Osimertinib in the Treatment of Non-small Cell Lung Cancer: Design, Development and Place in Therapy

The Phase II AURA extension study confirms the high activity of osimertinib at 80 mg, once-daily, in patients with EGFR-sensitizing and T790M-positive NSCLC progressing after EGFR TKI treatment.⁷⁴

Preliminary results from the extension component of AURA had been previously presented in a preplanned pooled analysis with the Phase II AURA2 study.⁷⁵ In this first analysis, including 411 EGFRT790M-positive patients, ORR was 66% and median PFS was 11.0 months (95% CI 9.6–12.4).⁷⁵ In a recent publication that reported only data from the AURA extension, the ORR (by BICR) was 62% among 198 evaluable patients, with a DCR of 90% and median DoR of 15.2 months (Table 1).⁷⁴ ORRs were high, ranging from 53% to 68%, across all predefined subgroups, including second/third line or more, Asian/non-Asian, male/female, age <65/≥65, exon 19 del/L858R, duration of most recent EGFR TKI: <6 months/≥6 months, CNS metastases: present/absent, never smoker/ever smoker, last EGFR TKI treatment: <30 days before osimertinib/ ≥30 days before osimertinib. Median PFS was 12.3 months (95% CI 9.5–13.8). Subset analysis revealed a nonsignificant trend toward longer median PFS in patients with exon 19 deletions (12.6 months) compared with L858R (9.6 months) and in Asian (12.6 months) versus non-Asian patients (9.7 months). Osimertinib showed substantial activity in patients with CNS metastases: 16 (64%) of 25 evaluable patients had an objective response, including 4 complete responses. Median PFS in patients with CNS metastases was encouraging, although it was shorter than in those without (7.1 vs 13.7 months, respectively). Median follow-up for OS was 13.8 months and 1-year survival rate was 79%. The safety profile was consistent with previous studies, with most AEs being mild and determining discontinuation of treatment only in 3% of patients. The most common possibly causally related AEs were diarrhea (43%; grade ≥3, <1%) and rash (40%; grade ≥3, <1%). ILD was reported in 8 patients (4%), including 3 fatal. QT prolongation was reported in 6 patients but only 3 were deemed possibly related to treatment. Patients had consistent and sustained improvements in key lung cancer symptoms, including dyspnea, cough, chest pain, and pain in arm or shoulder and in QoL compared with baseline.

Phase III studies

To confirm results of single-arm, Phase II studies, a randomized, Phase III trial (AURA3) was conducted to demonstrate the superiority of osimertinib over standard chemotherapy with platinum and pemetrexed for treatment of patients with EGFR-mutated and centrally confirmed T790M-positive advanced NSCLC with disease progression after first-line EGFR TKI therapy.⁷⁶ A total of 419 patients were randomized in a 2:1 ratio to osimertinib (80 mg once daily) or pemetrexed plus carboplatin or cisplatin every 3 weeks, for up to 6 cycles, with maintenance pemetrexed allowed. The primary efficacy end point was PFS as determined by investigator assessments, according to response evaluation criteria in solid tumors (version 1.1). Secondary objectives included ORR by investigator, response duration, DCR, tumor shrinkage, OS, patient-reported outcomes (PROs) and safety. Predefined subgroup analyses included the assessment of PFS and response rate among patients for whom EGFR T790M status was determined by means of a plasma ctDNA test and in patients with CNS metastases. At data cut-off date (April 15, 2016), the mean duration of treatment was 8.6 months in the osimertinib group and 4.8 months in the platinum-pemetrexed group, and a total of 59% of patients in the osimertinib arm and 12% in the chemotherapy arm were still receiving treatment. In the platinum-pemetrexed group, 60% of patients at progression crossed over to receive osimertinib. After a median follow-up of 8.3 months, the study met its primary endpoint showing a significantly longer PFS for patients in the osimertinib arm compared with platinum chemotherapy arm (10.1 vs 4.4 months, HR: 0.30, 95% CI 0.23–0.41, p<0.001) (Table 1). The benefit was observed across all predefined subgroups, including patients with asymptomatic CNS metastases at baseline (PFS: 8.5 vs 4.2 months, HR 0.32, 95% CI 0.21–0.49) and patients positive for T790M on both tumor and plasma. Treatment with osimertinib was also associated with better ORR compared with chemotherapy (71% vs 31%, odds ratio: 5.39, 95% CI 3.47–8.48, p<0.001) (Table 1) in the overall population and in the subgroup of patients with T790M-positive status on both tumor and plasma samples. Responses were more durable with osimertinib (DoR: 9.7 vs 4.1 months). Despite the longer treatment duration with osimertinib, this was associated with lower incidence of grade ≥3 AEs (23%) compared with platinum-pemetrexed (47%) and lower discontinuation rate (7% vs 10%, respectively). The most common AEs with osimertinib were diarrhea, rash, dry skin and paronychia, while in the chemotherapy group, the AEs were nausea, decreased appetite, constipation and anemia. ILD-like AEs were reported in 10 patients (4%) in the osimertinib group (including 1 fatal) and in 1 patient (1%) in the platinum-pemetrexed group. Also, PROs were better in the osimertinib group than in the platinum-pemetrexed group.⁷⁶

