Copanlisib Plus Rituximab Improves Progression-Free Survival in Indolent Non-Hodgkin Lymphoma

Combining copanlisib with rituximab reduced the risk of progression or death by 48%, compared with placebo plus rituximab, in patients with relapsed advanced indolent non-Hodgkin lymphoma (NHL). These findings are according to results from the phase III CHRONOS-3 trial.

Matthew Matasar, MD, from Memorial Sloan Kettering Cancer Center in New York, presented these findings during the American Association for Cancer Research’s 2021 virtual meeting. The findings also were published concurrently in Lancet Oncology.

“The CHRONOS-3 trial met its primary endpoint of progression-free survival (PFS), with improved outcomes seen in several subtypes of indolent lymphoma included in the study,” Dr. Matasar said. “To my knowledge, this is the first study to report such a broad benefit in patients with relapsed indolent non-Hodgkin lymphoma.”

Rituximab-based therapy is standard treatment for this patient population, Dr. Matasar noted, but “it does not work as frequently, or for as long, as we would like.”

“We are glad to see that copanlisib could be safely combined with rituximab for the long-term treatment of patients with relapsed indolent non-Hodgkin lymphoma.”

—Matthew Matasar, MD

The PI3K inhibitor copanlisib is approved as monotherapy in patients with relapsed follicular lymphoma (FL) who have had at least two prior systemic therapies. In the CHRONOS-3 study, researchers compared outcomes with rituximab to either copanlisib or placebo in 358 patients with relapsed indolent NHL who were progression-free and treatment-free for at least 12 months since last rituximab-based therapy or were unwilling/unfit to receive chemotherapy. Participants were randomized 2:1 to receive either:

  • copanlisib 60 mg on days 1, 8, and 15 plus rituximab 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9 (n=307)
  • placebo plus rituximab (n=151)

The median patient age was 63 years (range = 28-91). FL was the most common lymphoma histology subtype (60%), followed by marginal zone lymphoma (MZL; 20.7%), small lymphocytic lymphoma (SLL; 10.9%), and Waldenström macroglobulinemia (WM; 8.3%).

The study met its primary endpoint after a median follow-up of 19.2 months, with the copanlisib combination demonstrating a significantly longer PFS compared with the placebo group (21.5 vs. 13.8 months; hazard ratio [HR] = 0.52; 95% CI 0.39-0.69; p<0.001).

The PFS benefit was seen across all histology subtypes:

  • FL: HR=0.580
  • MZL: HR=0.475
  • SLL: HR=0.243
  • WM: HR=0.443

Response rates were also higher in the copanlisib group than the placebo group, the authors added. Overall response rates (ORRs) were 80.8% versus 47.7%, respectively, and complete response rates (CRRs) were 33.9% versus 14.6%. Again, higher ORRs and CRRs were seen across all indolent NHL subtypes with copanlisib plus rituximab treatment.

The most common treatment-emergent adverse (AEs) in patients receiving copanlisib were hyperglycemia (all-grade: 69.4%; grade ≥3: 56.4%), hypertension (49.2%; 39.7%), and diarrhea (33.6%; 4.9%). In the placebo group, the most common AEs were hyperglycemia (23.3%/8.2%), hypertension (19.2%/8.9%), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%). Dr. Matasar noted that, in the copanlisib group, “very few patients had to stop receiving treatment because of these side effects. Lung inflammation was an adverse event we watched for, but was reported in only 3% of patients receiving copanlisib plus rituximab.”

Grade 5 treatment-emergent AEs occurred in six patients receiving copanlisib and in one patient receiving placebo. One death (pneumonitis) was reported as drug-related in the copanlisib plus rituximab group.

“We are glad to see that copanlisib could be safely combined with rituximab for the long-term treatment of patients with relapsed indolent non-Hodgkin lymphoma,” said Dr. Matasar.

Study authors report relationships with Bayer, which sponsored this trial.


  1. Matasar MJ, Capra M, Özcan M, et al. CHRONOS-3: randomized phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). Abstract #CT001. Presented at the 2021 American Association for Cancer Research Annual Meeting, April 10, 2021.
  2. 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. [published online ahead of print, 2021 April 10]. Lancet. doi: 10.1016/S1470-2045(21)00145-5.