Pharmacokinetics (PK)

Osimertinib demonstrated good bioavailability, was widely distributed in tissues and had moderate clearance resulting in a half-life of around 3 h after oral dosing in the mouse. Preliminary clinical PK analysis on a small number of NSCLC patients indicated that osimertinib and its active metabolites, AZ5104 and AZ7550, have a half-life of at least 50 h, longer than would be predicted from the preclinical data, which resulted in a desirable flat PK profile after multiple once daily dosing.65


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Key secondary endpoint of the Phase I AURA study, enrolling EGFR-mutated NSCLC patients who had developed resistance to treatment with EGFR TKIs, included determination of the PK of osimertinib. Patients in the dose-escalation cohorts received a single dose of osimertinib (in capsule form, from 20 to 240 mg once daily) followed by a PK evaluation period; after 7 days, they received the same oral dose daily, with additional PK assessment after daily continuous dosing. PK analyses showed that osimertinib exposure, maximal plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner across the range from 20 to 240 mg after single and multiple doses, thus exhibiting linear PK.67

The PK of osimertinib was extensively characterized following a single-dose administration in healthy volunteers and advanced NSCLC patients of the AURA trial following single- and multiple-dose administration. The PK profiles between patients and healthy volunteers appeared similar, although there was an apparent higher clearance in healthy volunteers. Absorption was slow, regardless of formulation (capsule, solution or tablet). The median time to maximum plasma concentration (Cmax) of osimertinib after single oral dosing was 6 h (range 3–24 h) across all doses. Dose-proportional increase in osimertinib exposure (20–240 mg) was observed after single and multiple dosing. The distribution of the drug was extensive and clearance low to moderate, resulting in a mean half-life of ~48 h. Osimertinib steady state was achieved by 15 days of once daily dosing, with ~3- to 4-fold accumulation in exposure over single dose, resulting in a low Cmax to Cmin (minimal concentration) ratio (1.6), suggesting that concentrations are maintained throughout the dosing interval.71 The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two circulating pharmacologically active metabolites, AZ5104 and AZ7550, were measured in plasma at ~10% of osimertinib at steady state. In healthy volunteers, food caused a small increase in osimertinib exposure compared with fasted administration, but this was not considered clinically significant. Osimertinib exposure appeared to be similar in both Asian and non-Asian patients.71 In the Phase II AURA 2 study,72 192 patients were included in the PK analyses, which further demonstrated a flat PK for osimertinib and confirmed previous results from Planchard et al.71

On the basis of population PK analyses, no clinically significant differences in the PK of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild or moderate or severe renal impairment, or mild or moderate hepatic impairment.73

DEVELOPMENT OF THE DRUG

Phase I and II studies

The Phase I/II AURA trial was conducted to determine the safety and efficacy of osimertinib in patients with advanced NSCLC who had disease progression after previous treatment with EGFR-TKIs.67 In the study were included patients with known EGFR-sensitizing mutations or those who had prior clinical benefit from EGFR TKI therapy and had a documented disease progression while on treatment. Key secondary objectives included the determination of the maximum dose of the agent associated with an acceptable level of AEs, the PK and the antitumor activity. A total of 253 patients were included in the study: 31 in the dose-escalation cohorts and 222 in 5 dose-expansion cohorts. At data cut-off date (August 1, 2014), enrollment into additional cohorts, including patients who had not received prior treatment, and Phase II extension were ongoing.67 Most of the patients (62%) were Asian and women (62%) and 80% had received prior chemotherapy. In the dose-escalation part of the study in which patients received osimertinib at doses of 20–240 mg per dose, once daily, no dose-limiting toxicities occurred at any dose level and a maximum tolerated dose could not be defined. In the expansion cohorts, all patients underwent tumor biopsy for central assessment of EGFR T790M status and 138 (62%) were found positive for this mutation. 

Of the 239 patients evaluable for response, 123 (51%) had a confirmed objective response, including partial response in 122 patients and 1 complete response, with a disease control rate (DCR) of 84%.67The majority of patients (85%) showed a long-lasting response of ≥6 months. The median PFS was 8.2 months. In the subgroup of T790M-positive NSCLC patients evaluable for response (n=127), osimertinib showed high activity, with an ORR of 61%, a DCR of 95% and a median PFS of 9.6 months (95% CI 8.3 to not reached). In contrast, for the 61 evaluable patients with no detectable EGFRT790M, the ORR was 21% and PFS was 2.8 months (95% CI 2.1–4.3) (Table 1). The most frequent AEs were diarrhea (47% of patients), rash (40%) nausea and decreased appetite (21%). Among these, only the frequency of diarrhea and rash seemed to be dose dependent. Indeed, at doses of 160 and 240 mg, there was an increase in the incidence and severity of AEs, possibly explained by initial inhibition of non-mutant EGFR. Grade ≥3 AEs were observed in 32% of patients; however, the percentage of patients that needed to reduce the dose or discontinue the treatment was low. Treatment-related serious AEs were observed in 6% of patients. Six cases of potential pneumonitis-like events occurred, all leading to discontinuation of treatment, with resolution. However, pneumonia was reported as a fatal adverse event in 1 patient. Six patients had hyperglycemia and 11 a corrected QT interval prolongation, but none of these events led to drug dose reduction or discontinuation. Based on clinical activity and safety data, the dose of 80 mg once daily was selected for further clinical investigation.67

(To view a larger version of Table 1, click here.)

The encouraging efficacy and safety results from the Phase I study, led to AURA2, a multicenter, Phase II, single-arm study testing osimertinib at 80 mg orally daily in locally advanced or metastatic NSCLC patients with EGFR T790M-positive mutations, centrally confirmed by the Cobas® EGFR Mutation Test v2, who had progressed on prior EGFR TKI therapy.72 Patients could have received more additional lines of treatment, including platinum-based chemotherapy. Patients with asymptomatic, stable CNS metastases not requiring steroids could also be enrolled. A total of 210 patients were enrolled and treated with osimertinib. At data cutoff (November 1, 2015), with a median duration of treatment follow-up of 13 months, 58% of patients remained on treatment. Among the 199 evaluable patients, ORR as assessed by blinded independent central review (BICR), the primary endpoint, was 70%, including 3% of complete responses, with a DCR of 92%. The high proportion of objective responses was consistent across all subgroups, including patients with CNS metastases. Median duration of response (DoR) was 11.4 months and the median PFS was 9.9 months (95% CI 8.5–12.3) (Table 1). A higher number of objective responses, as well as a longer PFS, were noted in the group of patients with exon 19 deletions (ORR: 77%, 95% CI 69–84 and PFS: 10.9 months, 95% CI 9.5–13.6) than patients with L858R mutations (ORR: 59%, 95% CI 46–71 and PFS: 8.5 months, 95% CI 6.9–12.7). However, this difference was not significant and, as the authors underlined, could be in part explained by an apparent higher incidence of EGFR T790M in tumors with EGFR 19 deletions in the study population.72 One-year survival was 81%, while OS data were still immature. Osimertinib displayed a manageable toxicity profile. The most common possibly treatment-related grade 3 or 4 AEs were prolonged electrocardiogram QT (2%), neutropenia (1%) and thrombocytopenia (1%). Only 5% of patients discontinued osimertinib due to an AE. Among the reported deaths, the only death possibly related to treatment as reported by the investigator was due to interstitial lung disease (ILD). An improvement or stability of lung cancer symptoms and functioning domains from QoL was observed with osimertinib. For example, most patients reported a reduction in chest pain.72