P1138: COPANLISIB + RITUXIMAB VS RITUXIMAB + PLACEBO IN PATIENTS WITH RELAPSED INDOLENT NON-HODGKIN LYMPHOMA (NHL): UPDATED SAFETY AND EFFICACY FROM THE PHASE III CHRONOS-3 TRIAL

Abstract

Background: The Phase III CHRONOS-3 trial of copanlisib plus rituximab (C+R) vs placebo plus rituximab (P+R) in patients (pts) with indolent NHL (iNHL) showed a significant improvement in progression-free survival (PFS; hazard ratio [HR] 0.52; Matasar et al. Lancet Oncol 2021). At the time of data cut-off (August 31, 2020), 23% of pts were ongoing on treatment in the C+R arm and 43% of pts had discontinued treatment and entered active follow-up; corresponding numbers in the P+R arm were 19% and 17%. Aims: Here we report an updated 1-year follow-up analysis of efficacy and safety for all pts from CHRONOS-3 based on a data cut-off of August 6, 2021. Methods: Eligible pts with iNHL who relapsed after the last R-containing regimen and were progression-free and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to receive C+R or P+R. All pts provided informed consent. Treatment continued until progression or unacceptable toxicity and was administered i.v. on a 28-day cycle, with C 60 mg/P given on days 1, 8, and 15 and R 375 mg/m2 given on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS and secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). Results: 307 pts were randomized to C+R and 151 to P+R. As of the August 2021 cut-off, 46 pts (15.0%) receiving C+R and 16 (10.6%) receiving P+R were ongoing on treatment. The most common reason for discontinuation was adverse events (AEs) unrelated to clinical progression (35.8%) for C+R and radiologic progression (49.7%) for P+R. Similar to the initial disclosure, C+R reduced the risk of progression or death vs P+R by 47%, with median PFS of 22.3 mo (95% confidence interval [CI] 19.4, 30.7) for C+R and 13.8 mo (10.8, 17.5) for P+R (HR 0.53 [95% CI 0.41, 0.70]; p=0.000001). PFS benefit was preserved 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, 1.16]). Updated ORRs were 80.8% vs 49.7% and CRRs were 34.9% vs 14.6% for C+R vs P+R, respectively. Median OS was not estimable and no significant benefit was seen for C+R over P+R, although the risk of death was reduced (HR 0.86 [95% CI 0.55, 1.32]) vs the August 2020 disclosure (HR 1.07 [0.63, 1.82]). Median DoR was 25.7 mo (17.6, 31.5) for C+R vs 17.3 mo (12.6, 25.3) for P+R; for pts with complete responses, median DoR was 42.3 mo (29.2, not estimable) vs 24.7 mo (10.2, 29.7) (HR 0.46 [0.24, 0.87]). Safety profiles for C+R and P+R were mostly unchanged from the initial disclosure, and the most common treatment-related AEs for pts receiving C+R were hyperglycemia (69.4%), hypertension (49.5%), and diarrhea (33.9%). For C+R, 6 additional pts (2.0%) discontinued C due to an AE, bringing the total to 33.2%. The incidence of grade 3/4 treatment-related TEAEs was generally unchanged with the longer follow-up (2 new grade 4 for C+R; 1 new grade 4 for P+R), with no new grade 5 events. Summary/Conclusion: 1 year after the primary disclosure of CHRONOS-3, C+R continued to demonstrate acceptable safety and superior efficacy with durable complete responses vs P+R in pts with relapsed iNHL. These data support the long-term use of C+R in pts with relapsed iNHL.