Introduction: In the Phase III CHRONOS-3 trial investigating the efficacy and safety of the PI3K inhibitor copanlisib in combination with rituximab (C+R), superior efficacy in progression-free survival (PFS) was demonstrated vs placebo plus rituximab (P+R) in patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL; hazard ratio [HR] 0.52), including in the subset with follicular lymphoma (FL; HR 0.58) (data cut-off Aug 31, 2020) (Matasar et al. Lancet Oncol 2021). Here we report an updated 1-year follow-up analysis for the subset of pts with FL (data cut-off Aug 6, 2021).Methods: Eligible pts with relapsed iNHL who were progression- 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 C+R or P+R. Treatment continued until progression or unacceptable toxicity. C 60 mg flat dose was administered i.v. on days 1, 8, and 15 (28-day cycle) and R 375 mg/m2 i.v. 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. 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). As part of biomarker analysis, PTEN expression level was evaluated using immunohistochemistry.Results: The FL subset comprised 275 pts (184 C+R and 91 P+R). C+R reduced the risk of progression or death by 43% vs P+R; median PFS was 23.2 mo (95% confidence interval [CI] 19.2, 33.1) for C+R and 16.6 mo (11.0, 19.6) for P+R (HR 0.57 [95% CI 0.41, 0.80]. ORRs were 85% vs 56% for C+R vs P+R; CRRs were 38% vs 21%. Median DoR was 25.7 mo (17.2, 31.5) for C+R vs 18.2 mo (12.3, 26.3) for P+R (HR 0.75 [95% CI 0.49, 1.14]); for pts achieving a complete response, median DoR was not reached for C+R vs 24.7 mo (10.8, 29.7) for P+R (HR 0.41 [0.19, 0.87]), with DoR rates at 36 months 63% vs 23%. Median OS was not estimable, and no significant benefit was seen for C+R over P+R (HR 0.95 [95% CI 0.52, 1.74]). Hyperglycemia (76%), hypertension (54%), and decreased neutrophil count (38%) were the most common TEAEs in the C+R arm, consistent with the study population. Grade 5 events occurred in 5 pts (3%) in the C+R arm; 1 (1%) was deemed treatment-related. Of 119 pts with FL who were evaluable for PTEN analysis, 41 (34%) were positive. Percent PTEN positivity was not correlated to best overall response (p=0.44) or responsiveness (p=0.08). Median PFS was improved in PTEN-negative pts regardless of treatment. PTEN-positive pts had improved PFS with C+R vs P+R (p=0.005).Conclusion: Pts with FL from the CHRONOS-3 trial continued to show superior efficacy with C+R vs P+R and an acceptable safety profile 1 year after the primary disclosure, supporting the long-term use of C+R in pts with relapsed FL. Exploratory analysis suggests pts with PTEN-positive disease may experience significant benefit with C+R.

Citation Format: Marcelo Capra, Fangfang Lv, Wei Li, Tongyu Lin, Eduardo Yañez, Jifeng Feng, Aryan Hamed, Xiaoling Li, Toshiki Uchida, Ming-Chung Wang, Koji Izutsu, Antonio Salar, Katya Sapunarova, Guray Saydam, Jan Zaucha, Lidia Mongay Soler, Shalini Chaturvedi, Anjun Cao, Barrett H Childs, Pier Luigi Zinzani, Matthew J Matasar. Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A32.