Copanlisib and Rituximab Combination Therapy in iNHL: Chronos-3 Phase III Trial

Patients (pts) with indolent NHL (iNHL) treated with copanlisib plus rituximab (C+R) versus placebo plus rituximab (P+R) in Phase III CHRONOS-3 trial experienced a statistically significant increase in progression-free survival (PFS; hazard ratio [HR] 0.52; Matasar et al. Lancet Oncol 2021). By the data cut-off date (August 31, 2020), 23% of patients in the C+R arm were still receiving treatment, while 43% of patients in the P+R arm had stopped treatment and were in active follow-up. Here, using a data cutoff date of August 6, 2021, we report an updated analysis of the efficacy and safety at 1 year for all pts in CHRONOS-3.

Patients with iNHL who had relapsed after their last R-containing regimen and who had been progression-free and treatment-free for at least 12 months (mo), or at least 6 mo if they were unwilling or unable to receive chemotherapy were randomly assigned to receive either C+R or P+R in a 2:1 fashion. Informed consent was given by all pts. C 60 mg/P was given on days 1, 8, and 15 of cycle 1 and day 1 of cycles 3, 5, 7, and 9 of i.v. administration and R 375 mg/m2 were given on days 1, 8, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, and 9 of i.v. administration until progression or unacceptable toxicity. Overall survival (OS), objective response rate (ORR), duration of response (DoR), and complete response rate (CRR), as well as treatment-emergent adverse events (TEAEs), were secondary efficacy endpoints. The primary endpoint was progression-free survival (PFS).

There were 307 pts assigned to receive C+R and 151 pts assigned to receive P+R. There were 46 patients (15.0%) still in treatment with C+R and 16 patients (10.6%) in treatment with P+R as of the cutoff date in August 2021. Adverse events (AEs) unrelated to clinical progression accounted for 35.8% of C+R discontinuations and 49.7% of P+R discontinuations. The median progression-free survival (PFS) for C+R was 22.3 months (95% CI 19.4, 30.7) and 13.8 months (10.8, 17.5) for P+R (HR 0.53 [95% CI 0.41, 0.70]; p=0.000001], similar to the initial disclosure. Survival benefits were maintained across all cancer subtypes (HR [95% CI]): follicular lymphoma (n=275; 0.57 [0.41, 0.80]); marginal zone lymphoma (n=95; 0.53 [0.28, 0.99]); small lymphocytic lymphoma (n=50; 0.22 [0.10, 0.49]); lymphoplasmacytic/Waldenström macroglobulinemia (n=38; 0.42 [0.15, 1. C+R versus P+R had an updated ORR of 80.8% versus 49.7% and a CRR of 34.9% versus 14.6%.

Compared to the previous disclosure in August 2020, the risk of death was reduced (HR 0.86 [95% CI 0.55, 1.32]), but there was no significant benefit seen for C+R over P+R in terms of median OS (HR 1.07 [0.63, 1.82]). Patients who had complete responses had a median DoR of 42.3 months (29.2, not estimable) compared to 24.7 months (10.2, 29.7) for C+R and P+R, respectively (HR 0.46 [0.24, 0.87]). Hyperglycemia (69.4%), hypertension (49.5%), and diarrhea (33.9%) were the most common treatment-related AEs for patients receiving C+R, and the safety profiles for C+R and P+R were largely unchanged from the initial disclosure.

Six more pts (2.0%) stopped C due to an AE, bringing the total for C+R to 33.2%. No new grade 5 events occurred during the longer follow-up period, and the incidence of grade 3/4 treatment-related TEAEs was generally stable (2 new grade 4 for C+R; 1 new grade 4 for P+R). In patients with relapsed iNHL, C+R continued to show acceptable safety and superior efficacy with durable complete responses compared to P+R 1 year after the primary disclosure of CHRONOS-3. These findings lend credence to using C+R for the long haul in patients with relapsed iNHL.

source:https://library.ehaweb.org/eha/2022/eha2022-congress/357998/pier.luigi.zinzani.copanlisib.2B.rituximab.vs.rituximab.2B.placebo.in.patients.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26857%2Amarker%3D1769%2Afeatured%3D1766

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT02367040