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4053 Efficacy of Copanlisib Monotherapy in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Subset Analysis from the CHRONOS-1 Trial

Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies
Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III
Monday, December 11, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Martin Dreyling, MD, PhD1, Panayiotis Panayiotidis, MD, PhD2*, Miklos Egyed, MD, PhD3*, George Follows, MA, PhD, FRCP, FRCPath, BM, BCh4*, Luigina Mollica, MD, PhD5*, Arnon Nagler, MD6, Muhit Ozcan, MD7, Armando Santoro, MD8*, Tatiane Ishida, MD9*, Cindy Lu, PhD10*, Florian Hiemeyer, MSc11*, Jose Garcia-Vargas, MD10*, Barrett H. Childs, MD10 and Pier Luigi Zinzani, MD, PhD12

1Department of Medicine III, University Hospital, LMU, Munich, Germany
2National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
3Kaposi Mor Teaching Hospital, Kaposvar, Hungary
4Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
5Maisonneuve-Rosemont Hospital Research Centre, Montreal, QC, Canada
6Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel
7Ankara University School of Medicine, Ankara, Turkey
8Humanitas Clinical and Research Center, Rozzano, Italy
9Bayer SA, Sao Paulo, Brazil
10Bayer HealthCare Pharmaceuticals, Whippany, NJ
11Bayer AG, Pharmaceuticals Division, Berlin, Germany
12Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy

Introduction: Marginal zone lymphoma (MZL) is an indolent B-cell malignancy which comprises approximately 10% of non-Hodgkin’s lymphomas. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. In the recent phase II CHRONOS-1 trial, treatment of patients with relapsed or refractory indolent B-cell lymphoma with copanlisib resulted in an overall response rate (ORR) of 59%. A total of 23 patients (16%) in the trial had MZL histology. We describe here a subset analysis of the MZL patients in CHRONOS-1 .

Methods: Patients enrolled into the CHRONOS-1 trial with MZL had to have relapsed after, or were refractory to ≥2 prior lines of treatment. Previous treatment had to include rituximab and an alkylating agent. Copanlisib was administered at a fixed dose of 60 mg via 1-hour I.V. infusion on an intermittent schedule days 1, 8 and 15 of a 28-day cycle. Treatment continued until progression or unacceptable toxicity. The subset analysis comprised 23 MZL patients (15 nodal, 4 splenic and 4 MALT lymphomas). Objective tumor response rate (ORR) after ≥4 cycles was assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007). Secondary efficacy endpoints included duration of response (DOR). Adverse events were assessed using the CTCAE (v4.03) coding.

Results: The 23 MZL patients, as assessed by the investigator, included 4 (17.4%) mucosa-associated lymphoid tissue (MALT) lymphoma, 15 (65.2%) nodal MZL and 4 (17.4%) splenic MZL. Median age was 69 years (range 39-81) and ECOG status 0 and 1 roughly similar (52% and 48%). Prior treatment included a median of 3 (range 2-9) lines of therapy, with 48% being refractory to the last regimen, and 44% refractory to last rituximab regimen. As of the data cutoff date of 20 February, 2017, patients had received a median of 5.8 cycles of treatment with a median duration of treatment of 23 weeks (range 1-138).

A total of 16 patients had an objective tumor response, for an ORR of 70%. Complete responses (CR) were observed in 3 (13%) patients, all with splenic MZL. Twelve of 15 (80%) patients with nodal disease had an objective tumor response and 1 of 4 (25%) with MALT had a response. The median DOR had not been reached, with the range being 1-728 days and 85% estimated to be in response at 9 months. Individual plots of tumor shrinkage over time for responders indicated rapid and prolonged responses (See Figure). The most common treatment-emergent AEs (all grade/grade 3+) for the entire CHRONOS-1 study population were transient hyperglycemia (50.7%/41.5%) and hypertension (30.3%/23.9%). Other AEs included decreased neutrophil count (31.7%/25.4%), diarrhea (33.8%/5.6%), lung infection (24.6%/16%), pneumonitis (7%/2.1%), and colitis (0.7%/0.7%). Laboratory toxicities of interest were principally grade-1, including elevated ALT (24.1% all-grade/20.6% grade-1) and AST (30.5% all grade/27% grade 1-2). In the MZL subset, there were no non-fatal opportunistic infections and no deaths attributed to copanlisib. However, there were 3 treatment-related deaths in the total patient population of the CHRONOS-1 study.

Conclusions: Copanlisib treatment of relapsed or refractory MZL patients resulted in a promising ORR of 70% and CR rate of 13% in this cohort of 23 patients. Responses were durable, with the median DOR having not yet been reached (85% were estimated to be in response at 9 months), higher than what has been previously reported in the MZL treatment landscape, warranting further study of copanlisib in MZL.

Figure: Time course for tumor shrinkage (per investigator assessment) for individual MZL patients achieving an objective tumor responses (per independent central review) while receiving copanlisib treatment.

Disclosures: Dreyling: Gilead: Consultancy, Speakers Bureau; Sandoz: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; MorphoSys AG: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ishida: Bayer SA: Employment. Lu: Bayer HealthCare Pharmaceuticals: Employment. Hiemeyer: Bayer AG, Pharmaceuticals Division: Employment. Garcia-Vargas: Bayer HealthCare Pharmaceuticals: Employment. Childs: 11. Bayer HealthCare Pharmaceuticals: Employment. Zinzani: Celgene: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Merck: Consultancy.

*signifies non-member of ASH