Catherine C. Coombs, MD
Anthony R. Mato, MD, MSCE
The phase III DUO trial, reported by Flinn et al and reviewed in this issue of The ASCO Post, has led to the U.S. Food and Drug Administration (FDA) approval of a novel B-cell receptor (BCR) kinase inhibitor, duvelisib (Copiktra), which targets phosphoinositide 3-kinase (PI3K)-δ/γ in patients with chronic lymphocytic leukemia (CLL) who have received at least two prior therapies.1 As a result of this approval, the therapeutic armamentarium of novel oral agents for patients with CLL has continued to expand, as this marks the third BCR kinase inhibitor approved for treatment of CLL (joining ibrutinib [Imbruvica] and idelalisib [Zydelig]) in addition to the BCL2 inhibitor venetoclax (Venclexta).
Duvelisib vs Ofatumumab
The DUO trial arms were well balanced, with similar proportions of patients with del(17p)- and TP53-mutant disease and the median number of prior therapies (n = 2) in each arm. Duvelisib was superior to ofatumumab (Arzerra) with respect to progression-free survival and overall response rate, with a strikingly higher proportion of improvements in lymphadenopathy (defined as ≥ 50% reduction in target lymph nodes from baseline) in duvelisib-treated patients (85% vs 16% in ofatumumab arm). The overwhelming majority of responses in both arms were partial remissions (73% of duvelisib-treated patients and 45% of ofatumumab-treated patients). The overall response rate from the DUO trial (74%) was similar to the overall response rate seen in the idelalisib phase II monotherapy trial (overall response rate of 72%),2 the phase III trial combining idelalisib with rituximab (Rituxan; overall response rate of 81%),3 and the phase III trial combining idelalisib with ofatumumab (overall response rate of 75%).4
There was no observed difference in overall survival between the arms. The lack of difference of overall survival was not a surprising finding, as the DUO trial allowed for crossover, which would limit interpretation of a survival benefit, in addition to the availability of multiple effective subsequent therapies for those patients who experienced disease progression on either arm. However, the number of fatal adverse events on the duvelisib arm (n = 19, with 4 assessed as related to the study drug) outnumbered that on the ofatumumab arm (n = 7, with none assessed as related to the study drug).
Mechanism of Action
Expression of PI3K-δ and PI3K-γ is largely limited to hematopoietic cells. Duvelisib is thought to be distinct from its PI3K-inhibiting predecessor idelalisib, as it inhibits both δ and γ isoforms of PI3K. It is hypothesized that inhibition of PI3K-δ limits cell proliferation and survival, whereas PI3K-γ inhibition leads to disruption of the tumor microenvironment by interrupting cytokine signaling and generating the proinflammatory response. In preclinical studies, duvelisib led to direct cytotoxicity of primary CLL cells (including those with BTK C481S mutations) in addition to reduction in the viability of normal T and natural killer cells with reduction of antiapoptotic and inflammatory cytokines.5 Indeed, 10 chemokines showed a median decrease of at least 50% in duvelisib-treated patients.1
Closer Look at Toxicity
A consistent feature of both approved PI3K inhibitors in CLL is the incidence of adverse effects and infections. Neutropenia has been seen in both duvelisib- and idelalisib-treated patients, with an incidence of ≥ grade 3 neutropenia in 33%, 34%, and 35% for patients receiving duvelisib monotherapy, idelalisib/rituximab, and idelalisib/ofatumumab, respectively.3,4 In the DUO trial, hepatotoxicity was uncommon, with 3% of patients experiencing ≥ grade 3 transaminitis (median follow-up of 7 months), possibly less than that with idelalisib/rituximab, which reported a 5% incidence of ≥ grade 3 transaminitis (at a shorter median follow-up of 3.8 months).3 The rates of pneumonitis appear similar with duvelisib and idelalisib, occurring in 3% of patients receiving each drug.1,6
A consistent feature of both approved PI3K inhibitors in CLL is the incidence of adverse effects and infections.— Catherine C. Coombs, MD, and Anthony R. Mato, MD, MSCE
Tweet this quote
Among duvelisib-treated patients, 15% experienced ≥ grade 3 diarrhea, with 12% of patients having severe (≥ grade 3) colitis, at a median of 7 months into therapy; this rate is higher than the 4% ≥ grade 3 diarrhea incidence in the idelalisib/rituximab-treated patients, although the lower incidence may be related to shorter follow-up (3.8 months).3 In the DUO trial, infectious adverse events were more common in the duvelisib arm as well (69% vs 43%), with pneumonia being the most common event, occurring in 18% of patients.
Clinical Considerations
There are unlikely to be prospective data comparing duvelisib with idelalisib. Thus, in individual discussions with patients, the decision to choose one therapy over another may be a nuanced one, based on experiences and comfort with either agent. For duvelisib, the existing FDA label includes black box warnings regarding fatal and/or serious toxicities, including infections, diarrhea/colitis, cutaneous reactions, and pneumonitis.
Of note, the DUO trial excluded patients who had received prior treatment with BTK inhibitors or PI3K inhibitors, which limits extrapolation of reported response rates to a real-world CLL population, where many—if not all—will have been exposed to BTK inhibitors and/or BCL2 inhibitors. The efficacy of PI3K inhibitors in the setting of prior use of a BTK inhibitor has been less encouraging, although the assessment is based upon limited retrospective series (overall response rate of 46% in patients with prior ibrutinib exposure in a single series). Nonetheless, both disease progression and intolerance to novel agents such as ibrutinib and venetoclax are not infrequent, and thus additional treatment approaches remain of critical importance for our patients with relapsed or refractory CLL.8,9 ■
Dr. Coombs is a practicing hematologist/oncologist in the Leukemia, Lymphoma, and Myeloma Program at the University of North Carolina Cancer Center. Dr. Mato is Director of the Chronic Lymphocytic Leukemia Program at the Memorial Sloan Kettering Cancer Center, New York.
DISCLOSURE: Dr. Coombs has served as a consultant for AbbVie, received honorarium from Pharmacyclics, and has received institutional research funding from Gilead Sciences. Dr. Mato has received research funding from and is a consultant to TG Therapeutics, Gilead Sciences, Pharmacyclics, AbbVie, Sunesis, DTRM, Loxo, and AstraZeneca/Acerta.
REFERENCES
1. Flinn IW, Hillmen P, Montillo M, et al: The phase 3 DUO trial: Duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood. October 4, 2018 (early release online).
2. Brown JR, Byrd JC, Coutre SE, et al: Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123:3390-3397, 2014.
3. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.
4. Jones JA, Robak T, Brown JR, et al: Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: An open-label, randomised phase 3 trial. Lancet Haematol 4:e114-e126, 2017.
5. Dong S, Guinn D, Dubovsky JA, et al: IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 124:3583-3586, 2014.
6. Coutré SE, Barrientos JC, Brown JR, et al: Management of adverse events associated with idelalisib treatment: Expert panel opinion. Leuk Lymphoma 56:2779-2786, 2015.
7. Mato AR, Hill BT, Lamanna N, et al: Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: Results from a multicenter study of 683 patients. Ann Oncol 28:1050-1056, 2017.
8. Mato AR, Thompson M, Allan JN, et al: Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica 103:1511-1517, 2018.
9. Maddocks KJ, Ruppert AS, Lozanski G, et al: Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 1:80-87, 2015.
