Copanlisib-Rituximab Combination Cuts Lymphoma Progression or Death by Nearly Half in CHRONOS-3 Trial

PHILADELPHIA – A combination of copanlisib (Aliqopa) and rituximab led to a 48 percent reduction in the risk of disease progression or death compared with placebo and rituximab in patients with relapsed indolent non-Hodgkin lymphoma, according to data from the phase III trial CHRONOS-3, presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15.

Data from this trial were concurrently published in The Lancet Oncology.

“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 Matthew J. Matasar, MD, associate member of Lymphoma Service at Memorial Sloan Kettering Cancer Center (MSK).  

“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. To my knowledge, this is the first study to report such a broad benefit in patients with relapsed indolent non-Hodgkin lymphoma,” Matasar added. 

Rituximab given as monotherapy is a standard of care in patients with relapsed indolent lymphomas of many subtypes, Matasar said. “However, it does not work as frequently, or for as long, as we would like,” he added.   

Preclincial studies have shown that lymphoma cells rely on a cell-signaling pathway called the PI3K pathway for survival, and activation of PI3K plays a role in the resistance to rituximab, Matasar explained. Copanlisib is a potent PI3K inhibitor approved as monotherapy for patients with follicular lymphoma, a common indolent lymphoma, whose disease has relapsed after at least two courses of prior treatment.

In CHRONOS-3, patients with relapsed indolent non-Hodgkin lymphoma were randomly assigned to copanlisib plus rituximab (307 patients) or to placebo plus rituximab (151 patients). Of them, 60 percent had follicular lymphoma, 20.7 percent had marginal zone lymphoma, 10.9 percent had small lymphocytic lymphoma, and 8.3 percent had lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

After a median follow-up of 19.2 months, the study met its primary endpoint of PFS with a 48 percent reduction in the risk of lymphoma progression or death in the copanlisib-rituximab arm. Significant reductions were seen for follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma. Median PFS was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm.

Overall response rate was 80 percent in the copanlisib-rituximab arm, versus 47.7 percent in the placebo-rituximab arm. Complete response rate was 33.9 percent in the copanlisib-rituximab arm, versus 14.6 percent in the placebo-rituximab arm. Median overall survival could not be estimated at the time of assessment.

The most common adverse events with copanlisib treatment were increases in blood glucose and blood pressure. These effects are temporary and generally do not require treatment, Matasar noted. “Very few patients had to stop receiving treatment because of these side effects (3 percent and 1 percent, respectively). Lung inflammation was an adverse event we watched for, but was reported in only 3 percent of patients receiving copanlisib plus rituximab,” he said.

Earlier studies using the daily orally administered PI3K inhibitors idelalisib and duvelisib resulted in severe toxicity, including deaths, leading to early termination of clinical trials. Copanlisib is administered intravenously on an intermittent schedule, and has lower rates of such side effects compared with these oral PI3K inhibitors, Matasar said. “Thus, the overall results shown here with CHRONOS-3 are essentially a long-awaited proof of concept for combining a PI3K inhibitor with rituximab, and hopefully offer insight into ongoing and future studies of copanlisib and other investigational PI3K inhibitors in development,” he noted.

The primary analysis for this study was triggered when a pre-specified number of events (deaths or progressive disease) was seen, Matasar said. The median follow-up for this primary endpoint was 19 months, and many patients were still on treatment at the time of the analysis. Differences in overall survival, a secondary endpoint of the study, were not seen between arms, and longer follow-up will be required to determine whether copanlisib plus rituximab improves the expected lifespan on average, he added.

This study was sponsored by Bayer AG. Matasar has received honoraria from Bayer AG and subsidiaries of Bayer AG for advising and related activities. Bayer AG also provides research funding for Matasar through MSK. In addition, Matasar has received honoraria from Roche/Genentech for advising and related activities, and the company also provides research funding for him through MSK.