Abstract B105: Phase IB combination study of copanlisib and nivolumab in advanced solid tumors and lymphomas

Background: The PI3K pathway is frequently dysregulated in cancer, promoting tumorigenesis by facilitating aberrant cell growth, blocking apoptotic signaling, and suppressing immune surveillance in the tumor microenvironment (TME). The TME contains regulatory immune cells such as FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells, M2 macrophages, and N2 neutrophils, maintaining an immunologically isolating sheath. PI3K inhibition has been shown to slow tumor growth by inducing apoptosis and sensitizing tumors to T cell-mediated cytotoxicity. Copanlisib is a potent PI3K inhibitor, and combination with the PD-1 checkpoint inhibitor nivolumab is hypothesized to result in robust anti-tumor T cell responses. Materials and Methods: Open label phase I trial of copanlisib and nivolumab following a 3+3 design with an expansion phase at the maximally tolerated dose (MTD). Flat-dose nivolumab is administered intravenously (IV) on day 1 while copanlisib is administered IV weekly on days 1, 8 and 15 of a 28-day cycle; there is a 2-week copanlisib run-in during cycle 1 (expansion phase) to enable assessment of pharmacodynamic (PD) endpoints. Prior checkpoint inhibitor therapy is not permitted. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses are assessed by CT using RECIST 1.1 and iRECIST. Exploratory PD objectives include assessments on blood and tissue samples collected at baseline and post copanlisib -/+ nivolumab treatment; these studies will evaluate immune cell populations, PD-1/PD-L1 levels, markers of T cell activation/inhibition (Zap70 pY493 and SHP2 pY542), and apoptosis biomarkers using validated immunofluorescence and flow cytometry assays. Results: As of July 2019, 16 pts have been enrolled with 6 pts in the expansion phase; 14 pts are evaluable for toxicity. The MTD for the combination is copanlisib 60 mg days 1, 8 and 15 plus nivolumab 480 mg day 1 (recommended doses for each individual agent, 28-day cycles); no DLTs were identified. Median age on study is 62 (range 38-77). One pt (rectal cancer) has experienced a confirmed partial response (PR), and 4 pts have achieved stable disease (SD; 1 pt remains on study ≥10 months). Five pts are too early to assess for response. Tissue for molecular analysis and/or genomic sequencing has been collected for all patients. Adverse events include: grade 3 hypertension (1 pt, requiring dose reduction) and infusion-related reaction (hypertension, 1pt); grade 1/2 events include hypertension (7 pts), hyperglycemia (5 pts), nausea (5 pts) and infusion-related reaction (hypertension, 4 pts). Preliminary PD assessments show increases in the number of CD8+ T cells in peripheral blood samples after treatment, with changes in phospho-biomarkers of T cell activation (Zap70-pY493 and SHP-pY542). Conclusions: The combination is tolerable using the approved doses of each individual agent and shows treatment-induced immune PD changes as well as early anti-tumor activity. Enrollment at the expansion stage is ongoing (NCT03502733). Funded by NCI Contract No. HHSN261200800001E. Citation Format: Geraldine O9Sullivan Coyne, Timothy A Yap, Nancy Moore, Arjun Mittra, Naoko Takebe, Lamin Juwara, Sabrina Khan, Ecaterina Ileana Dumbrava, Howard Streicher, Richard Piekarz, Elad Sharon, Funda Meric-Bernstam, Ralph Parchment, Tony Navas, King Leung Fung, James Mitchell, Kristin Fino, Sandra Montez, Austin Doyle, Laurence Rubinstein, James H Doroshow, Alice P Chen. Phase IB combination study of copanlisib and nivolumab in advanced solid tumors and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B105. doi:10.1158/1535-7163.TARG-19-B105