Abstract CT119: CPI-444, an oral adenosine A2a receptor (A2aR) antagonist, demonstrates clinical activity in patients with advanced solid tumors

Abstract

Abstract Background: Accumulation of extracellular adenosine in the tumor microenvironment activates A2aR suppressing anti-tumor immunity. CPI-444 is an oral, selective A2aR antagonist with single agent (SA) antitumor efficacy in mouse models, and the addition of anti-PD-1/PD-L1 antibodies leads to synergistic anti-tumor activity. CPI-444 was well-tolerated in previous clinical trials in the non-oncology setting. This phase 1/1b open-label clinical trial uses a 2-step adaptive design to evaluate CPI-444 alone and in combination with atezolizumab (atezo, Tecentriq®) in patients(pts) with advanced cancers. Preliminary efficacy and safety results in the dose selection phase (Step 1) are reported. This is the first report of adenosine inhibition as a treatment for cancer. Methods: Adult pts who have failed up to 5 standard therapies with advanced solid tumors were enrolled. In Step 1, pts were randomized 1:1:1:1 to 1 of 4 dose cohorts (28 days/cycle) including 3 SA cohorts (100mg BID x 14 days(d), 100mg BID x 28d and 200 mg QD x 14d) or combined with atezo (CPI-444 50mg or 100 mg BID x 14d + atezo 840mg IV q2 weeks). Primary objectives: safety and efficacy and defining the optimal dose and schedule of CPI-444. Results: 48 pts were enrolled in Step 1; 47 received treatment. Median age was 65 years (range, 36-84).Tumor types enrolled were: non- small cell lung cancer(NSCLC, n=10), triple negative breast cancer (TNBC,n=10),melanoma(MEL,n=7), urothelial bladder cancer(UBC,n=6), renal cell cancer(RCC,n=5), MSI-H colorectal cancer(CRC,n=4), head and neck cancer (SCCHN, n=3)and prostate cancer (n=2). Median number of prior systemic regimens was 4(range, 1-5). Twenty-four pts received prior anti PD-1/PD-L1 therapy. One pt in the combination cohort had reversible grade 3 autoimmune hemolytic anemia which was the only DLT observed. Biomarker analyses defined the optimal dose of CPI-444 as 100 mg bid x 28 days. With a median follow-up time of 12 weeks(range, 2-32), the overall disease control rate (DC defined as CR, PR or SD) was 45% per RECIST. Nineteen pts had SD;15 pts received SA CPI-444. Two pts had a PR; both received SA. Of 5 RCC pts enrolled, 4 had DC (1 PR, 3 SD). Of these 4 RCC pts, 3 are receiving SA CPI-444 including the patient with PR. These 4 RCC pts remain on treatment with 2 pts on treatment for > 30 weeks. Of 7 MEL pts, 1 pt receiving SA had a PR and 2 had SD. SD was observed in 5/10 NSCLC pts, 4/10 TNBC pts, as well as 2/6 UBC pts and 1 pt each with CRC, SCCHN and prostate cancer. The proportion of pts with DC were similar for pts treated with CPI-444 alone and for pts treated with CPI-444 combined with atezo. 9/18(50%) pts who were naïve to anti-PD-1/PD-L1 treatment achieved DC as well as 10/24(42%) of pts who were resistant/ refractory to anti-PD1/PDL1 therapy. The most common (≥ 10% of pts) adverse events related to study drug were Grade 1 or 2 nausea (13%) and fatigue (19%). Conclusion: Inhibition of adenosine signaling through the A2aR results in anti-tumor activity in pts with advanced solid tumors. Responses are observed in multiple histologies both as a SA and in combination with atezo and in pts naïve or resistant/refractory to anti-PD-1/PD-L1 therapy. The optimal dose is 100 mg bid continuous. Enrollment in Step 2, evaluating disease-specific cohorts, is ongoing. Citation Format: Leisha Emens, John Powderly, Lawrence Fong, Joshua Brody, Patrick Forde, Matthew Hellmann, Brett Hughes, Shivaani Kummar, Sherene Loi, Jason Luke, Daruka Mahadevan, Benjamin Markman, Ian McCaffery, Richard Miller, Ginna Laport. CPI-444, an oral adenosine A2a receptor (A2aR) antagonist, demonstrates clinical activity in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT119. doi:10.1158/1538-7445.AM2017-CT119