These results definitively established the role of osimertinib as a standard of care for patients who progress to first-line EGFR TKI and who harbor the T790M resistance mutation. Moreover, the findings of AURA3 support the feasibility of detecting the EGFR T790M resistance mutation from plasma ctDNA and their reliable predictive role.

Activity of osimertinib against CNS metastases

Brain metastases are a common problem in NSCLC patients and are associated with a significant symptomatic burden. Several reports have demonstrated a certain activity of early generation EGFR TKIs in EGFR-mutated NSCLC patients with brain and leptomeningeal metastases.^77–80 It has also been demonstrated that a high-dose or pulsatile administration of high-dose EGFR TKIs may be able to improve their efficacy in these poor-prognosis patients.^81–84 However, more than 30% of patients who progress during or after treatment with EGFR TKIs have brain and/or leptomeningeal metastases,⁸⁵which represent a clinical issue because of poor penetration of drugs, including targeter agents, through the blood–brain barrier (BBB).⁸⁶

In preclinical studies, osimertinib demonstrated greater penetration of the BBB than gefitinib, afatinib or rociletinib and, in contrast to rociletinib, induced sustained tumor regression in an EGFR-mutated mouse brain metastases model at clinically relevant doses.⁸⁷ By using positron emission tomography imaging, osimertinib displayed markedly greater and faster distribution into the cynomolgus monkey brain than rociletinib and gefitinib.⁸⁷ A number of clinical reports, including subgroup analyses from the AURA trials, support these preclinical data by demonstrating relevant activity of osimertinib in EGFRmutation-positive patients with brain and/or leptomeningeal metastases.^72,74,76,88 Moreover, a different CNS activity among third-generation EGFR TKIs has been reported in clinical setting.⁸⁹ A Phase I trial (BLOOM; NCT02228369) is ongoing to assess the safety and preliminary activity of osimertinib (administered at 160 mg once daily) in patients with EGFR-mutated advanced NSCLC and leptomeningeal metastases, confirmed by positive cerebrospinal fluid (CSF). Responses are evaluated based on CSF cytology, intracranial imaging and neurological examination. Preliminary results on 21 patients from this trial have been recently reported.⁹⁰ A confirmed intracranial response was observed in 7 patients: 2 patients had a confirmed CSF cytology clearance and 5 patients had neurological improvement. The safety profile of osimertinib was manageable.⁹⁰

Overall, these results suggest that osimertinib can be an effective treatment option for EGFR-mutated patients with CNS disease, thus sparing patients from or delaying the use of radiotherapy, which, in the case of whole brain radiation (WBRT) can ultimately compromise patients’ cognitive function and QoL. Interestingly, due to the high risk of development of CNS metastases in EGFR-mutant NSCLC, an EGFR TKI specifically designed to penetrate the BBB and achieve high intracranial exposure, AZD3759, is currently being evaluated in an open-label, multicenter, Phase I study in patients with advanced EGFR mutation-positive NSCLC (NCT02228369).⁹¹

