FDA, EU Approval Sought for Copanlisib Plus Rituximab for Indolent Non-Hodgkin Lymphoma

A supplemental new drug application and a marketing authorization application seeking the approval of the combination of copanlisib and rituximab for the treatment of patients with indolent non-Hodgkin lymphoma have been submitted to the FDA and the European Medicines Agency, respectively.

A supplemental new drug application and a marketing authorization application seeking the approval of the combination of copanlisib (Aliqopa) and rituximab (Rituxan) for the treatment of patients with indolent non-Hodgkin lymphoma (NHL) have been submitted to the FDA and the European Medicines Agency, respectively.1

Specifically, the US submission is for the use of the doublet in patients with relapsed indolent B-cell NHL; it is outside of the FDA accelerated approved indication for the treatment of adult patients with relapsed follicular lymphoma (FL) who have previously received at least 2 systemic therapies.

The filing in the European Union (EU) is for the use of the combination in the treatment of patients with relapsed marginal zone lymphoma (MZL); this application has been accepted.

The applications are based on data from the phase 3 CHRONOS-3 trial (NCT02367040), which showed that the doublet reduce the risk of disease progression or death by 48% vs rituximab plus placebo in patients with relapsed indolent NHL.2,3

At a median follow-up of 19.2 months, the median progression-free survival (PFS) achieved with copanlisib plus rituximab was 21.5 months (95% CI, 17.8-33.0) vs 13.8 months (95% CI, 10.2-17.5) with rituximab alone (HR, 0.52; 95% CI, 0.39-0.69; P <.0001).

“The US and EU submissions of the novel combination of [copanlisib] and rituximab bring us forward in advancing new treatment approaches and addressing unmet needs of patients with different types of relapsed indolent NHL,” Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer, stated in a press release. “We are excited about the potential of this investigational combination therapy based on the findings from CHRONOS-3 and we look forward to working with global regulatory authorities.”

In the double-blind, placebo-controlled, phase 3 CHRONOS-3 trial, investigators set out to examine whether the combination of copanlisib and rituximab is superior to rituximab alone in prolonging PFS in patients with relapsed indolent NHL after previously receiving at least 1 rituximab-containing therapy.

To be eligible for enrollment, patients needed to be at least 18 years of age and have histologically confirmed CD20-positive indolent B-cell lymphoma, which included grade 1 to 3a FL, MZL, small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia.

Patients must have relapsed after their last rituximab-containing or other anti-CD20 monoclonal antibody–containing therapy and have been progression free and treatment free for at least 6 months following their last rituximab-containing treatment. Patients also needed to have measurable disease, an ECOG performance status of 0 to 2, and a life expectancy of at least 3 months.

Study participants received copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given intravenously (IV) at 60 mg on days 1, 8, and 15 of each 28-day treatment cycle, and rituximab was administered at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. In the control arm, placebo was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle.

The primary end point of the trial was PFS, and secondary end points included objective response rate, disease control rate, duration of response (DOR), complete response (CR) rate, time to progression, overall survival (OS), patient-reported outcomes, and safety and tolerability of copanlisib. Exploratory end points comprised pharmacokinetic and biomarker assessments.

Baseline characteristics were comparable between the 2 treatment arms. The median of patients enrolled to the study was 63 years (range, 28-91) and 52.0% were male. Moreover, 14.6% of patients had a medical history of diabetes and 36.5% had a history of hypertension. Sixty percent of patients had FL; 19.0% of these patients had grade 1 disease, 27.9% had a grade 2 disease, and 13.1% had grade 3 disease. Additionally, 20.7% of patients had MZL, 10.9% had SLL, and 8.3% had LPL/Waldenström macroglobulinemia.

The median time since the last systemic therapy was received was 25.2 months (range, 0.8-192.5) and the median time since initial diagnosis was 63.2 months (range, 10.3-.349.2). Moreover, the majority, or 80.3%, of patients were progression and treatment free for at least 12 months since they received their last rituximab-containing regimen; 19.7% of patients were unwilling or not fit to receive chemotherapy. Just under half, or 48.3%, of patients had previously received at least 1 line of systemic therapy, 25.1% had received 2 prior lines, and 26.6% had received 3 prior lines.

Primary efficacy data demonstrated that the PFS benefit achieved with the copanlisib regimen was noted across all histologies examined, including FL (HR, 0.58), MZL (HR, 0.48), SLL (HR, 0.24), and LPL/Waldenström macroglobulinemia (HR, 0.44).

The centrally assessed objective response rate (ORR) was 81% in the copanlisib/rituximab arm, with 34% of patients experiencing a CR and 45% experiencing a partial response with the regimen. In the rituximab-alone arm, the ORR was 48.0% (P <.0001).

In the investigative arm, the median time to first overall objective response was 1.8 months (IQR, 1.7-2.1) and the median time to CR was 3.7 months (IQR, 1.8-7.4); in the control arm, this was 2.1 months (IQR, 1.7-5.4) and 3.7 months (IQR, 1.8-5.6), respectively.

The median DOR in the investigative and control arms was 20.4 months (95% CI, 17.0-30.8) and 17.3 months (95% CI, 11.8-25.3), respectively.

Moreover, 98% of evaluable patients (n = 271/276) experienced tumor shrinkage with copanlisib plus rituximab vs 86% of those (n = 120/139) who were given rituximab alone per investigator assessment.

At a median follow-up of 30.1 months (IQR, 17.4-39.7), the median OS was not reliably estimable. No difference in estimated OS was observed at 24 months or 36 months in the investigative and control arms. The 24-month OS rates in the investigative and control arms were 86% (95% CI, 81-90) and 91% (95% CI, 86-96), respectively; at 36 months, the rates were 83% (95% CI, 78-88) and 81% (95% CI, 72-89), respectively (HR, 1.07; 95% CI, 0.63-1.82).

All-grade treatment-emergent adverse effects (TEAEs) were reported in all patients who received copanlisib plus rituximab vs 91.8% of those given rituximab alone. Grade 3 TEAEs were experienced by 26.7% and 13.0% of those in the investigative and control arms, respectively; grade 4 TEAEs were reported in 13.0% and 0.7% of patients, respectively.

The all-grade TEAEs that were most frequently reported with copanlisib plus rituximab included hyperglycemia (69.4%) and hypertension (49.2%); these are toxicities that are known to be linked with copanlisib.

Grade 3 and 4 hyperglycemia was reported in 48.2% and 8.1% of patients, respectively; grade 3 and 4 hypertension were experienced by 39.7% and 0% of patients, respectively. Moreover, 8.8% of patients who received copanlisib plus rituximab experienced grade 4 neutropenia.

Pneumonitis was an AE of special interest, and it was experienced by 6.8% of those who received the doublet vs 1.4% of those given rituximab monotherapy.

Grade 5 TEAEs were experienced by 2.0% (n = 6) of patients who received the doublet and 1 of these effects, pneumonitis, was determined to be related to the study treatment. One patient on the control arm died.


  1. Bayer submits regulatory applications for oncology treatment investigational combination of Aliqopa (copanlisib) and rituximab in the US and EU. News release. Bayer. June 21, 2021. Accessed June 21, 2021. https://bwnews.pr/3cUOvWU
  2. Matasar MJ, Capra M, Ozcan M, et al. CHRONOS-3: randomized phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT001.
  3. Matasar MJ, Capra M, Özcan M, 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;22(5):678-689. doi:10.1016/S1470-2045(21)00145-5