Osimertinib

Safety of osimertinib in egfr-mutated non-small cell lung cancer

Laura Mezquita, Andreea Varga & David Planchard

1 Medical Oncology Department, Gustave Roussy, Villejuif, France
2 Early Drug Development Department, Gustave Roussy, Villejuif, France

Abstract

Introduction: Osimertinib is a third-generation EGFR-TKI, specifically designed to inhibit EGFR sensitizing and T790M acquired mutations, minimizing exposure in EGFR-wildtype tissues. Areas covered: Osimertinib use in EGFR-mutated NSCLC patients is described, focusing on safety and tolerability from studies supporting its approval.

Expert opinion: Osimertinib demonstrated greater efficacy, including CNS activity, compared to chemotherapy, with a manageable safety profile in pretreated T790M+ EGFR-mutated patients, leading to FDA approval in 2015 within record time in the oncology field. However, the therapeutic strategy in the EGFR-mutated population is changing, following the FLAURA study in untreated EGFR- mutated patients, in which osimertinib improved PFS compared to other TKIs, with a similar toxicity profile but a lower serious adverse event rate. In April 2018, the FDA and EMA approved osimertinib as first-line therapy for EGFR-mutated patients. Long-term survival data will ultimately establish the true benefit of upfront versus sequential strategies guided by T790M status. These studies favor osimertinib for tolerability and safety, except for the slightly higher rate of interstitial lung disease, but which was nonetheless manageable. In the coming years, osimertinib will be consolidated as standard therapy in the EGFR population and in naïve and pretreated patients, based on mature survival data and the toxicity profile.

Keywords
Osimertinib, AZD9291, NSCLC, EGFR, tyrosine kinase inhibitor

1. Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide (1). According to histological classification, non-small-cell-lung cancer (NSCLC) represents around 85% of all lung cancers (1,2). The discovery of actionable target molecular alterations, such as oncogenic somatic mutations (EGFR, BRAF, etc.) or chromosomal fusions (ALK, ROS1, etc.), is changing the paradigm for these NSCLC patients. The epidermal growth factor receptor (EGFR) mutation was the first key mutation identified in NSCLC, reported in 2004. It is more common in patients with adenocarcinoma histology, non- smokers, women and patients of Asian ethnicity. About 90% of all EGFR mutations are the in-frame exon 19 deletion and exon 21 point mutation (L858R). Other rare but active EGFR mutations are L861Q and G719X, located in exon 18 (3). All these oncogenic mutations render tumors high sensitive to targeted inhibition by EGFR tyrosine kinase inhibitors (TKIs). In populations restricted to harboring EGFR-activating mutations (exon 19 deletions and L858R), TKIs have demonstrated higher responses and longer progression-free survival (PFS) compared to chemotherapy in TKI-naive advanced NSCLC. First-generation (gefitinib, erlotinib) and second-generation TKIs (afatinib, dacomitinib) have demonstrated median PFS between 9.5 to 14.7 months (4–6), making them the standard of care in first-line. With the exception of dacomitinib, all of these agents have been approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) for the treatment of untreated EGFR-mutated NSCLC patients. In April 2018, the FDA granted a priority review designation to dacomitinib as first-line therapy in this population.

Unfortunately, most patients receiving first- and second-generation EGFR-TKIs ultimately progress, with the most common mechanism of resistance being the EGFR-T790M mutation, reported in around 50-60% of progressing patients. The EGFR-T790M mutation is more commonly found with the exon 19 deletion than with the L858R genotype, and germline or somatic de novo mutations are rare (7–9).EGFR-T790M status at progression can be determined in a tumor biopsy or using alternative diagnostic techniques such as circulating tumor DNA (ctDNA), known as a liquid biopsy (10), which is currently the first step when the patient progress on TKIs. Establishment of EGFR-T790M status is now mandatory because a next-generation TKI has been specifically developed to overcome this mechanism (11). Osimertinib is an oral, irreversible third-generation TKI that can overcome acquired resistance caused by the T790M mutation, while remaining effective in sensitive EGFR-mutations, and with minimal activity on EGFR wild-type cells (11,12). Initial approval of osimertinib was in advanced EGFR-T790M mutation-positive (+) NSCLC. However, the therapeutic strategy in the EGFR- mutated population is currently changing, due to the recently reported FLAURA study (13), demonstrating improved outcomes in untreated patients. The FDA and EMA approved Osimertinib in April 2018 as front-line therapy for advanced EGFR-mutated patientIn this review, we summarize available data of osimertinib in advpk/pd data

2.1. Mechanism of action

Osimertinib (AZD9291, Tagrisso®; AstraZeneca) is an irreversible EGFR inhibitor against tumors harboring activating-mutations and the T790M TKI-resistance mutation. It is a mono- anilinopyrimidine compound, with lower potency for inhibiting phosphorylation in EGFR-wild-type cell lines, with ~200 times greater potency against L858R/T790M-mutant than EGFR-wild-type (14). In xenograft and transgenic murine tumor models, osimertinib demonstrated remarkable activity with tumor regression in EGFR-mutated and T790M+ NSCLC, and impressive intracranial activity in several animal models with brain metastasis (15).

