Final safety and efficacy results of copanlisib monotherapy in patients with relapsed or refractory iNHL: 6-year follow-up of CHRONOS-1

Introduction: The phosphatidylinositol 3-kinase inhibitor copanlisib was approved for use in the US in 2017 as monotherapy in patients with relapsed follicular lymphoma (FL) who have progressed after ≥2 therapies based on results from the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) (Dreyling et al. J Clin Oncol 2017). Here, we describe efficacy and safety data at the 6-year follow-up. Methods: CHRONOS-1 enrolled patients with FL, marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and Waldenström macroglobulinemia/lymphoplasmacytoid lymphoma (WM/LPL) who had received ≥2 therapies. Copanlisib 60 mg was administered intravenously on days 1, 8, and 15 of a 28-day cycle. The primary efficacy endpoint was objective response rate (ORR) per independent radiologic review (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). CTCAE v4.03 was used to grade adverse events (AEs). Results: 142 patients with iNHL (104 FL, 23 MZL, 8 SLL, 6 WM/LPL, 1 other) received treatment. 99.3% of patients had discontinued treatment by the data cut-off (June 30, 2022). During follow-up, 74% of patients (n = 105) received ≥1 line of subsequent systemic anti-cancer therapy, including 46% of patients treated with rituximab-based regimens. ORR was 59.9% (n = 85) with complete responses in 23 patients (16.2%). Median DoR was 14.9 months (mos) (range 0–80.6). With a median follow-up of 14 mos (95% confidence interval [CI] 10.3, 20.7), median PFS was 11.3 mos (range 0–82.1) with a 2-year PFS rate of 33%. With a median follow-up of 82.3 mos (95% CI: 79.3, 84.2), median OS was 59.1 mos (73 events, range 0.2–100.6) with a 6-year OS rate of 45% (Figure). Median duration of treatment was 6.0 mos (range 0.23–81.0). Transformation to aggressive lymphoma (diffuse large B-cell lymphoma) was not observed. Treatment was discontinued primarily due to radiologic disease progression (35.2%; n = 50) and AEs not associated with clinical disease progression (28.2%; n = 40). Copanlisib safety data were consistent with the 2-year follow-up (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent AEs (all grades/grades 3–4) were infusion-related hyperglycemia (50.7%/39.4%), diarrhea (35.9%/8.5%), hypertension (29.6%/23.9%), neutropenia (29.6%/24.7%), and pyrexia (26.8%/4.2%). The research was funded by Bayer AG with medical writing and editorial assistance from Complete HealthVizion Keyword: Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. M. Dreyling Consultant or advisory role: AstraZeneca, BeiGene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche Honoraria: AstraZeneca, BeiGene, Gilead/Kite, Janssen, Roche, Lilly, Novartis Research funding: AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche A. Santoro Consultant or advisory role: BMS (BRISTOL MYERS SQUIBB)/SERVIER/GILEAD/PFIZER/EISAI/BAYER/MSD (MERCK SHARP & DOHME), SANOFI/ INCYTE Other remuneration: Speaker's Bureau: TAKEDA/BMS/ROCHE/ABB-VIE/AMGEN/CELGENE/SERVIER/GILEAD/ASTRAZENECA/PFIZER/LILLY/SANDOZ/EISAI/NOVARTIS/BAYER/MSD S. Leppä Consultant or advisory role: Gilead Sciences, Novartis, Roche, BeiGene, Orion Clinical, Incyte, Pfizer, SOBI Honoraria: Gilead Sciences, Novartis, Incyte Research funding: Roche, Bayer, Celgene, Novartis, Genmab, Hutchison MediPharma G. A. Follows Consultant or advisory role: AbbVie, Roche, Janssen, AstraZeneca, Lilly, Centessa Honoraria: AbbVie, Roche, Janssen, AstraZeneca, Lilly Educational grants: Takeda G. Lenz Employment or leadership position: President elect German Lymphoma Alliance, Board of director German Lymphoma Alliance Consultant or advisory role: Roche, Janssen, Celgene, AstraZeneca, BMS, AbbVie, MorphoSys, Karyopharm, ADC, PentixaPharm, Hexal/Sandoz, Genase, Gilead, Bayer, Novartis, Takeda, NanoString, Incyte, Genmab, Constellation, Miltenyi, Sobi, Immagene, Lilly Honoraria: Roche, Bayer, Takeda, AbbVie, MorphoSys, Hexal/Sandoz, Janssen, Celgene, BMS, Incyte, Sobi Research funding: Roche, Gilead, Janssen, AstraZeneca, Bayer, Celgene, Novartis, MorphoSys Educational grants: Janssen, BMS, AbbVie P. Panayiotidis Other remuneration: Bayer AG, clinical trial support M. Özcan Research funding: AbbVie, Bayer, Janssen, Roche, Takeda, MSD, Pfizer, Acerta Educational grants: AbbVie M. Kosinova Other remuneration: Bayer AG, clinical trial support M. Provencio Consultant or advisory role: AstraZeneca, Bristol Myers Squibb Company, Eli Lilly, F. Hoffmann-La Roche, Janssen Global Services, LLC, Laboratorios Pfizer Ltda., Merck, Takeda Oncology. Research funding: Boehringer Ingelheim, Bristol Myers Squibb Company, F. Hoffmann-La Roche, Pierre Fabre Pharmaceuticals, Inc., Takeda Oncology. Educational grants: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb Company, Eli Lilly, F. Hoffmann-La Roche, Pierre Fabre Pharmaceuticals, Inc., Other remuneration: PATENTS, ROYALTIES, OTHER INTELLECTUAL PROPERTY: P201731067. Prognosis methods for patients with folicular lymphoma. España. 16/05/2017. FIBHUPH; PCT/ES2018/070463. Method for designing J. Munoz Consultant or advisory role: Pharmacyclics/AbbVie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosun Kite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, BeiGene, Servier, Novartis, MorphoSys/Incyte, MEI, Zodiac, TG Therapeutics, Lilly/Loxo Honoraria: Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics Research funding: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium Other remuneration: Speaker's Bureau: Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, BeiGene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche A. Cao Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. F. Hiemeyer Employment or leadership position: Bayer AG F. Odongo Employment or leadership position: Bayer SA J. Garcia-Vargas Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. B. H. Childs Employment or leadership position: Bayer HealthCare Pharmaceuticals, Inc. P. L. Zinzani Consultant or advisory role: SECURA BIO, CELLTRION, GILEAD, JANSSEN- CILAG, BMS, SERVIER, SANDOZ, MSD, ASTRAZENECA, TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, ADC Therap., Incyte, BeiGene Other remuneration: Speaker's Bureau: CELLTRION, GILEAD, JANSSEN- CILAG, BMS, SERVIER, SANDOZ, MSD, ASTRAZENECA, TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, ADC Therap., Incyte, BeiGene