On 4 October 2018, Ian W. Flinnfrom the Sarah Cannon Research Institute, TN, USA, and colleagues, published in Blood the results of the phase III DUO trial ( NCT02004522) on duvelisib versusofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Duvelisib is an orally-administered dual inhibitor of phosphoinositide 3-kinase (PI3K)-γ and -δ that has shown significant clinical activity and good tolerability in a phase I trial, in patients with indolent Hodgkin lymphoma ( NCT01476657). Duvelisib blocks the survival and proliferation of malignant B-cells, meanwhile disrupting the recruitment of T cells and macrophages to the tumor location. Based on the promising phase I outcomes, the investigators in this multicenter, open-label, randomized phase III clinical trial compared the efficacy and safety of duvelisib against ofatumumab, the current standard of care for R/R CLL/SLL. The primary endpoint of this study was progression-free survival (PFS), and safety, while secondary endpoints included, overall response rate (ORR), and overall survival (OS).
- N = 319 patients with R/R CLL/SLL from 62 clinical sites in 11 countries, were randomized 1:1 to either duvelisib (n = 160) or ofatumumab (n = 159)
- Eligible patients were required to have active CLL/SLL, radiologically measurable (one lymph node or tumor mass > 1.5 cm by computer tomography)
- Key exclusion criteria included prior treatment with PI3K-δ or Bruton's tyrosine kinase (BTK) inhibitors, being refractory to ofatumumab treatment or history of Richter’s transformation, prolymphocytic leukemia or allogeneic stem cell transplantation (allo-SCT)
- Prophylactic treatment against Pneumocystis jiroveciiwas concomitantly administered to all study participants
- Duvelisib dosing included, self-administration of 25 mg orally, twice a day, for 28-day cycles, and for up to 18 cycles (except for first cycle: 21 days)
- Ofatumumab infusion followed the approved product labeling for monotherapy in relapsed CLL and could not exceed 12 doses
- No significant differences were observed in the baseline characteristics (age, time from diagnosis, lymphocyte counts, Eastern Cooperative Oncology Group [ECOG] score, median number of prior therapies etc.) of the two study populations (duvelisib vsofatumumab)
- Median follow-up = 22.4 months for both arms
- Median PFS by blinded independent review was significantly longer for duvelisib-treated patients than those in the ofatumumab arm (13.3 months vs9 months; HR = 0.52; P< 0.0001)
- Six-month PFS was 78% for duvelisib-treated patients and 72% for ofatumumab-treated patients
- One-year PFS was 60% for duvelisib-treated patients and 39% for the ofatumumab arm
- Duvelisib maintained a favorable odds ratio relative to ofatumumab for all subgroups analyzed, including patients with the del(17q)/ TP53deletion (HR = 0.41), R/R early relapse (HR = 0.51), baseline Grade 4 cytopenia (HR = 0.14), or prior anticancer therapy within the past 12 months (HR = 0.40)
- ORR was significantly higher in the duvelisib group (73.8%), as compared to ofatumumab-treated patients (45.3%; P< 0.0001)
- In the duvelisib arm, 72.5% of patients had a partial response (PR) with n = 1 (0.6%) patient achieving a complete response (CR)
- In the ofatumub arm, 44.7% of patients achieved PR with n = 1 (0.6%) patient achieving CR
- Duvelisib treatment was very effective at lymph node targeting, with lymph node response of 85% (95% CI, 79.5−5), compared to 15.7% (95% CI, 10.1−21.4) in the ofatumuab group ( P< 0.0001)
- Median OS was not reached in either treatment group
- Median treatment duration for duvelisib was 50 weeks, while 23 weeks for ofatumumab
- The most common hematological AEs experienced under duvelisib or ofatumumab treatment were: neutropenia (33% and 21%), anemia (23% and 10%) and thrombocytopenia (15% and 6%)
- The most common non-hematological adverse events (AEs) reported with duvelisib were: diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%)
- The most common non-hematological AEs reported with ofatumumab were: infusion-related reaction (19%), cough (14%), as well as diarrhea, rash, and fatigue (12% each)
- Serious AEs (SAEs) ≥ Grade 3 occurred in 87% of duvelisib-treated patients and in 48% of ofatumumab-treated patients
- The most common SAEs with duvelisib were: neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%), while with ofatumumab, only neutropenia (17%) was reported
- Infectious AEs were more commonly reported in the duvelisib arm (69%) than the ofatumumab arm (43%)
- At data cut-off (May 2017), n = 124 duvelisib-treated patients discontinued treatment as a result of AEs (35%), disease progression (22%), study withdrawal (8%) or death (8%).
- All ofatumumab-treated patients had discontinued treatment at data cut-off (May 2017) due to: completion of treatment protocol (67%), disease progression (20%), study withdrawal (5%) or AEs (4%)
The results of this phase III trial demonstrate that duvelisib treatment in R/R CLL/SLL patients results in significantly longer PFS and higher ORR, when compared to the approved standard of care, ofatumumab. The investigators state that the PFS and ORR improvements were consistently observed across all sensitivity and subgroup analyses. Moreover, the authors discussed the tolerability and safety of duvelisib and how the longer treatment exposure with duvelisib (50 weeks) resulted in a longer AE reporting period, as compared to ofatumumab (23 weeks).