Copanlisib Plus Rituximab Versus Placebo Plus Rituximab in Patients with Relapsed Indolent Non-Hodgkin Lymphoma (Chronos-3): A Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial

Copanlisib Plus Rituximab Versus Placebo Plus Rituximab in Patients with Relapsed Indolent Non-Hodgkin Lymphoma (Chronos-3): A Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial

In the May 2021 issue of the Lancet Oncology, investigators reported on the utility of copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin’s lymphoma in the CHRONOS-3 trial.

Background and Purpose

Copanlisib, is a pan class I PI3K inhibitor, which is administered intravenously, with proven efficacy as monotherapy in patients with relapsed or refractory indolent non-Hodgkin’s B-cell lymphoma with exposure to 2 lines of therapy. The CHRONOS-3 study attempted to assess the efficacy as well as the safety of copanlisib in addition to rituximab in patients with indolent non-Hodgkin lymphoma who had relapsed on prior therapy

Methods

CHRONOS-3 was a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial.  It was carried out across 186 centers.  Adult patients, with histologically confirmed CD20 positive indolent B-cell lymphoma, who had relapsed after an anti-CD20 targeting monoclonal antibody and progression free and treatment free durations of at least 1 year, or 6 months for patients unwilling or unfit to receive chemotherapy, underwent randomization in a 2:1 fashion.  Randomization was 2:1 in favor of copanlisib, 60 mg intravenous administration on day 1, 8, 15 on the 28-day cycle plus rituximab 375 mg/m² on days 1, 8, 15 and 22 during cycle 1 and day 1 of cycle 3, 5, 7 and 9 or placebo plus rituximab.  The primary outcome was progression free survival.

Findings

652 patients were screened for eligibility.  370 of 458 patients were randomly assigned to the copanlisib arm.  151 patients were randomly assigned to the placebo arm.  After a median follow-up of 19.2 months, 205 total events were recorded.  Copanlisib plus rituximab showed a statistically significant improvement as well as a clinically significant improvement in progression free survival versus placebo plus rituximab.  The median progression free survival was 21.5 months versus 13.8 months.  The hazard ratio for progression free survival was reported as 0.52, 95% confidence interval of 0.39–0.69 with a P < 0.0001.  The most common grade 3 or 4 adverse events were hyperglycemia, seen in 173 patients, 56% in the copanlisib plus rituximab from versus 12 patients, 8% of the placebo group.  Hypertension was seen in 40% versus 9%.  Serious treatment emergent adverse events were reported in 47%.  1 death as a result of pneumonitis was seen in the copanlisib treatment arm.

Conclusion

The authors concluded “Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, 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.”

Reference:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00145-5/fulltext

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