RADICAL Trial: A Phase Ib/IIa Study To Assess The Safety And Efficacy Of AZD4547 In Combination With Either Anastrozole Or Letrozole In ER Positive Breast Cancer Patients Progressing On These Aromatase Inhibitors (AIs).
Background: Patients with metastatic ER positive breast cancer invariably experience disease progression whilst taking AIs. Fibroblast growth factor receptor inhibitors (FGFRI) such as AZD4547 can reverse endocrine resistance in breast cancer cells. Consequently, we designed the RADICAL trial to test the safety and efficacy of AZD4547 combined with letrozole (L) or anastrozole (A). Methods: Patients with prior disease progression on either AI were initially recruited to a Phase Ib study which showed that L 2.5mg or A 1mg daily continuously could be safely combined with AZD4547 80mg twice daily on a 1wk on/1 wk off schedule. Pharmacokinetic data showed no significant interactions. Subsequently, 52 patients progressing on these AIs were recruited, either continuing, or, if other therapies had subsequently been given, restarting their prior AI together with AZD4547. Primary endpoint was change in tumour size (RECIST v 1.1) at 12 weeks compared to baseline. Results: Enrolled patients had previously received a median of 4 (range: 1-11) systemic therapies, including endocrine treatments with a median of 2 (range: 1-6). The mean tumour size change at 12 and 28 weeks was 7% (95%CI: -4%, 17%) and 8% (95%CI: -4%, 20%), respectively. Clinical benefit assessed by partial response (PR) or stable disease (SD) occurred in 36.5% (1 PR and 18 SD) and 25% (2 PR and 11 SD) of patients at 12 and 28 weeks, respectively. The median progression free survival was 3.1 months (95%CI: 2.4-5.4). Most adverse events (AEs) were G1/2 (95.3%). 11 (21%) patients developed asymptomatic AZD4547-induced retinal pigment epithelial detachment, all resolved and 1 and 6 were able to continue on study medication at full and half dose, respectively. Among 34 G3/4 AEs, only 6 were probably/possibly related to AZD4547. Out of 13 unrelated serious AEs, 2 were fatal. Conclusions: Combined AZD4547 with L or A appears to be safe and shows anti-tumour activity in advanced ER+ patients resistant to these AIs. Development of a biomarker to select patients for this therapy will facilitate future studies. Clinical trial information: NCT01791985.