Abstract P239: Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors
Authors: Carneiro Benedito A. , Jotte Robert , Gabrail Nashat , Hamid Omid , Huang Funan , Chaturvedi Shalini , Herpers Matthias , Soler Lidia Mongay , Childs Barrett H. , Hansen Aaron 
Published: December 2021

Abstract
Introduction: Copanlisib (C) is a pan-class I PI3K inhibitor, with predominant activity against the PI3K-α and -δ isoforms, approved for patients (pts) with relapsed follicular lymphoma. The PD-1 inhibitor nivolumab (N) is approved for several advanced or metastatic solid tumors. Following preclinical demonstration of the immunomodulatory activity of C (Glaeske et al. AACR 2018), we report Phase Ib results evaluating the safety and efficacy of C+N in pts with advanced solid tumors (NCT03735628). Methods: PD-1 inhibitor-naive adult pts with advanced solid tumors received C 45 mg or 60 mg i.v. (days 1, 8, and 15; 28-day cycle) and N 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles). The primary objective was determination of the recommended Phase II dose (RP2D) of C in combination with N. Secondary endpoints were safety/tolerability, pharmacokinetics (PK), and efficacy. Exploratory real-time evaluation of 77 pharmacodynamic and predictive immune cell biomarkers by flow cytometry on whole blood was performed. Results: 16 pts were treated (C 45 mg + N 240 mg, n=5; C 60 mg + N 240 mg, n=11). Median age was 65 years (range 37–89), 12 pts (75%) were male, and 8 pts (50%) had stage IV disease at diagnosis; the most common tumor types were head and neck squamous cell carcinoma (HNSCC; 7 pts) and bladder cancer (BC; 4 pts). No dose-limiting toxicities were reported. The RP2D of C+N 240 mg was 60 mg. As of 13 May 2020, 4 pts remain on treatment. The most common treatment-emergent adverse events (TEAEs) of any grade were hypertension and diarrhea (7 pts [44%] each, ≤ grade [G] 3) and maculo-papular rash and fatigue (6 pts [38%] each, ≤G3). C-related TEAEs were reported in 88% of pts, all ≤G3. AEs leading to C dose interruption/reduction were reported in 31%/19% of pts; TEAEs led to C discontinuation in 1 pt (60 mg; hematuria). Serious AEs occurred in 5 pts (31%). One G5 TEAE occurred (45 mg; general physical health deterioration, unrelated to C or N). No PK interactions were observed between C and N. Two pts had a partial response: 1 in the C 45 mg group (HNSCC) and 1 in the 60 mg group (BC; benefit sustained after 19 cycles). Stable disease was seen in 10 pts and disease progression in 3 pts; disease control rate (DCR) was 75%. Maximum decrease in circulating monocytic myeloid-derived suppressor cells (M-MDSCs; p&lt;0.05) from baseline occurred on day 2 after C, returning to baseline on day 8. A significant increase in activated (HLA-DR+ and CD38+) natural killer and CD8+ T cells was seen 2 weeks post-treatment with C+N. Lower baseline levels of CD8+ Teffector memory (TEM) subset CD45RA-/CCR7- (CD3+/CD8+) seemed to associate with higher DCR. Conclusions: C+N showed acceptable safety and preliminary efficacy in pts with advanced solid tumors. The immunomodulatory effect of C on M-MDSCs was seen 2 days post-treatment, and lower TEM subset levels seemed to associate with better disease control. These results support further investigation of C+N in pts with advanced solid tumors. Funding: Bayer AG. Writing support: Complete HealthVizion.
Citation Format: Benedito A. Carneiro, Robert Jotte, Nashat Gabrail, Omid Hamid, Funan Huang, Shalini Chaturvedi, Matthias Herpers, Lidia Mongay Soler, Barrett H. Childs, Aaron Hansen. Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P239.