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.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

“…The efficacy of PI3K inhibitors in human cancers is consistent with the evidence linking gain of function mutations in PI3Ks (α,β and γ) as drivers of malignancy . Unfortunately, the efficacy often requires complete/sustained inhibition of PI3K signaling resulting in dose‐limiting toxicities (eg, colitis, hepatitis, pneumonitis, hypertension, hyperglycemia, skin rash, and opportunistic infections), likely driven by the disruption of homeostatic innate/adaptive immune PI3K signaling .…”

“…Duvelisib (also known as IPI‐145) is the only dual PI3Kδ/γ inhibitor approved to treat relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, at a dose of 25 mg, twice‐a‐day, associated with dual δ/γ inhibition. Duvelisib demonstrated compelling activity in various preclinical models of autoimmunity, including arthritis, however, efficacy could not be demonstrated in rheumatoid arthritis clinical trials in the dose range associated with a predominant PI3Kδ inhibition (0.5‐5 mg, twice a day, PO).…”

“…[1][2][3][4][5][6][7][8][9] These efforts have focused initially on pan-PI3K inhibitors, and subsequently on isoform-selective and dual isoform inhibitors. 8,[10][11][12][13] Nearly 15 compounds of varying PI3K isoform selectivity have been explored in the clinic culminating in the launch of four drugs to treat different forms of cancers: idelalisib [Zylidig®, a PI3Kδ selective inhibitor], 5 ] duvelisib [Copiktra®, a dual PI3Kδγ inhibitor], 14 alpelsib [Piqray®, a PI3Kα inhibitor], 15 and copanlisib [Aliqopa®,BAY 80-6946, a dual PI3Kδα inhibitor]. 16 Dual inhibitors of PI3Kδ and PI3Kγ are considered high-value targets both for inflammation/ autoimmunity and oncology.…”

Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options

“…The study demonstrate a significant improvement in PFS (13.3 vs 9.9 months), including patients who had del17p and/or TP53 mutation, and higher a ORR (74% vs 45%) regardless of 17p status. That study led to the FDA approval of duvelisib for use in all patients with relapsed/refractory CLL who have received at least 2 prior lines of therapy …”

“…That study led to the FDA approval of duvelisib for use in all patients with relapsed/refractory CLL who have received at least 2 prior lines of therapy. 42…”