Copanlisib-rituximab combo extends PFS in relapsed indolent non-Hodgkin lymphoma

The combination of copanlisib and rituximab extended progression-free survival (PFS) compared with rituximab alone in patients with relapsed indolent non-Hodgkin lymphoma, results of the phase III CHRONOS-3 trial showed.

“The CHRONOS-3 trial met its primary endpoint of PFS, with improved outcomes seen in several subtypes of indolent lymphoma included in the study,” presented Dr Matthew Matasar from the Memorial Sloan Kettering Cancer Center, New York, New York, US, at AACR 2021. “[This demonstrated] a global patient benefit irrespective of histology,” said Matasar and co-authors.

This multinational, double-blind trial included 458 adults with CD20+ indolent B-cell lymphoma* and ECOG performance status ≤2 who had relapsed following the last anti-CD20 monoclonal antibody-containing therapy and had been progression- and treatment-free for ≥12 months** after the last rituximab-containing treatment. They were randomized 2:1 to receive intravenous copanlisib (60 mg given over 1 hour on days 1, 8, and 15 on a 28-day cycle [intermittent dosing]***) + rituximab (375 mg/m² weekly on days 1, 8, 15, and 22 during cycle 1, and on day 1 of cycles 3, 5, 7, and 9) or placebo + rituximab.

Patients had received a median two prior systemic therapies, and 99 percent had received rituximab. They were followed up for a median 19.2 months, during which time 205 PFS events occurred.

PFS was significantly improved with copanlisib + rituximab vs rituximab + placebo (median 21.5 vs 13.8 months; hazard ratio [HR], 0.52, 95 percent confidence interval, 0.39–0.69; p<0.0001; estimated 2-year PFS: 46 percent vs 27 percent). [AACR 2021, abstract CT001; Lancet Oncol 2021;doi:10.1016/S1470-2045(21)00145-5]

Median time to progression was 22.3 and 13.8 months in the copanlisib + rituximab and rituximab + placebo groups, respectively. Objective response rate was higher with copanlisib + rituximab vs rituximab + placebo (81 percent vs 48 percent), with 34 percent vs 15 percent demonstrating complete response and 45 percent vs 29 percent demonstrating partial response.

Time to first overall objective response was a median 1.8 vs 2.1 months with copanlisib + rituximab vs rituximab + placebo, while time to complete response was 3.7 months in both groups. Duration of response was a median 20.4 vs 17.3 months.

Overall survival at a median 30.1 months was immature, with longer follow-up necessary to assess this outcome.

Tolerable safety profile

According to the authors, the safety profile of copanlisib + rituximab was acceptable and “consistent with the known safety profile of each drug as monotherapy.”

Dose interruption or delay of copanlisib and placebo occurred in 75 and 57 percent of patients, respectively, 68 and 48 percent of the events, respectively, due to adverse events (AEs).

Copanlisib- and placebo-related any-grade treatment-emergent (TE)AEs occurred in 95 and 65 percent of the respective groups, and serious TEAEs in 34 and 8 percent. TEAEs led to discontinuation in 31 and 8 percent of copanlisib + rituximab and rituximab + placebo recipients, respectively.

The most frequent grade 3–4 AEs were hyperglycaemia (56 percent [copanlisib + rituximab] vs 8 percent [rituximab + placebo]) and hypertension (40 percent vs 9 percent).

“[C]opanlisib-related hyperglycaemia and hypertension were infusion-related, transient, and manageable, and did not lead to significant treatment discontinuation, … [and were] managed primarily by means of glucose-lowering agents after infusion and antihypertensives, respectively,” the authors said.

Serious TEAEs were more common with copanlisib + rituximab than rituximab + placebo (47 percent vs 18 percent). Twenty-five percent of copanlisib recipients permanently discontinued treatment due to TEAEs.

TEAE-related deaths occurred in six copanlisib + rituximab and one rituximab + placebo recipient. There was one drug-related death due to pneumonitis in the copanlisib + rituximab and none in the rituximab + placebo group.

Take-home message

“The … study showed that the addition of copanlisib to standard rituximab treatment is superior to rituximab alone in patients with previously treated relapsed B-cell indolent non-Hodgkin lymphoma,” said the authors.

“[T]o our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad superior efficacy in combination with rituximab in patients with indolent non-Hodgkin lymphoma across subtypes,” they pointed out. “[T]his combination could, therefore, be a potential substitute for rituximab backbone treatment in this patient population,” they said.