March 11, 2021

Umbralisib in Patients with CLL who are Intolerant to Prior BTK or PI3K-delta Inhibitor
Therapy

- CLL (chronic lymphocytic leukemia)

- Most common symptoms: fatigue, swollen lymph nodes, infection, fever
- Treatment:
- BTK inhibitors (ex: ibrutinib)-1st line therapy
- ADE: fatigue, diarrhea, bruising
- NCCN: CLL
- PI3K inhibitors (ex: duvelisib, idelalisib)-2nd line therapy
- ADE: diarrhea, neutropenia, rash, hypertriglyceridemia, hyperglycemia,
fever
- NCCN: relapsed CLL

Study: Phase 2 study of safety & efficacy of Umbralisib in Patients with CLL Who Are Intolerant
to BTK or PI3K-delta Inhibitor Therapy
- Phase 2 multicenter study
- Umbralisib: once daily oral PI3K delta/CK1 epsilon inhibitor
- Improved selectivity for delta isoform; favorable toxicity profile
- Taken with food
- Not metabolized through CYP pathway
- Common ADEs: infections, neutropenia, diarrhea
- Overall discontinuation rate due to ADEs <10%
- Genotyping/Phenotyping:
- TaqMan SNP genotyping assays used to genotype for: Cyp3A5*3, 6, 7
- CYP3A4*1b, 22
- CYP2D6*2, 3, 4, 6, 10, 17, 29, 41
- Study procedure:
- Umbralisib 800mg PO once daily
- Inclusion: confirmed diagnosis ofCLL,d/c of prior BTK inhibitor or PI3K delta inhibitor,
presence of measurable disease, no disease progression 14 days following prior KI
discontinuation, ≥18 years old, ECOG ≤2, adequate bone marrow and organ function
- Primary endpoint:
- Determine the PFS of umbralisib in pts who were intolerable to prior BTK and or
PI3K-delta inhibitor
- Secondary endpoints:
- Characterize genotype and metabolizer phenotype frequencies
- Evaluate safety profile
- Statistical analysis:
- Enroll 50 ptsprovide 82% power to detect median PFS of at least 12 months
- Survival outcomes estimated using kaplan-meier method
- Trial protocol & length
 - 51 enrolled analyzed for safety
- Baseline characteristics
- Median age: 70
- Median # of prior therapy: 2
- Had measurable disease at the time of study entry 71%
- Deletion of chromosome 17p
- Primary Endpoint Findings:
- Median PFS 23.5 months, 95% CI 13.1-NE, investigators found to be non-
estimable
- % of progression free pt at 12 and 24 months were 72% and 46%
- Secondary endpoint
- Median OS not reached, median follow up 23 months
- 3 deaths reported (disease progression)
- ORR was 44% (for 48 pts)
- 94.4% of pts with a baseline measurable disease experienced a decrease in
nodal size
- Study dropout
- 17 pts due to disease progression (most common)
- Most common ADEs that lead to discontinuation of umbralisb = pneumonitis
- ADE - Diarrhea, nausea, neutropenia
- Authors Conclusion:
- Pts with KI intolerance can have durable responses when transitioned to
alternative targeted agents
- Currently no consensus on optimal sequencing of treatment
- Umbralisib demonstrated favorable safety profile
- Provides additional line of tx
- Strengths
- Approved by IRB at each site
- Power was met
- Minimal dropout rate due to AE
- Median PFS was 23.5 months
- Limitations:
- Pooled population of prev treated BTK and PI3K treated patients
- Predominantly BTK exposed
- Interpretability of response rate is limited due to inclusion of some patients w/o
measurable disease
- No P values to relay significance
- Funded by manufacturer
- Clinical and speciality pharmacy Significance
- No generic available
- $159/200mg tablet
- Financial assistance programs available
- Optum does not have access
 - Cardinal, McKesson, Plasma and Biologics, ASD healthcare, Oncology
Supply
- Potentially high volume
- Outcomes:
- Overall response rate of 44%
- 94.4% patients with measurable disease had any decrease in nodal size
- Student conclusions:
- Umbralisib has promising results based on patients duration of therapy compared
to other PI3K inhibitors and limited dropouts due to AE’s
- Reached power of the study
- The genotyping and phenotyping leads to an opportunity of future studies