PI3K Inhibitor Duvelisib Is an Option for Refractory Indolent NHL

Indolent non-Hodgkin lymphoma (iNHL) is a chronic, incurable disease in which patients often require multiple lines of therapy. iNHL include several subtypes including follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and marginal zone B-cell lymphoma (MZL). While chemotherapy and anti-CD20 antibodies are the standards of care in early lines of treatment, there are limited options for patients who have relapsed or become refractory to these agents and development of novel treatment approaches for heavily pretreated patients is a major area of investigation. Duvelisib is a small molecule inhibitor of phosphoinositide-3-kinase (PI3K) – δ and γ and was recently granted FDA approval for treatment of relapsed or refractory chronic lymphocytic leukemia (CLL), SLL, and FL. The approval, particularly in FL, was supported by results from the open-label, global phase II DYNAMO trial (N = 129) that evaluated the safety and efficacy of duvelisib monotherapy in patients with iNHL who were refractory to rituximab and either chemotherapy or radioimmunotherapy.

At a median follow-up of 32.1 months, treatment with duvelisib in these heavily pretreated patients yielded an overall response rate (ORR) of 47.3%, including complete response in two patients. Response rates varied between NHL subtypes, from 67.9% in patients with SLL to 42.2% and 38.9% in patients with FL and MZL, respectively. A total of 83% of patients treated with duvelisib experienced a reduction in lymph node tumor volume. Responses occurred within the first two months of treatment and were durable. The median duration of response was 10 months, and the estimated median progression-free survival (PFS) was 9.5 months. The one-year rate of overall survival (OS) was 77%, and the estimated median OS was 28.9 months.

The adverse event (AE) profile of duvelisib in refractory iNHL was manageable and consistent with the known safety profile of the drug. The most common treatment-related AEs of any grade were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Grade 3/4 AEs occurred in 88.4% of patients, with neutropenia, diarrhea, anemia, and thrombocytopenia as the most common events. Treatment-related AEs including pneumonitis, transaminase elevations, colitis, and rash led to treatment discontinuation in 31% of patients. There were 5 deaths (3.9%) considered to be treatment-related. Serious opportunistic infections were observed in less than 5% of patients. However, patients received prophylaxis for Pneumocystis jirovecii pneumonia (PJP), herpes simplex virus (HSV), and herpes zoster virus (HZV).

The investigators concluded that treatment with duvelisib is safe, with clinically meaningful activity in heavily pretreated patients with refractory iNHL. They pointed out that this oral monotherapy may in particular be beneficial for elderly patients who may not be eligible for aggressive infusion therapies.

J Clin Oncol. 2019 Feb 11. [Epub ahead of print.]

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