Introduction:

Diffuse large B-cell lymphoma (DLBCL) is a genomically heterogenous disease, which can be classified into distinct subgroups or clusters (Chapuy et al., Nat. Medicine, 2018, Wright et al., Cancer Cell, 2020). Leveraging knowledge of genetic alterations to design novel personalized treatment strategies may improve outcomes. Preclinical data suggest that the pan-phosphoinositide 3-kinase (PI3K) inhibitor, copanlisib, plus the BCL-2 inhibitor, venetoclax, are synergistic in genetically defined, high-risk, subtypes of DLBCL (Bojarczuk et al., Blood, 2019). We therefore hypothesized that copanlisib plus venetoclax would be an active treatment for patients with relapsed/refractory DLBCL, particularly in those with perturbed B-cell receptor (BCR)/PI3K signaling, which were predicted to be enriched in the relapsed setting. Here, we report the results of a phase I study of copanlisib plus venetoclax for patients (pts) with R/R DLBCL.

Methods:

This is an investigator-initiated, phase I, multicenter trial (NCT04572763) with the primary objective of determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib and venetoclax in pts with R/R DLBCL. A standard 3+3 dose escalation design was employed, in which pts were treated with 60 mg IV copanlisib on days 1, 8, and 15 in addition to escalating doses of daily venetoclax for each 28-day cycle. During cycle 1, a venetoclax dose ramp-up was performed in the outpatient setting to a target dose of 200 mg (dose level (DL) +1), 400 mg (DL +2) and 800 mg (DL +3). The DLT observation period was the first cycle. Patients with progressive disease prior to the end of the DLT window were replaced. Key eligibility criteria included a confirmed diagnosis of DLBCL or high-grade B-cell lymphoma (HGBCL), relapse after or not a candidate for autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy, and adequate hematologic and organ function. Key exclusion criteria were poorly controlled hypertension or diabetes. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively.

Results:

As of July 21, 2023, 12 pts were evaluable. Patients were treated in DL +1 (n=5), DL +2 (n=3), and DL +3 (n=4). The median age was 62 years (range 24-87). Eighty three percent were male. Median number of prior treatments was 6 (range 1-11) and 10 pts had received prior CAR T-cell therapy. No DLTs were observed, though 2 pts in DL +3 were not able to escalate to 800 mg due to recurrent neutropenia and noncompliance, respectively. The most common toxicities were neutropenia (50%, all gr3/4), thrombocytopenia (42%, 8% ≥ gr3), nausea (33%, 8% ≥ gr3), fatigue (25%, 8% ≥ gr3), and headache (25%, 8% ≥ gr3) (Figure). Hyperglycemia occurred in 2 pts (both gr1). Serious adverse events occurred in 50% of pts and included fracture (n=1), hypoxia (n=2), and death (n=3), which were not related to study treatment. The deaths were related to progressive disease. Fifty percent of pts required drug holds (n=5 for venetoclax, n=5 for copanlisib). Sixty percent required growth factor support. There were no cases of laboratory or clinical tumor lysis syndrome. Sponsor support was withdrawn prior to completion of enrollment to DL+3, but DL+2 (copanlisib plus 400 mg venetoclax) was safe and well tolerated.

The overall response rate (ORR) and complete metabolic response (CMR) rate was 8% (90% CI: 0 - 34%), as 1 pt in DL +1, who had received >5 lines of prior therapy, achieved a CMR, with response lasting 3 months. The median follow-up was 9.1 months. The median overall survival (OS) and progression-free survival (PFS) were 3.5 and 1.8 months, respectively.

Conclusions:

Copanlisib plus venetoclax is feasible and safe in pts with R/R DLBCL, with no DLTs observed. While it is possible that copanlisib plus venetoclax is active in select genomic subgroups of DLBCL, there was limited activity in this unselected, heavily pre-treated patient population.

Crombie:Incyte: Consultancy; ADC therapeutics: Consultancy; Kite: Consultancy; Seagen: Consultancy; Roche: Research Funding; Genmab: Consultancy; Merck: Research Funding; Bayer: Research Funding; Abbvie: Research Funding; Karyopharm: Consultancy. Bartlett:ADC Therapeutics, Autolus, BMS/Celgene, Forty Seven, Gilead/Kite Pharma, Janssen, Merck, Millennium, Pharmacyclics, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Research Funding; ADC Therapeutics, Foresight Diagnostics, Kite, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Washington University School of Medicine: Current Employment. Merryman:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Merck: Research Funding; Intellia: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alphasights: Membership on an entity's Board of Directors or advisory committees. LaCasce:Research to Practice: Consultancy; Seagen, Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Jacobson:Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau; Precision BioSciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Daiichi Sanko: Consultancy, Honoraria; ImmPACT Bio: Consultancy, Honoraria; Instil Bio: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Ispen: Consultancy, Honoraria; Lonza: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support; Bristol Myers Squibb: Consultancy, Honoraria; Kite, A Gilead Company: Consultancy, Honoraria, Research Funding. Jacobsen:Merck: Honoraria, Research Funding; Celgene: Research Funding; Bayer: Honoraria; Pharmacyclics: Research Funding; UpToDate: Patents & Royalties; Hoffman-LaRoche: Research Funding; BMS: Honoraria; Daiichi: Honoraria. Herrera:Merck: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Allogene Therapeutics: Consultancy; AstraZeneca/MedImmune: Consultancy; BMS: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding; Genmab: Consultancy; Pfizer: Consultancy; Karyopharm Therapeutics: Consultancy; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Tubulis GmbH: Consultancy; Regeneron: Consultancy; Caribou Biosciences: Consultancy; Adicet Bio: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Research Funding. Davids:Mingsight Pharmaceuticals: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biosciences: Consultancy; Aptitude Health: Consultancy; BeiGene: Consultancy; BMS: Consultancy; Curio Science: Consultancy; Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; Surface Oncology: Research Funding; MEI Pharma: Research Funding; Secura Bio: Consultancy; ONO Pharmaceuticals: Consultancy; AbbVie: Consultancy, Research Funding. Shipp:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Abbvie: Research Funding. Armand:IGM: Research Funding; Kite - a Gilead company: Research Funding; Enterome: Consultancy; GenMab: Consultancy; ADC Therapeutics: Consultancy; Genentech/Roche: Consultancy, Research Funding; ATB Therapeutics: Consultancy; Foresight Diagnostics: Consultancy; Adaptive Biotechnologies: Research Funding; Xencor: Consultancy; MSD: Consultancy, Research Funding; Tessa Therapeutics: Consultancy; Regeneron: Consultancy; Affimed Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Shouse:Beigene, Inc.: Speakers Bureau; Kite Pharmaceuticals: Consultancy, Speakers Bureau.

The abstract will review the results of the phase I trial of venetoclax and copanlisib in DLBCL

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2023
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