The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Abstract

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Graphical abstract

Figure 1.

PFS in the study population. Kaplan-Meier curves of PFS assessments in CLL/SLL patients treated with monotherapy duvelisib or ofatumumab. PFS was significantly longer for duvelisib-treated patients compared with ofatumumab-treated patients by assessments of blinded IRC (13.3 months vs 9.9 months, HR = 0.52, P < .0001) (A) and investigators (17.6 months vs 9.7 months, HR = 0.40, P < .0001) (B). BID, twice daily; DUV, duvelisib; OFA, ofatumumab.

Figure 2.

PFS in selected study subgroups. (A) Forest plot and hazard ratios for PFS per IRC assessment on duvelisib or ofatumumab monotherapy for predefined subgroups within the total study population. Kaplan-Meier curves of PFS per IRC assessment (B) and investigator assessment (C) in the subgroup of patients with del(17p)/TP53 mutation. In this high-risk subgroup, median PFS was 12.7 months and 9.0 months (HR = 0.40, P = .0002) by IRC assessment and 13.8 months and 9.5 months (HR = 0.41, P = .0003) by investigator assessment for duvelisib and ofatumumab, respectively. “Refractory/early relapse” indicates refractory/early relapse to purine analog-based therapy; “prior anticancer therapy” indicates most recent prior anticancer therapy from randomization. LCL, lower confidence limit; UCL, upper confidence limit.

Figure 3.

ORR per IRC assessment and lymph node response rate for the total CLL/SLL study population for duvelisib vs ofatumumab monotherapy. Lymph node response was defined as ≥50% decrease in the sum of the products of target lymph nodes. Both the ORR (P < .0001) and the lymph node response rate (P < .0001) were significantly higher in duvelisib-treated patients.

Figure 4.

Cytokine and chemokine changes in CLL/SLL patients treated with duvelisib or ofatumumab. The median percent change from baseline to cycle 2 day 1 is depicted. The 10 cytokines and chemokines that showed >50% median reductions in duvelisib patients from baseline are denoted with an asterisk.