Characterization of duvelisib in patients with refractory marginal zone lymphoma: data from the phase 2 DYNAMO trial

Purpose of the Study: Duvelisib, a first-in-class oral dual PI3K-, inhibi- tor, was approved by the US FDA for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after 2 prior therapies and for follicular lymphoma (FL) after 2 prior systemic therapies. DYNAMO is a phase 2 trial that evaluated the safety and efficacy of duvelisib monotherapy in a double-refractory iNHL population (NCT01882803; Flinn J Clin Oncol 2019), which included patients with marginal zone lymphoma (MZL). Here, we characterize the efficacy and safety of duvelisib for patients with MZL from the DYNAMO trial.

Summarized Description of the Project: DYNAMO was an open-label, single-arm trial in patients with FL, CLL/SLL, or MZL whose disease was double refractory to rituximab (monotherapy or as part of a combination regimen) and to chemotherapy or radioimmunotherapy. Patients received duvelisib 25 mg BID in 28-day treatment cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) per revised International Working Group (IWG) criteria. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, time to response, adverse events (AEs), and other safety parameters. Pneumocystis jiroveci prophylaxis was mandated for all patients.

Results: Of the 129 patients in the DYNAMO study, 18 (14%) were patients with MZL histology, of which 50% were of extranodal subtype, 22.2% nodal subtype, and 27.8% splenic subtype. Median age was 67 years (range, 61-77 years), and 72% (n = 13) were male. Median number of prior regimens was 2 (range, 1-8 prior), and 67% (n = 12) were refractory to 2 regimens. Median exposure to duvelisib was 8.35 months (range, 0.9-31.3 months).

The ORR per IRC was 39% (7 patients; 95% CI, 17.3%-64.3%), including 1 complete response (ORR by subtype: 0% extranodal, 75% nodal, 80% splenic). Median time to response was 3.7 months. As of the data cutoff (18May2018), the median duration of response had not been reached. With a median follow-up of 31.2 months, the median PFS by IRC was 15.5 months (95% CI, 3.6-27.8 months).

AEs were mostly grade 1/2. Most common grade 3 AEs (> 15%) were neutropenia (28%) and diarrhea (17%). 33% of patients discontinued duvelisib due to an AE, including 3 who were in PR at the time of dis- continuation. Follow-up imaging is not available for 1 patient, but the other 2 had sustained responses of > 1 year as of most recent imaging after treatment discontinuation. There was 1 grade 5 non-PD related AE of pancolitis (classified as potentially related to duvelisib).

Conclusion: Duvelisib monotherapy demonstrated clinically meaningful antitumor activity in patients with MZL. Duvelisib had a manageable safety profile, consistent with previous reports. These preliminary findings suggest that duvelisib represents a promising treatment option that warrants further investigation in patients with double-refractory MZL for whom limited treatment options exist.