said Fowler. “Moreover, we were able to manage the side effects for the patients, making umbralisib a well-tolerated treatment.
“The adverse event and clinical activity data are highly encouraging at this early timepoint,” added Fowler. “We are excited to continue following patients for a longer time to further establish the long-term activity and side effects of umbralisib. With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed/refractory marginal zone lymphoma.”
According to Fowler, the main limitations of the data presented are that it was based on a small number of patients and a short follow-up time.
This study was funded by TG Therapeutics. Fowler serves on scientific advisory boards for TG Therapeutics, Bayer, Gilead Sciences, and Verastem Oncology; he also receives research funding from TG Therapeutics.
Abstract Session Type: Clinical Trials Minisymposium Session Number: CTMS02 Session Title: The Next Generation of Clinical Trials in Molecularly-driven Therapy Location: Marcus Auditorium- Bldg A-GWCC Session Time: Monday, April 1, 2019, 3:00 pm - 5:00 pm Presentation Number: CT132 Publishing Title:
Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, registration directed Phase II study Author Block: Nathan H. Fowler1, Felipe Samaniego1, Wojciech Jurczak2, Ewa Lech-Maranda3, Nilanjan Ghosh4,
Bertrand Anz5, Piers Patten6, James A. Reeves7, Lori A. Leslie8, Piotr Smolewski9, Julio C. Chavez10, Paolo Ghia11, Corrado Tarella12, John M. Burke13, Jeff Sharman14, Kathryn Kolibaba15, Owen A. O'Connor16, Chan Y. Cheah17, Hari P. Miskin18, Peter Sportelli18, Michael S. Weiss18, Pier Luigi Zinzani19. 1MD Anderson Cancer Center, Houston, TX; 2Jagiellonian University, Kraków, Poland; 3Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 4Levine Cancer Institute, Charlotte, NC; 5Sarah Cannon Research Institute/Tennessee Oncology, Chattanooga, TN; 6King's College Hospital NHS Foundation Trust, London, United Kingdom; 7Sarah Cannon Research Institute/Florida Cancer Specialists, Fort Myers, FL; 8John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; 9Copernicus Memorial Hospital, Lodz, Poland; 10H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 11Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy; 12European Institute of Oncology, Milan, Italy; 13Rocky Mountain Cancer Centers, US Oncology Research, Aurora, CO;
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14Willamette Valley Cancer Institute, US Oncology Research,, Eugene, OR; 15Compass Oncology, US Oncology Research, Vancouver, WA; 16Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY; 17Sir Charles Gairdner Hospital, Perth, Australia; 18TG Therapeutics, Inc., New York, NY; 19University of Bologna, Bologna, Italy
Abstract Body:
Background: 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.
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