Umbralisib Achieves Impressive ORR in Relapsed/Refractory MZL

Nathan Fowler, MD

The PI3K-delta inhibitor umbralisib (TGR-1202) was found to demonstrate an overall response rate (ORR) of 52% and show an encouraging tolerability profile in patients with relapsed/refractory marginal zone lymphoma (MZL), according to findings from a cohort of the phase IIb UNITY-NHL trial that were presented at the 2019 AACR Annual Meeting.¹

“This oral selective inhibitor of PI3K-delta, umbralisib, is highly active against marginal zone lymphoma, including multiple subtypes, and single-agent dosing appeared to be effective,” said lead study author Nathan H. Fowler, MD, associate professor of medicine and director of clinical research at The University of Texas MD Anderson Cancer Center. “Durable responses were observed, and toxicity did not appear to worsen with prolonged exposure; this is a bit difficult with what we’ve seen with some of the other drugs in this class.”

MZL is an indolent B-cell lymphoma that comprises 10% of all non—Hodgkin lymphoma (NHL) cases, said Fowler, adding that although there are high response rates associated with frontline induction therapy, most patients still relapse. Options are limited for those who progress on CD20-directed antibodies and who are not appropriate to receive chemotherapy-based treatments, hence the need for investigational agents.

As B-cell receptor (BCR) signaling is a crucial component of normal B-cell development and maturation and is implicated in lymphomagenesis, PI3K is a downstream intermediary in the BCR pathway that is imperative for BCR-dependent B-cell survival, he explained.

Umbralisib is an oral next-generation PI3K-delta inhibitor with improved selection of the PI3K-delta isoform and inhibits CK1-epsilon. Long-term, ongoing safety data with the agent have demonstrated low rates of immune-mediated toxicities.²

“There is some preclinical evidence that this could explain differential effects on function observed in regulatory T cells,” said Fowler.

In January 2019, the FDA granted umbralisib a breakthrough therapy designation for the treatment of adult patients with MZL who have received 1 prior anti-CD20 regimen, based on interim data from a UNITY-NHL cohort.

In the ongoing, multicenter, multi-cohort, phase IIb UNITY-NHL trial (UTX-TGR-205; NCT02742090) investigators are evaluating umbralisib as a single agent or in various combination regimens in patients with previously treated NHL.

Enrollment on the MZL cohort is now complete, Fowler said, with 72 patients enrolled between July 2017 and August 2018. Sixty-nine patients have received umbralisib therapy, 42 of which have 9 months of follow-up—these patients comprised the data from the interim efficacy cohort presented during the 2019 AACR Annual Meeting.

Patients were treated with 800 mg of umbralisib monotherapy daily until disease progression or unacceptable toxicity. To be eligible for enrollment, patients could have splenic, nodal, or extranodal MZL that required treatment; relapsed/refractory disease that progressed on ≥1 prior lines of therapy that included at least 1 CD20-directed regimen; and an ECOG performance status ≤2.

In the interim efficacy population, 23 patients (55%) had extranodal disease, followed by 12 (29%) with nodal and 7 patients (17%) with splenic MZL; this was comparable with the safety population of all patients treated (n = 69). The median age in both cohorts was 67 (range, 34-81); there were more females in the interim efficacy (n = 25; 60%) and safety (n = 36; 52%) populations. The majority of patients in the interim efficacy group (n = 32; 76%) had received rituximab (Rituxan)-based chemoimmunotherapy compared with 50 (72%) in the safety population. Moreover, 8 patients (19%) in the interim efficacy cohort were refractory to their most recent therapy; in the safety population, 18 patients (26%) were refractory to their last treatment. Similarly, 6 (14%) and 15 patients (22%) were refractory to prior anti-CD20 therapy in the interim efficacy and safety populations, respectively.

The primary endpoint was ORR by an independent review committee (IRC) by 2007 International Working Group criteria; secondary endpoints included duration of response (DOR), progression-free survival (PFS), time to response, and safety.

At a median follow-up of 12.5 months (range, 8.3-18.5) in the interim efficacy population, the ORR was 52% as assessed by both IRC and investigator assessment. The complete response (CR) rates were 19% and 12%, and partial response rates were 33% and 40%, in the IRC- and investigator-assessed cohorts, respectively. The stable disease rates were 36% and 31%, respectively, and progressive disease rates were 7% and 10%. Additionally, the clinical benefit rate was 88% as determined by IRC assessment.

The median duration on treatment was 10.1 months (range, 5.6-15.7), and 55% of patients remain on therapy; this includes all patients who were in CR via IRC assessment.

When stratified by MZL subtype, the ORRs by IRC were 57%, 42%, and 43% for extranodal, nodal, and splenic disease, respectively. Moreover, for patients who had prior chemoimmunotherapy (n = 32), the ORR was 53% via IRC; the ORR was 38% in those who were refractory to their last line of therapy (n = 8).

The median time to initial response was 2.7 months, and 86% of patients (n = 36) experienced a reduction in tumor burden. Though the data are immature, Fowler noted that the median DOR has not been reached (95% CI, 8.4—not estimable) and the median PFS has not been reached. The estimated 1-year PFS rate was 66%.

Ten patients (24%) discontinued therapy for disease progression, 5 (12%) for treatment-related adverse event (TRAE), 2 (5%) due to a non-TRAE, 1 (2%) withdrew consent, and 1 (2%) discontinued due to the investigator’s decision.

Overall, umbralisib was found to be well tolerated in all treated patients, with the highest grade ≥3 adverse event (AE) being diarrhea (10%). Grade 3 infections—comprising bronchitis, pneumonia, and influenza—occurred in 3 patients.

“The average duration of diarrhea was 10 days and resolved in all patients,” Fowler added.

The median duration of exposure to umbralisib was 6.9 months. AEs that led to dose reductions occurred in 6 patients (9%), and 10 patients (14%) discontinued umbralisib for AEs that were potentially treatment related. No deaths have occurred.

AEs of interest and long-term tolerability were also reported. For patients on study for more than 6 cycles, 41 patients were evaluable. The median age was 66 (range, 34-80) and the median number of prior therapies was 2 (range, 1-6). Beyond diarrhea (24%; grade 3/4, 5%), all-grade AEs of interest occurring following 6 cycles with the PI3K-delta inhibitor were alanine aminotransferase (ALT; 2%) and pneumonitis (2%; grade 3/4, 2%).

Fowler noted that the elevated ALT and aspartate aminotransferase levels appeared time related, as all but 1 case occurred within the first 6 cycles of umbralisib treatment. However, grade 3/4 diarrhea occurred before and after the 6 cycles. There were no treatment discontinuations for treatment-related AEs after 6 months.

Follow-up will continue for mature overall response, duration, and safety analysis. In conclusion, Fowler said that phase III clinical trials with umbralisib are planned in MZL as well as other subtypes of indolent NHL.

“The ‘holy grail’ is to find curative regimens; one of the nice things about this drug is that the side effect profile suggests you may be able to combine it with other drugs,” Fowler said in closing. “That is where we are going to see more ‘triples’ and ‘home runs’—when we move these drugs into the frontline [setting] or as combination therapy.”

References

1. Fowler NH, Samaniego F, Jurczak , et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, registration directed phase II study. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT132.
2. Davids MS, Flinn IW, Mato AR, et al. Long term integrated safety analysis of umbralisib (TGR-1202), a PI3K-DELTA/CK1-EPSILON inhibitor with a differentiated safety profile, in patients with relapsed/refractory lymphoid malignancies. Presented at: 2018 European Hematology Association Congress; June 14 to 17, 2018; Stockholm, Sweden. Abstract PF444.

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