A phase I, open-label, multicenter study to assess the safety, pharmacokinetics, and preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: Results from prostate cancer patients (NCT02740985).

Abstract

5518 Background: AZD4635 inhibits adenosine 2a receptor (A2aR) signaling and improves immune activation and anti-tumor activity in preclinical models. This phase I study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of AZD4635 monotherapy (mono) and in combination (combo) with durvalumab (durva) in patients (pts) with refractory solid tumors. Here we present data for immune checkpoint-naïve pts with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Pts with refractory mCRPC received AZD4635 mono (75 mg or 100 mg QD oral nanosuspension [(RP2D]) or in combination (75 mg or 100mg QD) with durva 1.5g IV q4wk. Results: Between 30Aug16 and 20Jun19 (data cutoff [DCO]) 94 mCRPC pts were treated with mono (n = 49) or combo (n = 45): median age 70.5 yrs; ECOG 0-1 = 99%. The median number of prior treatment regimens was 5 (range = 1-10); 61% of pts (57/94) had prior chemotherapy, 90% had prior new hormonal therapy. PK data suggest AZD4635 concentrations at 75-100 mg QD are above the in vitro IC50 for A2aR inhibition throughout the dosing interval. Modeling predicts 80-90% A2aR occupancy at steady state for doses at ≥75 mg QD. Most common treatment-related AEs ( > 10%) were nausea, vomiting, fatigue, decreased appetite, dizziness, and diarrhea. At the DCO in this ongoing study, 70 pts were evaluable for response by RECIST v1.1 (mono = 33, combo = 37). Confirmed response occurred in 8 pts: mono = ORR 6.1% (2PRs) and combo = 16.2% (2CRs, 4PRs). The duration of response across cohorts ranged from 1-18.5 mo (5 pts ongoing). PSA response (defined as ≥50% decrease from baseline of ≥1ng/ml) was observed in 6.4% (3/47 pts; 95% CI, 1.3-17.5) of mono-treated patients and 20% (9/45 pts; 95% CI, 9.6-34.6) of combo-treated patients. Patients with high adenosine (ADO) gene expression signature (N = 46) in peripheral blood, showed a median PFS of 21 weeks v. 8.7 weeks in ADO signature low patients (N = 46) (HR 0.5, CI 0.3-0.9) (DCO 20Jun19). In addition, baseline TCR clonality and diversity were linked with response. Conclusions: In mCRPC pts, AZD4635 alone or in combination with durva was tolerable and associated with clinical benefit. A mCRPC phase II trial is ongoing with continued exploration of predictors of response to treatment. Clinical trial information: NCT02740985 .

Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy

“…87 As opposed to Open access checkpoint inhibitor response, this score was highly predictive of improved outcomes to A2AR blockade in a cohort of patients with mCRPC. 88 In assessing all tumors within TCGA, the adenosine signaling signature has a wide range of expression; and as with AdenoSig, there does not appear to be a consistently elevated score among the cancer types best studied for response to A2AR inhibition (NSCLC, RCC, melanoma, mCRPC). 86 Again, elucidation of additional biomarkers will be crucial for more accurate interpretation of this genomic signature moving forward.…”

Influence of the Metabolism on Myeloid Cell Functions in Cancers: Clinical Perspectives

“…AZD4635 was assessed as monotherapy or combined with durvalumab in advanced solid tumors (Figure 1). Results from a highly pretreated metastatic prostate cancer patient cohort were reported at ASCO 2020 [138]. The molecule was associated with a good safety profile but modest efficacy, with an ORR of 6.1% as monotherapy and 16.2% in combination.…”

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

“…For instance, a phase I/II trial targeting CD38 (Isatuximab) and PD-1 (Cemiplimab) reported a manageable safety profile, reduction of CD38 + immune subsets in the tumor microenvironment, and enhanced activation of peripheral T cells, and that 20.8% and 65% of metastatic castration-resistant prostate cancer and non-small cell lung cancer (NSCLC) patients, respectively, achieved stable disease. 146 Phase I trials of CD73-targeting antibodies (Oleclumab) or A 2A AR antagonists (Ciforadenant, AZD4635) alone, or in combination with approved αPD-L1 checkpoint inhibitor antibodies (durvalumab, atezolizumab), showed manageable safety profiles, [147][148][149][150] and combination therapy of CPI-006 (αCD-73 antibody) and Ciforadenant was also well-tolerated. 151 Larger trials testing efficacy of A 2A AR inhibition and CD73 blockade are ongoing, and a dual A 2A AR/A 2B AR antagonist, etrumadenant, showed promising safety and PK/PD in a phase I clinical trial and is being evaluated further.…”