P1.04-32 Phase I/II Study of the A2AR Antagonist NIR178 (PBF-509), an Oral Immunotherapy, in Patients (pts) with Advanced NSCLC

Abstract

Background: ATP is catabolized to adenosine in the tumor microenvironment, leading to excess adenosine and immunosuppressive effects via immune checkpoint protein adenosine 2A receptor (A2AR). NIR178 is an oral A2AR antagonist that selectively binds and inhibits A2AR, reactivating T cell-mediated antitumor immune response. This Phase I/II study evaluated NIR178 in previously treated pts with advanced NSCLC (NCT02403193). Method: Pts (ECOG PS 0-1) had received 1 prior line of therapy; EGFR/ALK pts had failed prior TKI therapy. Objectives: primary e determine MTD of single-agent NIR178; secondary e efficacy endpoints, PK, and evaluation of PD-L1 expression. Result: At 13 Dec 2017 data cut-off, 24 pts had been treated: median age 68 yrs, 46% male; 79% received prior immunotherapy; 22/24 (92%) pts had discontinued (due to progression [n¼13], death [n¼2], AEs [n¼2] or other reasons [n¼5]) and 2/24 (8%) pts remained on treatment. Dose levels evaluated: 80 (n¼3), 160 (n¼3), 320 (n¼7), 480 (n¼6), 640 mg BID (n¼5). There was 1 DLT: Gr 3 nausea (640 mg). The most frequent (20%) any-Gr AEs regardless of causality were nausea (67%), fatigue (63%), dyspnea (46%), vomiting (33%), chest pain and other (29%), gastroesophageal reflux disease, anemia, diarrhea (all 25%), anorexia, back pain, generalized muscle weakness and cough (all 21%). Drug-related Gr 3 AEs were pneumonitis (8%) and nausea (4%); no Gr 4 AEs were reported. Potential immune-related any-Gr AEs were rash (8%), pneumonitis (8%), hypothyroidism, increased ALT/AST (all 4%). NIR178 systemic exposure (Cmax, AUC) increased more than proportionally with dose. Efficacy data for 17/24 treated pts demonstrated responses and SD across the dose range, including 1 confirmed CR (480 mg) and 1 PR (80 mg), both in immunotherapynaïve pts. Durable SD >44 wks with tumor shrinkage was observed in 2 ongoing immunotherapy-exposed pts. Disease control was seen in pts with both high and low baseline PD-L1 expression. Conclusion: NIR178 was well tolerated; AEs were manageable and there were no Gr 4 drug-related AEs. Immune-related AEs may indicate immune stimulation. Clinical benefit was observed in immunotherapy-exposed and -naïve pts irrespective of PD-L1 status.

Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies

“…在临床试验阶段，靶向CD39或CD73的单克隆抗体和小分子抑制剂也有显著的治疗效果。CD39抑制剂ES002023通过稳定细胞外ATP和抑制肿瘤微环境内腺苷的合成来恢复抗肿瘤免疫（NCT05075564）。CD73选择性抑制剂AB680具有良好的药代动力学特性，已进入Ⅰ期临床试验。在一项Ⅰb/Ⅱ期临床试验（NCT03381274）中，抗CD73单克隆抗体MEDI9447联合酪氨酸激酶抑制剂奥希替尼在既往接受治疗的晚期EGFR突变NSCLC患者中具有中等活性和可接受耐受性 ［ 79 ］ 。目前，进入临床试验的A2aR抑制剂有CPI-444、NIR178、AZD4635等。一项Ⅰ/Ⅱ期临床试验（NCT02403193）显示，24例晚期NSCLC患者对NIR178具有良好的耐受性，不良反应可控且无第四级药物相关不良事件 ［ 80 ］ 。…”

Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

“…Oral administration of PBF-509 (15 or 30 mg/kg/day) significantly reduced the tumor burden of mice in both models [18]. A phase I/II study of PBF-509 both alone and in combination with anti-PD-1 mAb PDR001 in non-small cell lung cancer patients was started in October 2015 (NCT02403193); the results showed that the compound was well tolerated, and clinical benefit was observed in immunotherapy-exposed and -naive patients, irrespective of the PD-L1 status [62].…”