Adding copanlisib to standard rituximab therapy led to significant improvement in progression-free survival (PFS) in patients with relapsed indolent non-Hodgkin's lymphoma (iNHL), compared with rituximab alone, in the CHRONOS-3 trial. "Copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combination with rituximab in all iNHL histologies," said Dr. Matthew Matasar in presenting the results during a press briefing at the American Association for Cancer Research (AACR) virtual annual meeting. The CHRONOS-3 results were simultaneously published in The Lancet Oncology. AACR president and briefing co-moderator Dr. Antoni Ribas called the results from the randomized, double-blind, placebo-controlled phase-3 trial "practice-changing." Rituximab monotherapy is the standard of care in relapsed iNHL, but the clinical benefit may be short-lived, said Dr. Matasar of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York City. Preclincial studies have found that lymphoma cells rely on the PI3K cell-signaling pathway for survival, and activation of PI3K plays a role in the resistance to rituximab, he explained. Copanlisib, marketed as Aliqopa by Bayer, which funded the study, is a potent PI3K inhibitor approved as monotherapy for adults with relapsed follicular lymphoma who have received at least two prior systemic therapies. In the CHRONOS-3 trial, 458 patients with relapsed iNHL were randomly assigned to copanlisib plus rituximab given intravenously (307 patients) or to rituximab plus placebo (151 patients). The two groups were well-balanced and stratified based on histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. After a median follow-up of 19.2 months, the study met its primary endpoint of PFS with a 48% reduction in the risk of disease progression or death in the copanlisib-rituximab group. Median PFS was 21.5 months with the copanlisib-rituximab combination versus 13.8 months with rituximab alone (hazard ratio, 0.52; 95% confidence interval: 0.393 to 0.688; P<0.0001). A benefit in PFS was observed across all iNHL histologic subtypes (follicular lymphoma, marginal-zone lymphoma, and small lymphocytic lymphoma). The objective response rate was significantly higher in the copanlisib-rituximab group (81% vs. 48%; P<0.0001). The addition of copanlisib to rituximab had a "manageable safety profile, consistent with previous reports of copanlisib and rituximab as monotherapies," Dr. Matasar reported. The most common grade-3 to -4 adverse events were hyperglycemia, occurring in 56% of patients in the combination group versus 8% of patients in the placebo plus rituximab group, and hypertension (40% vs. 9%, respectively). Serious treatment-emergent adverse events were reported in 47% of patients in the copanlisib-rituximab group versus 18% of patients in the placebo-rituximab group. One drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. "Overall, copanlisib plus rituximab represents a potential new treatment option for patients with relapsed disease across all subtypes of indolent non-Hodgkin lymphoma," Dr. Matasar concluded. Briefing co-moderator Dr. Charles Swanton of University College London (UCL) Cancer Institute noted that the study was "strongly positive for an improvement in progression-free survival across histologies." He said it's "important to state that there are also more toxicities" in the copanlisib-plus-rituximab group, "as would be expected." The study was sponsored by Bayer AG. Dr. Matasar reported relationships with the company. —Megan Brooks Source
