The PI3K-delta inhibitor umbralisib demonstrated a favorable toxicity profile as treatment for patients with chronic lymphocytic leukemia who have become intolerant to a prior kinase inhibitor, of either BTK or PI3K inhibition, according to results from a phase II study presented at the 18th International Workshop on CLL.
Anthony R. Mato, MD
The PI3K-delta inhibitor umbralisib (TGR-1202) demonstrated a favorable toxicity profile as treatment for patients with chronic lymphocytic leukemia (CLL) who have become intolerant to a prior kinase inhibitor (KI), of either BTK or PI3K inhibition, according to results from a phase II study presented at the 18th International Workshop on CLL.
“Primary endpoint was met with a median PFS [progression-free survival] of 23.5 months in a high-risk population,” study authors, led by Anthony R. Mato, MD, wrote in their poster, “and 94% of patients with measurable disease at baseline had a reduction in lymphadenopathy.”
This phase II multicenter, single-arm clinical trial of single-agent umbralisib enrolled 51 patients, of which 50 were evaluable for PFS. To be eligible, patients with CLL had to be in need of a subsequent treatment after discontinuing prior therapy of either a BTK inhibitor (ibrutinib [Imbruvica] or acalabrutinib [Calquence]) or PI3K-delta inhibitor (idelalisib [Zydelig] or duvelisib [Copiktra]) due to intolerance. Patients had to be off prior KI treatment for at least 14 days following discontinuation without disease progression.
Study authors defined KI intolerance as “unacceptable toxicity where, in the opinion of the investigator, treatment should be discontinued in spite of optimal supportive care as a result of one of the following: 2 or more grade ≥2 non-hematological toxicities; 1 or more grade ≥3 non-hematological toxicity; 1 or more grade 3 neutropenia with infection or fever; or grade 4 hematologic toxicity which persists to the point that the investigator chose to stop therapy due to toxicity not progression.” Toxicities of grade ≥1 had to be resolved prior to the start of umbralisib.
The primary objective of this study was to determine the PFS of 800 mg daily umbralisib in KI-intolerant patients with CLL. Additionally, investigators also sought to evaluate the objective response rate, duration of response, time to treatment failure, and safety.
Overall, 36 patients had measurable disease upon study entry, and the median age of patients was 70 years (range, 48-96). The majority of patients had an ECOG performance status of either 0 (45.1%) or 1 (47.1%). Twelve patients had either a 17p deletion orTP53mutation (24%), and 9 had an 11q deletion (18%). Additionally, 65% of patients were IGHVunmutated and 41% had bulky disease.
Forty-four patients were previously treated with a BTK inhibitor (86%) while 7 were treated with a prior PI3K inhibitor (14%). The median number of prior therapies was 2, ranging from 1 to 7 lines of therapy, and the median time on prior treatment was 9 months (range, 0.7-38).
Data on CLL-related variants were available in 46 of the 51 patients. Eleven patients presented withATM(24%), 9 withTP53(20%), 7 with SF3B1(15%), 4 with NOTCH1(9%), 2 with PLCG2(4%), and 1 with BTK(2%).
The estimated median PFS with umbralisib was 23.5 months (95% CI, 13.1not evaluable), but the median overall survival had not yet been reached. As of the cut-off date, 58% of patients in the study remained on treatment with umbralisib for longer than their prior duration of a KI.
With a median follow-up of 15.7 months, 4 patients had recurrence of an adverse event (AE) that had led to prior KI intolerance. However, 3 of these patients had less severe cases of the AE and did not require a dose modification. One patient discontinued treatment due to recurrent rash that was previously noted on treatment with ibrutinib.
The most common AEs reported included diarrhea (n = 32), nausea (n = 27), thrombocytopenia (n = 13), fatigue (n = 13), and insomnia (n = 13). The most common grade 3/4 events were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), and pneumonia (12%). There was 1 case of colitis reported after 6 weeks on umbralisib, in a patient with 17p deletion. However, the patient recovered after a 2-week hold and did not recur. This patient achieved a complete response and remained on study for 25 months.
Overall, no AEs led to fatality. Eight patients had dose reductions (16%), and 6 (12%) discontinued treatment due to treatment-related AEs, including 2 cases of pneumonitis, pancreatitis, pneumonia, dermatitis, and rash.
Mato AR, Schuster SJ, Lamanna N, et al. A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic Lymphocytic Leukemia (CLL) who are Intolerant to Prior BTK or PI3Kδ Inhibitor Therapy. Poster presented at: 18th International Workshop of CLL; September 20-23, 2019; Edinburgh, UK.