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Umbralisib yields ‘highly encouraging’ results in marginal zone lymphoma
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ATLANTA — Single-agent umbralisib provided effective PI3K-delta inhibition and appeared well-tolerated among patients with relapsed/refractory marginal zone lymphoma according to data from the UNITY-NHL phase 2 trial presented at American Association for Cancer Research Annual Meeting.
“Umbralisib is a PI3 kinase inhibitor, and the PI3 kinase signaling pathway is usually used in B-cell malignancies and other cancers; it’s an important driver of cell proliferation,” Felipe Samaniego, MD, associate professor in the department of lymphoma/myeloma, division of cancer medicine at The University of Texas MD Anderson Cancer Center, said in an interview with HemOnc Today. “This project is one component of a much larger research enterprise. We happen to concentrate on marginal zone lymphoma only because there is [only one] approved therapy for this designation.”
In January, the FDA granted breakthrough therapy designation to umbralisib (TGR-1202, TG Therapeutics) for adults with marginal zone lymphoma who had at least one prior anti-CD20 treatment.
For the phase 2 clinical trial, Samaniego and colleagues enrolled 69 patients with histologically confirmed marginal zone lymphoma. Eligible participants had an ECOG performance status of 2 or lower and had received at least one previous treatment, including an anti-CD20 regimen.
Participants received 800 mg oral umbralisib twice a day until progression or intolerable toxicity. Overall response rate as assessed by an independent review committee served as the primary endpoint. Duration of response and PFS served as secondary endpoints.
Researchers reported investigator-assessed ORR among 38 patients (median age, 67 years; range, 34-81) who had at least 6 months of follow-up (median, 9.6 months). Most of the patients (68%) had received at least one anti-CD-20-containing immunotherapy, and seven had previous rituximab (Rituxan; Genentech, Biogen) monotherapy only.
Results showed an ORR among the 38 patients of 55%, including four complete responses and 17 partial responses. Additionally, 11 participants had stable disease, resulting in a clinical benefit rate of 84%.
“We saw that over 50% of patients responded, and the cool thing is that it appears the responses occurred regardless of the subtype of marginal zone lymphoma,” lead author Nathan Fowler, associate professor of medicine and director of clinical research in the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “For example, with splenic marginal zone lymphoma, extranodal marginal zone lymphoma and nodal marginal zone lymphoma, we actually saw responses around 57%, which is impressive.”
Initial response occurred at a median of 2.7 months, whereas median duration of response was not reached (95% CI, 8.4-not reached). PFS at 12 months was 71%.
The most common adverse events included diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and reduced appetite (21%). The most prevalent grade 3 to grade 4 adverse events included neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). At the time of data cutoff, 16 patients had ceased treatment.
The researchers noted study limitations, including the small patient population and short follow-up time.
According to Fowler, the relative lack of significant adverse events that occurred with prolonged exposure to umbralisib is an important finding.
“With PI3K inhibitors specifically, we worry about things like colitis or pneumonitis occurring with more exposure to a drug, and we didn’t seem to see that,” he said. “In fact, if you look at the incidence of grade 3 diarrhea, only one patient had that for 6 months; that’s it. That’s really relevant, because we have a lot of drugs that are now FDA approved that are hitting PI3K-delta, and we’re thinking, ‘Which of these drugs is going to emerge as a drug used in the community?’ Unfortunately, because of diarrhea and other adverse events, not a lot of people have been using these drugs.”
Fowler added that the study shows that trials of cancers like marginal zone lymphoma are possible and worthwhile.
“This trial shows that we can take a fairly rare subtype of non-Hodgkin lymphoma, we can enroll patients, we can see activity with a single agent and we can potentially get FDA approval,” he said. “In the past, there’s not been a lot of attention with marginal zone lymphoma, because a lot of folks thought it was too rare of a subtype to study, and that we wouldn’t be able to enroll patients and get approval. This trial and a previous trial published about a year ago suggest that moving forward in this space is feasible.” – by Jennifer Byrne
Reference:
Fowler NH, et al. Abstract CT132. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: TG Therapeutics funded the study. Fowler reports scientific advisory board roles with Bayer, Gilead Sciences, TG Therapeutics and Verastem Oncology and research funding from TG Therapeutics. Samaniego reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Michael A. Caligiuri, MD
This study is preliminary but very exciting. Marginal zone lymphoma is a type of lymphoma for which there is no known curative therapy when the disease has spread beyond the organ of origin. Yet, slowly but surely, with drugs like ibrutinib (Imbruvica: Janssen, Pharmacyclics) that target specific pathways known to be constitutively active in certain lymphoid malignancies, we’re starting to chip away at this disease with promising early results.
PI3-kinase delta is another signaling molecule that is often in overdrive in this malignancy. Umbralisib is a next-generation inhibitor of PI3-kinase delta; this particular drug has a different structure, is better tolerated with less toxicity and is orally administered.
A short while ago, before ibrutinib, taking an oral medication for this disease was not really an option. However, as more and more of these aberrant pathways are dissected and “druggable” molecules in that pathway are identified, medicinal chemists start to work away at creating the drugs that have great on-target effects and limited off-target effects. Such appears to have been the case for this trial of oral umbralisib given twice a day for relapsed or progressive marginal zone lymphoma.
This phase 2, multicenter trial shows an impressive response rate with a single agent in previously treated patients with marginal zone lymphoma. Except for the 5% incidence of grade 3 gastrointestinal toxicities in this small study, other grade 3 adverse effects might be expected (eg, neutropenia and neutropenic fever) or of lower grade and largely manageable. Looking at the duration of response, PFS and the waterfall plot, it seems as if we are getting better and better at developing these oral inhibitors. In some instances, we’re seeing durable responses without a lot of toxicity.
As we continue to develop these drugs, the marriage of biology and medicinal chemistry is very important. Once researchers can identify an aberrant signaling pathway or molecule for a subset of patients such as those lymphoma patients with marginal zone lymphoma, medicinal chemists can often successfully find a way to inhibit that pathway and, in some instances, such as seen in this clinical trial, see a patient’s disease respond with largely tolerable off target effects.
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