Phase 1a/b, Open-label, Multicenter Study of AZD4635 (an Adenosine 2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

PURPOSE: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors.

EXPERIMENTAL DESIGN: In phase 1a (dose escalation), patients had relapsed/refractory solid tumors; in phase 1b (dose expansion), patients had checkpoint-inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma (CRC); non-small cell lung cancer (NSCLC) with prior anti-PD-1/PD-L1 exposure; or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg QD or 125 mg BID) or in combination with durvalumab (AZD4635 75 or 100 mg QD). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in mCRPC patients.

RESULTS: As of September 8, 2020, 250 patients were treated (AZD4635, n=161; AZD4635+durvalumab, n=89). In phase 1a, DLTs were observed with monotherapy (125 mg BID; n=2) and with combination treatment (75 mg; n=1) in patients receiving nanosuspension. The most common treatment-related AEs included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg QD, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule QD. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and PSA responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median PFS of 21 weeks versus 8.7 weeks.

CONCLUSIONS: AZD4635 monotherapy or combination therapy was well-tolerated. Objective responses support additional phase 2 combination studies in mCRPC patients.