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.

BACKGROUND

Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

METHODS

CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m

FINDINGS

Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.

INTERPRETATION

Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

FUNDING

Bayer.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests MJM reports consultancy with Bayer, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, ImmunoVaccine Technologies, Juno Therapeutics, Merck, Rocket Medical, Seattle Genetics, Takeda, Teva, and TG Therapeutics; honoraria from Bayer, F Hoffmann-La Roche, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Seattle Genetics, Takeda, and TG Therapeutics; and research funding from Bayer, F Hoffmann-La Roche, Genentech, GlaxoSmithKline, IGM Biosciences, Janssen, Pharmacyclics, Rocket Medical, and Seattle Genetics. MÖ reports research funding from AbbVie, Archigen Biotech, Bayer, Celgene, F Hoffmann-La Roche, Janssen, MSD, and Takeda; travel support from AbbVie, Amgen, Bristol Myers Squibb, F Hoffmann-La Roche, Janssen, and Takeda; honoraria from Amgen and Takeda; and other financial relationships with Abdi İbrahim, Jazz Pharmaceuticals, and Sanofi. WJ reports research funding from Bayer, Gilead, MEI Pharma, and TG Therapeutics. RB reports clinical trial support from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CSL Behring, Daiichi Sankyo, Janssen-Cilag, MorphoSys, Pfizer, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; institutional research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Portola, Takeda, and Technoclone; and clinical advisory board participation with Janssen-Cilag and Roche. KG reports honoraria for advisory boards from Amgen, Celgene, Novartis, Ratiopharm, and Roche. TU reports personal fees from Bristol Myers Squibb, Celgene, Chugai Pharmaceutical, Eisai, Janssen, Kyowa Kirin, Mundipharma, Nippon Shinyaku, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, and Takeda. LMS, AC, AM, and BHC are employees of Bayer HealthCare Pharmaceuticals. FH is an employee of Bayer. PLZ reports honoraria from AbbVie, ADC Therapeutics, Bristol Myers Squibb, EUSA Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, MSD, Roche, Servier, Takeda, TG Therapeutics, and Verastem; board of directors or advisory committee memberships with AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Sandoz, Servier, Takeda, and Verastem; speakers' bureau involvement with AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Servier, Takeda, TG Therapeutics, and Verastem; consultancy for EUSA Pharma, Janssen, MSD, Sanofi, and Verastem; and research funding from Portola. All other authors declare no competing interests.