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  • The AURA trial was a

    2019-08-21

    The AURA trial was a phase I/II study evaluating the safety, tolerability and activity of Osimertinib in patients with EGFR-mutated NSCLC progressing after a previous EGFR TKI. The phase I component of the study included a dose escalation part (Osimertinib 20mg to 240mg), using a rolling six design, and an expansion part with multiple biomarker-guided cohorts of patients. Before enrollment in the expansion cohort, the T790M status of the tumor was mandatory. The recommended phase II dose (RP2D) was 80mg once daily. The phase II (extension part) component of the study enrolled T790M+ NSCLCs progressing on a previous EGFR TKI at the dose of 80mg/d. A total of 253 patients (31 in the dose-escalation cohorts and 222 in the expansion cohort) were enrolled. EGFR T790M was detected in 62% of patients enrolled in the expansion cohort (Jänne et al., 2015). A maximum tolerated dose (MTD) was not found, however at the 160mg and 240mg dose levels there were an increase in the incidence and severity of adverse events (AEs) associated with EGFR wild type inhibition (namely, Xylazine HCl and gastrointestinal AEs), therefore the dose of 80mg once daily was considered the RP2D dose. Of the 239 patients evaluated for response 51% had PR or CR, 33% SD and 14% PD. The disease control rate (DCR) was 84% (95% CI, 79–88). Among patients with EGFR T790M, the objective response rate (ORR) was 61% (78 of the 127 patients; 95% CI, 52–70), and the DCR was 95% (121 of the 127 patients; 95% CI, 90–98). Although the data published were immature, the median PFS was 8.2 months in the overall population, 9.6 months in the T790M+ group (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1–4.3) in patients with no detectable EGFR T790M (Jänne et al., 2015). These promising results were recently confirmed in the updated analysis of the phase I expansion cohort and the pooled analysis of the phase II studies AURA extension and AURA2, evaluating Osimertinib at 80mg/daily in T790M+ TKI-pretreated NSCLCs. Osimertinib was associated with a 71% and 66% ORR, 9.7 months and 11.0 months PFS, respectively. The safety profile was relatively favorable with the most common AEs being skin rash (37–41% of all grades, 0–1% G3/4) and diarrhea (35–38% of all grades, 1–2% G3/4) (Yang et al., 2016a). Moreover, quality of life (QoL) analysis of the AURA2 trial revealed a significant improvement in functioning and health status/QoL from baseline assessments up to the first 36 weeks (Rudell et al., 2016). The intriguing preclinical intracranial activity of Osimertinib prompted the development of the phase I BLOOM trial, evaluating Osimertinib and AZD3759 in EGFR-mutated NSCLC patients with BMs and LMs. At the recent 2016 ASCO annual meeting, the preliminary results of the Cohort 1 of the study (EGFR-mutated NSCLCs with LMs) were presented, reporting a promising activity with Osimertinib 160mg/d in this unfavorable prognostic subgroup of patients (Yang et al., 2016b). The Cohort 2 of the study is enrolling T790M+ NSCLC patients with LMs. Osimertinib is being evaluated in multiple clinical trials across different settings and combinations, to understand its potential benefit for overcoming newly identified forms of resistance. The ongoing phase III trials are summarized in Table 1. On 13 November 2015, Osimertinib received FDA approval for patients carrying a T790M mutation and whose disease has progressed after treatment with other EGFR TKI, followed by EMA approval on 2 February 2016, making Osimertinib the first new drug approved under the EMA expedited process (Osimertinib, 2016)
    Rociletinib (CO-1686) Rociletinib is a potent 2,4-disubstituted pyrimidine molecule that covalently modify the Cys797 in the ATP-binding pocket of the EGFR kinase domain. Studies conduced in vitro demonstrated that CO-1686 is a potent inhibitor of L858R/T190M and approximately 22-fold more selective than wild type EGFR. Twenty-three targets inhibited more than 50% at 0.1μmol/L; EGFR del19-, T790M-, L858R/T790M-, and L858Rmutant kinases have the highest degree of inhibition, however, other kinase targets were observed to be inhibited at lower potency, including focal adhesion kinase (FAK), CHK2, ERBB4, and Janus-activated kinase 3 (JAK3) (Walter et al., 2013, Tjin Tham Sjin et al., 2014).