Study Shows Bayer’s Aliqopa, Rituximab Combo Improves Survival of Relapsed Lymphoma Patients

The combination of copanlisib (Aliqopa), a phosphatidylinositol-3-kinase (PI3K) inhibitor, and rituximab, a CD20-targeting monoclonal antibody, led to a 48% reduction in the risk of disease progression or death compared with placebo and rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL), according to a latest conference report.

These new results were presented at the 2021 virtual AACR Annual Meeting by the investigator of Phase 3 CHRONOS-3 trial, Matthew J. Matasar, MD, an associate member of Lymphoma Service at Memorial Sloan Kettering Cancer Center. The trial data were concurrently published in The Lancet Oncology.

Superior Benefits of Combo Therapy

In the CHRONOS-3 trial, 307 patients received the copanlisib plus rituximab combo, while 151 received the placebo plus rituximab. After a median follow-up of 19.2 months, the study met its primary endpoint of progression-free survival (PFS), with significant reductions observed in the risk of disease progression or death across all histology subtypes. The copanlisib plus rituximab combo registered a median PFS of 21.5 months (95% CI 17.8, 33.0) in comparison to the placebo-rituximab arm’s 13.8 months (95% CI 10.2, 17.5).

The combo therapy also achieved superior secondary endpoints. While the copanlisib plus rituximab combo registered an objective response rate (ORR) of 80.8% and a complete response rate (CRR) of 33.9%, the placebo-rituximab arm showed an ORR of 47.7% and CRR of 14.6%.

The higher ORRs and CRRs of the combo therapy were seen across several subtypes of iNHL. “To my knowledge, this is the first study to report such a broad benefit in patients with relapsed indolent non-Hodgkin lymphoma,” Matasar said.

Toxicity of PI3K Inhibitors

Despite the improvements in prognosis, relapse is often a big challenge with patients suffering from iNHL. Rituximab (Biogen/Genentech’s Rituxan) is currently a standard of care in patients with relapsed indolent lymphomas of many subtypes. However, it does not work as frequently or for as long, Matasar said. Studies have shown that lymphoma cells rely on the PI3K cell signaling pathway for survival. The activation of the PI3K pathway has been associated with the development of rituximab resistance.

Several PI3K inhibitors have shown promising results in preclinical and early clinical studies, but the high cellular toxicity is a concern. For instance, the daily oral administration of PI3K inhibitors, idelalisib, and duvelisib, have resulted in severe toxicity, including deaths.

First Safe Combination of PI3K Inhibitor with Rituximab for iNHL

Compared to oral PI3K inhibitors, Bayer’s intravenously administered Copanlisib (Aliqopa) has lower rates of adverse effects, Matasar said. Copanlisib was previously FDA approved in 2017 as a monotherapy for patients with follicular lymphoma, whose disease has relapsed after two courses of systemic therapies.

In the CHRONOS-3 trial, the most common adverse events observed with copanlisib treatment were increases in blood glucose (hyperglycemia), blood pressure (hypertension), and diarrhea. “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 percent of patients receiving copanlisib plus rituximab,” Matasar added.

“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.

Copanlisib is now the first PI3K inhibitor to be safely combined with rituximab in relapsed iNHL, a pleasing development, according to Matasar. He said this combination represents a potential new treatment option for patients with relapsed iNHL. Besides, this will lay the foundation for other combinatorial therapies involving copanlisib.

Author

Rajaneesh K. Gopinath