Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors

Abstract

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

Patients and methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer 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 once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC.

Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, 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 once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks.

Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Figure 1.

Patient flow diagram. ^aDurvalumab was administered at 1,500 mg, once every 4 weeks. Combo, combination therapy; DCO, data cutoff; Durva, durvalumab; IO, immune-oncology therapy; Mono, monotherapy; n, number; QD, once per day; R/R, relapsed/refractory. Patient numbers are based on actual treatment received.

Figure 2.

A–C, Best percentage change from baseline in phase Ia patients with measurable disease at baseline (A); best percentage change from baseline in patients with mCRPC and measurable disease at baseline (B); and PSA responses relative to baseline over time in patients with IO-naïve mCRPC treated with AZD4635 + durvalumab (C). Durva, durvalumab; IO, immune-oncology therapy; Mono, AZD4635 monotherapy; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1. Best objective response was based on the investigator-assessed RECIST v1.1 response at each tumor assessment. Target lesion sum of diameters are scaled up if ≤1/3 of measurements are missing. If >1/3 of measurements are missing, then the percentage change is not calculated. * and Δ indicate that the patient is still on treatment. Percentage change from baseline in tumor lesion size exceeds + 100%; waterfall plot was truncated for the patient at this point. PSA response is defined as ≥50% reduction from baseline. Spider plot is truncated for some patients where PSA relative to baseline exceeds 5.

Figure 3.

Time from first dose to end of treatment for IO-naïve patients with mCRPC for monotherapy cohort (A), and combination cohort (B) (safety analysis set). CR, complete response; IO, immune-oncology therapy; PR, partial response.

Figure 4.

Progression-free survival for patients with mCRPC by treatment (A), and by adenosine level (B) (efficacy analysis set). CI, confidence interval; combo, AZD4635 plus durvalumab combination therapy; Durva, durvalumab; HR, hazard ratio; IO, immune-oncology therapy; Mono, AZD4635 monotherapy. Patients not known to have died or progressed are censored at their last evaluable investigator overall response assessment. The plots are truncated at week 75. Two patients in the adenosine high group and the adenosine low group remained progression free after week 75.