Phase II DYNAMO trial: Duvelisib in heavily pre-treated R/R iNHL patients

On 11 February 2019, Ian Flinn from Sarah Cannon Research Institute, Nashville, TN, USA, and colleagues, published in the Journal of Clinical Oncology  the results of the phase II trial DYNAMO. patients. 

Duvelisib has been approved by the Food and Drug Administration (FDA) for relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and R/R follicular lymphoma (FL) patients, after two or more prior lines. In this open-label, global, phase II trial (NCT01882803) the efficacy and safety of single-agent, oral duvelisib were assessed in patients with R/R indolent non-Hodgkin lymphoma (iNHL). The primary endpoint of this study was overall response rate (ORR) assessed by an Independent Review Committee (IRC) according to the International Working Group (IWG) criteria for malignant lymphoma. Secondary endpoints, included progression-free survival (PFS), and safety.

Study design & baseline characteristics 

• N = 129 iNHL patients, aged ≥ 18, histologically-confirmed iNHL, who were double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radiotherapy, with either or the following subtypes:
  • FL (n = 83)
  • SLL (n = 28)
  • Marginal zone lymphoma (MZL; n = 18)
• Dosing:
  • Self-administration of 25 mg of oral duvelisib twice daily in 28-day cycles, until disease progression (PD), unacceptable toxicity, or death
  • Dose reductions were allowed in the case of treatment-emergent adverse events (TEAEs; up to two dose reductions)
  • Pneumocystis jirovecii pneumonia (PJP), herpes simplex virus (HSV), and herpes zoster virus (HZV) prophylaxis was given
• Males: 89.9% of patients (total cohort)
• Median patient age (range): 65 (30−90) years
• The majority of patients had advanced disease stage (III or IV): 85%
• Patients with elevated lactate dehydrogenase: 67%
• Eastern Cooperative Oncology Group (ECOG) performance status at enrolment:
  • 1: 94.6%
  • 2: 5.4%
• Median number of prior lines (range): 3 (1−18)
• Patients having received ≥ 4 prior lines: 40% (n = 52)
• Patients refractory to rituximab (monotherapy or in combination): 98% (n = 127)
• Patients refractory to an alkylating agent or purine analog: 92% (n = 119)
• Patients refractory to combination therapy with rituximab and an alkylating agent: 91% (n = 117)
• Responses were assessed at cycles 3, 5, 7, and 10; and thereafter every four cycles until two years
• Data cut-off: May 2018 

Key findings

• Median follow-up: 32.1 months
• ORR (total cohort): 47% (95% CI, 38−56%)
  • Partial response (PR): n = 59
  • Complete response (CR): n = 2
• ORR was higher in US patients (59%; n = 46 patients)
• ORR was lower in patients who received prior bendamustine (62%; n = 47 patients)
• ORR per iNHL subtype:
  • FL: 42%
  • SLL: 68%
  • MZL: 39%
• Overall, 83% of patients (n = 99/119) experienced reduction in lymphnode tumor burden
• Median time-to-response (TTR; range): 1.87 (1.4−11.7) months
• Patients responding to treatment by month 2: 59%
• Patients responding to treatment by month 4: 84%
• Median duration of response (DoR): 10 months (95% CI, 6.5−10.5)
• Median PFS: 9.5 months (95% CI, 8.1−11.8)
• Probability of survival and being progression-free at six months: 62%
• Median OS: 28.9 months (95% CI, 21.4−not estimable)
• One-year OS: 77%
• Mean duration of treatment exposure (range): 6.7 months (0.4−45.5)
• Initiated duvelisib cycles:
  • Six or more cycles: 59.7% (n = 77 patients)
  • Twelve or more cycles: 32.6% (n = 42 patients) 

Safety

• Most common any-grade AEs were:
  • Diarrhea: 48.8%
  • Nausea: 29.5%
  • Neutropenia: 28.7%
  • Fatigue: 27.9%
  • Cough: 27.1%
• Most common Grade ≥ 3 AEs were:
  • Neutropenia: 24.8%
  • Diarrhea: 14.7%
  • Anemia: 14.7%
  • Thrombocytopenia: 11.6%
  • Colitis: 7.8%
  • Pneumonitis: 4.7%
• Most common Grade ≥ 3 non-hematological TEAEs were:
  • Elevated serum lipase: 7%
  • Alanine aminotransferase (ALT): 5.4%
  • Aspartate aminotransferase (AST): 3.1%
• Patients discontinuing duvelisib due to TEAEs: 31%
• Duvelisib dose reduction occurred in 19.4% f patients (n = 25)
• Deaths occurring on treatment: 13.2% (n = 17 deaths), which were attributed to:
  • PD: 7% (n = 9)
  • Unrelated to treatment: 2.3% (n = 3)
  • Treatment-related: 3.9% (n = 5) 

Conclusions

• In heavily pre-treated R/R iNHL patients, duvelisib led to an ORR of 47%, with primarily PRs
• Responses to duvelisib occurred generally within the first two months of therapy with a median duration of 10 months
• Duvelisib monotherapy in R/R iNHL patients showed a similar safety profile across iNHL subtypes (FL, MZL, CLL), and AEs were manageable