Author: By Hannah Kitt, medwireNews Reporter
medwireNews: Patients with relapsed indolent non-Hodgkin lymphoma (iNHL) derive a significant progression-free survival (PFS) benefit from the addition of the PI3K inhibitor copanlisib to rituximab, suggest findings from the CHRONOS-3 trial.
Details of the phase III study were published in The Lancet Oncology to coincide with their presentation at the virtual AACR Annual Meeting 2021 by Matthew Matasar, from Memorial Sloan Kettering Cancer Center in New York, USA.
The investigators enrolled 458 patients who had relapsed on at least one prior regimen of rituximab, a rituximab biosimilar or an anti-CD20 monoclonal antibody, and were progression- and treatment-free for a minimum of 12 months or 6 months if they were unwilling or unfit for chemotherapy. The majority (60.0%) had follicular lymphoma, followed by marginal zone lymphoma (20.7%), small lymphocytic lymphoma (10.9%) and lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (8.3%).
After a median follow-up of 19.2 months, the primary endpoint of centrally assessed PFS was significantly prolonged for the 307 patients who were randomly assigned to receive intravenous copanlisib 60 mg on days 1, 8 and 15 of each 28-day cycle plus rituximab 375 mg/m2 every week in the first cycle and then on day 1 of cycles 3, 5, 7 and 9, compared with their 151 counterparts who instead received placebo plus rituximab.
Indeed, the median PFS was 21.5 months for patients given copanlisib plus rituximab compared with 13.8 months for those given placebo plus rituximab, which translated into a significant 48% reduced risk of disease progression or death with the combination. The estimated 2-year PFS rates were 46% and 27%, respectively.
The PFS benefit offered by the addition of copanlisib to rituximab was evident across all histological subtypes, albeit without reaching statistical significance in lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia, which the presenter said may partly be due to the small sample size of this subgroup.
Adding copanlisib to rituximab also significantly improved the secondary endpoint of objective response rate (81 vs 48%), with once again significant improvements were observed in all histological subtypes except for lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia.
The median duration of response was also longer with the combination than rituximab alone (20.4 vs 17.3 months), albeit not significantly, and median overall survival was not yet reached at data cutoff.
Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 89.2% and 56.2% of patients in the combination and monotherapy arms, respectively. The most common events of this severity in both the combination and monotherapy groups were hyperglycaemia (56.3 vs 8.2%) and hypertension (39.7 vs 8.9%), but Matthew Matasar pointed out that “copanlisib-related hyperglycaemia and hypertension were infusion-related, typically transient and manageable.”
Pneumonitis was a prespecified AE of interest, but it only occurred in 6.8% and 1.4% of patients at any grade in the combination and monotherapy arms, respectively.
A total of 31.3% of combination-treated patients discontinued treatment due to a TEAE of any grade, as did 8.2% of those given rituximab alone. There were six grade 5 TEAEs in the copanlisib–rituximab group, although only one was considered related to study treatment, and one in the rituximab alone group.
“Copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad superior efficacy in combination with rituximab in all iNHL histologies”, summarised the presenter.
And he concluded that “copanlisib plus rituximab represents a new treatment option for patients with relapsed disease across all subtypes of iNHL.”
References
Abstract CT001. Matasar MJ, Capra M, Özcan M, et al. CHRONOS-3: Randomized Phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). AACR Annual Meeting 2021; 10–15 April.
Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol; Advance online publication 10 April 2021. DOI: 10.1016/S1470-2045(21)00145-5
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