Combo Provides 'Broad Benefit' Across NHL Subtypes

M. Alexander Otto

April 13, 2021

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report "a broad benefit" across histologic subtypes of relapsed, indolent NHL, and the results are "essentially a long-awaited proof of concept" for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results "strongly positive" and said the copanlisib-rituximab combination is "a potential new treatment option" for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Swanton noted, however, that "one should also bear in mind" the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don't have severe baseline diabetes or uncontrolled hypertension.

Patient and Treatment Details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients' median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given 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.

Progression-Free Survival Benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

  • Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)

  • Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)

  • Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)

  • Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia was likely not statistically significant because of the small sample size, Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.

More Than Double the Rate of Serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these — pneumonitis — was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

This article originally appeared on, part of the Medscape Professional Network.


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