CELL-FREE ctDNA GENOTYPING FOR EGFR T790M MUTATION

Genotyping post-progression tumor samples for EGFR T790M has become a crucial step for guiding treatment decisions and is recommended in current NSCLC guidelines.^14,37 However, in clinical practice, rebiopsies of recurrent or metastatic tumors can often be difficult to obtain, due to the potential risks involved in invasive diagnostic procedures that can also be painful for patients. For the same reasons, it is rarely feasible to obtain serial biopsies from the same patient at different points during treatment. Moreover, tumor tissue from some biopsies is not sufficient for genetic analysis or, even when adequate, it only represents a single snapshot in time and is subject to selection bias resulting from tumor heterogeneity. Due to these limitations, a great number of studies in recent years have addressed the question of whether cell-free circulating DNA derived from tumors, also known as ctDNA, could be used as a surrogate liquid biopsy for noninvasive assessment of tumor genetic alterations, including EGFR TKI sensitizing- and T790M-resistant mutations.⁹² While tissue biopsies only describe genetic characteristics of the primary tumor, ctDNA is potentially able to provide a portrait of the whole tumor genome landscape of both primary and metastatic lesions. Serial analysis of ctDNA can track molecular dynamic evolution of the tumor during the course of treatment and identify the emergence of heterogeneous subclonal populations of tumor cells. A number of studies have demonstrated that the T790M mutation can be detected in plasma samples by highly sensitive genotyping assays, including droplet digital polymerase chain reaction (ddPCR) and the bead, emulsion, amplification and magnetics (BEAMing) technique.^92–95

In a retrospective analysis of Phase I AURA, Oxnard et al reported a sensitivity of 70% of the plasma-based test for detecting T790M mutation. Remarkably, patients with T790M mutation detected in plasma ctDNA had comparable responses and PFS to osimertinib as those with positive tissue-based assay results.⁹⁶ The predictive value of plasma ctDNA genotyping for T790M was prospectively confirmed in the Phase III AURA3 trial showing a longer PFS and higher ORR for osimertinib compared with platinum-pemetrexed chemotherapy (PFS: 8.2 vs 4.2 months, HR 0.42, 95% CI 0.29–0.61; ORR: 77% vs 39%, odds ratio, 4.96, 95% CI 2.49–10.15, p<0.001).⁷⁶

However, due to the relatively high false negative rates with plasma T790M testing, the absence of this mutation in blood cannot exclude its presence in the tissue and, hence, its potential sensitivity to osimertinib. Indeed, in the analysis of AURA, tumour genotyping was positive for T790M in 45 out of 102 patients with T790M-negative plasma. This subgroup of patients had a good response to osimertinib with a median PFS of 16.2 months. For this reason, if plasma genotyping for T790M at disease progression is negative, a new tissue biopsy is highly recommended to correctly classify patients for treatment with osimertinib (Figure 2).

(To view a larger version of Figure 2, click here.)

Remon et al further highlighted the predictive role of T790M mutation detected in plasma-based assay.⁹⁷ In this study, the efficacy of osimertinib was evaluated in 48 EGFR-mutated, advanced NSCLC patients in progression after a prior EGFR TKI therapy, in whom T790M status was determined only in ctDNA by Inivata InVision^™ assay (Inivata Ltd, Cambridge, UK), by using enhanced Tagged Amplicon-Sequencing (eTAm-Seq^™ assay, Inivata Ltd). The ctDNA T790M mutation was found in 50% of patients and, among evaluable patients, osimertinib was associated with a partial response rate of 62.5% and a stable disease rate of 37.5%. In a small series of T790M-positive NSCLC who received osimertinib, no correlation was found between EGFR T790M mutation copy numbers evaluated by plasma-based assay (ddPCR) and response to osimertinib.⁹⁸