To date, rituximab-based immunochemotherapy is a standard treatment option for patients with recurrent indolent non-Hodgkin lymphoma. However, development of resistance to rituximab is well documented. Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies (phase II CHRONOS-1 study). This single-agent efficacy and tolerability in heavily pre-treated indolent non-Hodgkin lymphoma has now prompted the investigation of copanlisib in combination with rituximab-based therapies to determine whether such a regimen could improve outcomes for patients with relapsed indolent lymphoma who are either rituximab-sensitive or unwilling or unfit to receive chemotherapy (CHRONOS-3).
The phase III CHRONOS-3 trial randomised 458 patients with histologically confirmed CD20-positive indolent non-Hodgkin lymphoma from 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. All patients were at least 18 years old and had an ECOG performance status of no more than 2. Patients must have relapsed after the last rituximab-containing or other anti-CD20 monoclonal antibody-containing therapy and been either progression-free and treatment-free for at least 12 months after the last rituximab-containing treatment or unwilling or unfit to receive chemotherapy and progression-free and treatment-free for at least 6 months after the last rituximab-containing treatment. All eligible patients were randomly assigned (2:1) to copanlisib (60 mg given as a one hour intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab. The median number of previous systemic therapies was two (IQR 1–3); 48% had received one previous line of therapy. Nearly all patients (99%) had received rituximab, and 24% had received at least one line of rituximab monotherapy.
After a median follow-up of 19.2 months, copanlisib plus rituximab demonstrated a statistically and clinically significant improvement in progression-free survival (PFS) as compared to placebo plus rituximab (median PFS 21.5 vs. 13.8 months, HR[95%CI]: 0.52[0.39-0.69], p< 0.0001). The estimated 2-year PFS rate was 46% (95%CI: 39–54) in the copanlisib plus rituximab group and 27% (95%CI: 18–37) in the placebo plus rituximab group. Centrally assessed objective response rate was 81% in the copanlisib plus rituximab group versus 48% in the placebo plus rituximab group, with complete responses observed in 34% and 15% of patients, respectively. The median duration of response was 20.4 months in the copanlisib plus rituximab group versus 17.3 months in the placebo plus rituximab group. The most commonly reported grade 3-4 adverse events were hyperglycaemia in 56% of patients in the copanlisib plus rituximab arm vs. 8% in the placebo plus rituximab arm, and hypertension (40% vs. 9%, respectively). Serious treatment-emergent adverse events were reported in 47% of patients in the copanlisib arm and in 18% of patients in the placebo arm. In the copanlisib arm, one drug-related death (pneumonitis) occurred whereas no drug-related deaths were reported form the placebo plus rituximab group.
Authors conclude that copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.
Matasar MJ, et al. Lancet Oncol. 2021;22(5):678-89.