Copanlisib combined with rituximab can significantly improve the prognosis of patients with recurrent iNHL

Patients with indolent non-Hodgkin's lymphoma (iNHL) are incurable and are characterized by repeated relapses and progressive resistance to treatment.

Rituximab-based immunochemotherapy is the standard treatment option for patients with recurrent iNHL.

For patients with recurrent iNHL, patients whose remission duration> 6-12 months after previous treatment with rituximab are generally considered to be sensitive to rituximab treatment and can choose rituximab Anti-retreatment.

However, previous studies have shown that in patients with iNHL who are resistant to rituximab, small molecule targeted therapy may have better efficacy than chemotherapy.
In recent years, researchers have been seeking treatments to further improve the efficacy.
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Copanlisib is a highly selective, pan-type I PI3K inhibitor, which mainly has targeting activity on PI3K-α and PI3K-δ.

Previous studies have shown that Copanlisib as a single agent has good efficacy and safety in patients with relapsed or refractory indolent B-cell NHL who have previously received ≥2 line therapy.

Based on this, Professor Matthew J Matasar and others conducted the CHRONOS-3 study, which is a multi-center, double-blind, randomized, placebo-controlled phase III clinical trial that evaluated Copanlisib combined with rituximab versus placebo Efficacy and safety of combined rituximab in patients with relapsed iNL.

The main contents of the research are summarized as follows.

Research methods The study recruited patients from 186 medical centers around the world.
All patients were ≥18 years old and had CD20-positive iNHL histopathology, including follicular lymphoma (FL) grade 1-3a, marginal zone lymphoma ( MZL), small lymphocytic lymphoma (SLL) and lymphoplasmacytic lymphoma/Wahrenheit's macroglobulinemia (WM).

If the patient's last treatment is rituximab or other anti-CD20 monoclonal antibody treatment, it is required that there is no progression for at least 6-12 months after the last treatment with rituximab.

Eligible patients were randomly assigned (2:1) to receive Copanlisib combined with rituximab or placebo combined with rituximab.

The primary study endpoint is to evaluate whether Copanlisib has better progression-free survival (PFS) than placebo combined with rituximab in the treatment of iNHL.

Study Results 01 Patient Characteristics The study screened a total of 652 patients from August 2015 to December 2019, of which 458 patients participated in random allocation, of which 307 cases were in the Copanlisib combined with rituximab group, and placebo combined with rituximab There were 151 cases in the tuximab group.

The median number of previous treatments for all patients was 2, and 99% of patients had previously received rituximab treatment.

In addition, 15% of patients have diabetes and 36% of patients have hypertension.

02 The median follow-up for efficacy was 19.
2 months.
The median PFS of patients in the Copanlisib combined with rituximab and placebo combined with rituximab groups were 21.
5 months (95%CI 17.
8-33.
0 months) and 13.
8 months, respectively (95%CI 10.
2-17.
5 months) (HR is 0.
52, 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 18-54) in the placebo plus rituximab group.
37).

The overall response rate (ORR) of patients in the Copanlisib combined with rituximab and placebo combined with rituximab group was 81% and 48%, respectively, and the complete response (CR) rate was 34% and 15%, respectively; the two groups of patients The median time to first objective remission was 1.
8 months and 3.
7 months, respectively, and the median duration of remission was 20.
4 months (95% CI 17.
0-30.
8) and 17.
3 months (95% CI 11.
8-25.
3), respectively.

03 Safety Overall, the most common grade 3-4 adverse events (AE) in patients were hyperglycemia and hypertension, and hyperglycemia in patients in the Copanlisib combined with rituximab group and in the placebo combined with rituximab group The incidence was 56% and 8%, respectively, and the incidence of hypertension was 40% and 9%.

In addition, the incidence of serious AEs in the two groups of patients during treatment was 47% and 18%, respectively.

Drug-related death (pneumonia) occurred in 1 patient (<1%) in the Copanlisib combined with rituximab group, and there were no treatment-related deaths in the placebo combined with rituximab group.

Research conclusions The study shows that compared with placebo combined with rituximab, Copanlisib combined with rituximab can significantly improve the PFS of patients with recurrent iNHL, or can change the treatment practice of patients with recurrent iNHL.

References: Matthew J Matasar, Marcelo Capra, MuhitÖzcan, et al.
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.
Lancet Oncol .
2021 May;22(5):678-689.
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