1. Samson, Kurt

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ATLANTA-Monotherapy with the experimental PI3K delta inhibitor umbralisib reduced tumors in more than half of patients with relapsed/refractory marginal zone lymphoma, according to early results from a phase IIb clinical trial presented at the American Association for Cancer Research annual meeting (Abstract CT132).

marginal zone lympho... - Click to enlarge in new windowmarginal zone lymphoma; AACR. marginal zone lymphoma; AACR

Interim results from the UNITY-NHL clinical trial showed that 55 percent of treated patients had complete or partial response at 6 months, and one in five had complete remission. A total of 64 patients participated in the safety portion of the study, while efficacy figures were based on responses in 42 subjects at 9 months.


Even patients who had extensive prior treatment responded well to therapy, said 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, the FDA granted a breakthrough therapy designation to umbralisib for adults with marginal zone lymphoma who have had at least one anti-CD20 treatment.


At a press conference, Fowler said that 86 percent of treated patients had reduced tumor burden, with a median time of 2.7 months until first response. There was no sign of cancer in 19 percent of patients, while one-third had some tumor shrinkage.


"This disease is initially quite treatable with several good options for patients that result in high response rates. Unfortunately, for about 70 percent of these patients, relapse occurs and there are limited treatment options at that time. That relapse can occur within a year or it can take several years, but most patients will eventually stop responding to standard treatment," said Fowler


"Marginal zone lymphoma ... is often first treated with the anti-CD20 therapy rituximab. 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."


At that point, treatment options are limited to more rituximab, chemotherapy, or the tyrosine kinase inhibitor ibrutinib, he noted.


PI3K-delta is a component of a key signaling pathway in promoting the survival and expansion of many cell types.


Toxicity did not appear to be worsening with prolonged exposure, and this is a bit different from what we've seen with other drugs in this class, Fowler.


Trial Details: Safety

As of Oct. 20, 2018, 69 patients had been enrolled in the safety portion of the trial. They received 800 mg of umbralisib orally once daily until disease progression or unacceptable toxicity. At that time, 38 patients had at least 6 months of follow-up and the median follow-up time was 9.6 months. Four had a complete response and 17 had a partial response, Fowler said.


An additional 11 patients had stable disease, for a clinical benefit rate (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, while nausea, fatigue, headache, cough, and decreased appetite affected between 20-30 percent of patients. The most common grade 3 or 4 adverse events were neutropenia, febrile neutropenia, and diarrhea, which affected 8 percent, 5 percent, and 5 percent, 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," Fowler explained, noting that the investigators were able to manage these side effects.


The results now need to be confirmed in a larger, randomized trial comparing umbralisib to other drugs, he noted. In addition, phase III trials in other B-cell malignancies, including follicular lymphoma and chronic lymphocytic leukemia, are ongoing.


"Patients continue to be followed for overall response, duration, and toxicity analysis, and phase III studies are planned in marginal zone lymphoma and other indolent NHL subtypes," Fowler noted.


"It's exciting to see the newer, targeted, nonchemotherapy options have activity in rare subtypes of lymphoma such as marginal zone lymphoma. Patients who traditionally have had to rely on standard chemotherapy in the relapsed/refractory setting may have better options in the future."



All patients had histologically confirmed marginal zone lymphoma., ECOG PS <=2, and had previously received >=1 prior therapy, including at least one CD20 monoclonal antibody-containing regimen. Patients received 800 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was overall response rate as assessed by an independent review committee (IRC). Secondary endpoints included duration of response, progression-free survival, and safety.


Among the 42 patients, 23 had extranodal disease, eight had nodal tumors, and seven had splenic involvement. The median number of prior systemic therapies was two, seven patients had received monotherapy RTX only and 26 had received at least one CD20 mAb-containing chemoimmunotherapy.


The clinical benefit rate was 84 percent and tumors were reduced in 91 percent of patients with at least one post-baseline assessment.


"The Holy Grail"

"The adverse event and clinical activity data are highly encouraging at this early time point," noted Fowler. "With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed/refractory marginal zone lymphoma."


Because the side effect profile was so manageable, Fowler said that it is likely that in the future umbralisib will be used in combination with other agents. "The holy grail is to find frontline curative regimens," he said. "I think that [with other drugs] this is where we are going to start seeing triples and home runs."


Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, D.C., moderated the session. "These are provocative findings," he said. "This drug is a select inhibitor against marginalized lymphoma in some subtypes, and toxicity did not seem any higher than other drugs in this class."


Kurt Samson is a contributing writer.