Umbralisib and ublituximab combination is superior to current standard of care for patients with untreated, relapsed, or refractory CLL

The synergistic activity of umbralisib, a dual inhibitor of phosphoinositol 3-kinase delta (PI3Kδ) and casein kinase-1 epsilon (CK1ε), and ublituximab, which targets CD20, has been demonstrated in preclinical studies and early-phase clinical trials for chronic lymphocytic leukemia (CLL).

In May 2020, the Lymphoma Hub reported early findings from the Unity-CLL trial (NCT02612311), which showed a  progression-free survival (PFS) benefit of umbralisib plus ublituximab (U2) compared with obinutuzumab plus chlorambucil (O + Chl) for patients with treatment-naïve (TN) and relapsed/refractory (R/R) CLL at the interim analysis; read the article from the Lymphoma Hub, here. U2 was subsequently given fast track designation by the U.S. Food and Drug Administration (FDA) for the treatment of CLL.

At the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, John Gribben presented further findings from the Unity-CLL study, including safety data, and extended follow-up results.

Study design

• Multicenter, international, randomized phase III trial
• February 2016–October 2017
• 421 patients

Patient criteria

• Age ≥ 18 years
• TN or R/R CLL
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2
• Adequate organ function

Stratification according to treatment status (TN vs R/R) and chromosomal abnormality, del(17p) status

Randomization

• Initial randomization was 1:1:1:1 U2 vs O + Chl vs umbralisib monotherapy vs ublituximab monotherapy (requirements of the umbralisib and ublituximab monotherapy arms were met in May 2017, allowing closure of these arms)
• Data presented here is for the secondary randomization: 1:1 U2 vs O + Chl 

Study endpoints

Assessed by an independent review committee (IRC), the study endpoints were defined as

• primary
  • PFS for U2 vs O + Chl
• secondary
  • overall response rate (ORR)
  • complete response
  • undetectable minimal residual disease
  • duration of response
  • safety: assessed from the first dose until 30 days after the last dose of study medication in each arm

Results

Patient characteristics and efficacy

• Key patient characteristics (n = 421) are shown in Table 1
• Median follow-up was 36.7 months
• A statistically significant improvement in PFS was identified in patients receiving U2 compared with those receiving O + Chl (p < 0.0001; Table 2). 2-year PFS was 60.8% for the U2 arm compared with 40.4% for the O + Chl arm.
• This PFS benefit was maintained in all subgroups, including TN and previously treated patients (Table 2)
• The IRC-assessed ORR rate was 83.3% for the U2 arm vs 68.7% for the O + Chl arm (p < 0.001; Table 2)
• Higher response rates for U2 compared with O + Chl were maintained across TN (84% vs 78%), previously treated (82% vs 57%) and prior Bruton's tyrosine kinase inhibitor (BTKi)-treated (57% vs 25%) subgroups.
• Minimal residual disease data are yet to be published

Table 1. Key patient characteristics¹

BTKi, Bruton's tyrosine kinase inhibitor; Chl, chlorambucil; Del, deletion; IGHV, immunoglobulin heavy chain variable region; O, obinutuzumab; TN, treatment-naïve; U2, umbralisib plus ublituximab.
Characteristic	U2 arm (n = 210)	O + Chl arm (n = 211)
Median age (range)	67(39–88)	68 (36–91)
Del 17p, n (%)	19 (9)	23 (11)
Del 11q, n (%)	47 (22)	38 (18)
Unmutated IGHV, n (%)	113 (54)	115 (55)
TN, n (%)	119 (57)	121 (57)
Previously treated, n (%)	91 (43)	90 (43)
Median number of prior therapies (range)	2 (1–9)	1 (1–8)
Prior BTKi therapy, n (%)	12 (15)	12 (13)

Table 2. PFS and ORR for patients receiving U2 vs O + Chl¹

PFS and ORR	U2 arm	O + Chl arm	HR (95% CI)	p value
Chl, chlorambucil; IRC, independent review committee; ITT, intention-to-treat; NE, not estimable; O, obinutuzumab; ORR, overall response rate; PFS, progression-free survival; TN, treatment-naïve; U2, umbralisib plus ublituximab.
Median PFS for ITT patients, months (95% CI)	31.9 (28.2–35.8)	17.9 (16.1–22.6)	0.546 (0.413–0.720)	< 0.0001
Median PFS for TN patients, months (95% CI)	38.5 (33.2–NE)	26.1 (19.4–33.1)	0.482 (0.316–0.736)	< 0.001
Median PFS for previously treated patients, months (95% CI)	19.5 (14.6–27.7)	12.9 (11.1–16.1)	0.601 (0.415–0.869)	< 0.01
IRC assessed ORR, % (95% CI)	83.3	68.7	—	< 0.001

Safety

U2 had a similar adverse event (AE) profile to O + Chl (Table 3). It is notable that patients receiving U2 had a considerably longer median treatment exposure compared with O + Chl.

Table 3. Safety overview¹

AE, adverse event; ALT, alanine transaminase; AST, aspartate aminotransferase; PI3K, phosphoinositol 3-kinase.
Safety	U2	O + Chl
Median treatment duration, months	21	5
Grade ≥ 3 AE, %	82	66
Neutropenia (Grade 3–4)	31	36
Diarrhea (Grade 3–4)	12	3
Thrombocytopenia (Grade 3–4)	4	14
Grade ≥ 3 events of clinical interest (PI3K-specific), %
AST/ALT elevation	14	3
Colitis	2	0.5
Pneumonitis	0.5	0
Rash	2	0.5
Opportunistic infections	5.8	1.5

Conclusion

In this study, the combination of umbralisib and ublituximab resulted in a significantly improved PFS for patients with either TN or R/R CLL, relative to the current standard of care, O + Chl. U2 was well tolerated, with an acceptable safety profile. Larger clinical trials are required to confirm these findings.