2.2 pharmacokinetics

Pharmacokinetic (PK) parameters of osimertinib have been characterized in both healthy subjects and NSCLC patients. In the phase 1 AURA study, osimertinib PK was evaluated to define the optimal dose and dosing interval, whether a fixed-dose approach can be used, and the impact of formulation and food on exposure. Planchard et al reported the comparison of osimertinib PK between Western and Asian patients and healthy volunteers (16). Osimertinib was absorbed slowly with dose- proportional increases in exposure from 20 to 240 mg, supporting once daily dosing. Distribution was extensive, with a mean half-life of ~48 h. Steady state was achieved after 15 days. Two active metabolites (AZ7550 and AZ5104) were present at ~10% of osimertinib exposure. Osimertinib PK profiles were similar between patients and healthy volunteers and were unaffected by formulation. Food caused a clinically non-significant minimal increase in exposure. In healthy volunteers osimertinib was not affected for elevated gastric pH by omeprazole for 5 days, in contrast to other EGFR-TKIs.

3. Clinical applications including key efficacy data

Osimertinib is the protagonist of an extraordinary clinical drug development program, with a very short interval between the first clinical study, which started in March 2013, and granting of the FDA accelerated approval in November 2015. The impressive efficacy data together with a good tolerance and safety profile, strongly facilitated this development. The main clinical data for efficacy of osimertinib are discussed below.

3.1 Osimertinib in the pretreated EGFR-mutated population

Osimertinib was initially evaluated in the first-in-human phase 1/2 AURA trial. In this single-arm, multicenter study, the safety, tolerability, pharmacokinetics and activity of ascending doses of osimertinib was assessed in EGFR-mutated NSCLC patients who had progressed following a prior EGFR-TKI (NCT01802632). A total of 603 patients were included in six cohorts: a) 80 mg extension (pretreated EGFR-T790M+ patients, n=201), b) dose escalation (pretreated patients at 20, 40, 80, 160 and 240 mg, n=31), c) dose expansion (pretreated EGFR-T790M+ patients; dose groups were expanded to include more patients, n=271), d) first-line (with 80 mg and 160 mg, n=60), e) 80 mg US- only (pretreated EGFR-mutated patients, n=12), and f) 80 mg Japan-only (EGFR-T790M status determined from cytology samples, n=28). The primary outcomes were the objective response rate (ORR) for the dose expansion and extension populations and best ORR (BORR) for the dose escalation population. The first data reported come from the dose-escalation cohort (N=31), and the 222 patients enrolled in the dose expansion cohort including five osimertinib doses (17). The overall ORR was 51% (95% CI, 45 to 58). Of these 253 patients, for the 127 EGFR-T790M+ patients (centrally confirmed), the ORR was 61% (95% CI, 52 to 70). However, in 61 T790M-negative patients, the ORR was 21% (95% CI, 12 to 34). Median PFS was 9.6 months (95% CI, 8.3 to not reached [NR]) in T790M+ patients vs. 2.8 months (95% CI, 2.1-4.3) in T790M negative groups.

In the AURA 2 study (NCT02094261), advanced NSCLC patients with a centrally confirmed EGFR- T790M+ mutation, previously treated with an EGFR-TKI were enrolled (11). Patients with asymptomatic, stable CNS metastases not requiring steroids were eligible. The primary endpoint was ORR by blinded independent central review (BICR) using RECIST v1.1. Patients received oral osimertinib 80 mg once daily, and therapy could continue beyond progression in cases of clinical benefit. Out of 472 patients screened, 210 started osimertinib treatment, and the ORR was 70% (95% CI 64% to 77%). Yang et al reported the results from the phase 2 extension cohort (NCT01802632) (18). A total of 201 patients received osimertinib. Among 198 evaluable patients, the ORR was 62% (95% CI, 54 to 68). Median duration of response was 15.2 months (95% CI, 11.3 to NR) and median PFS was 12.3 months (95% CI, 9.5 to 13.8). The CNS ORR (n=25/74 patients evaluable with CNS metastases) was 64% (n=16; 95% CI, 43 to 82), 4 complete and 12 partial responses, wih tumor shrinkage in the majority of patients.
The efficacy and safety of osimertinib was then compared to standard of care in the phase 3 AURA 3 study (NCT02151981). A total of 419 patients with T790M+ advanced NSCLC, who had progressed after first-line EGFR-TKI, were assigned (2:1) to osimertinib or platinum-based chemotherapy (pemetrexed plus carboplatin or cisplatin every 3 weeks –q3w- for up to 6 cycles, with maintenance allowed) (12). Patients with asymptomatic or stable CNS metastases were eligible for enrollment. Crossover to the osimertinib arm was permitted after confirmation of disease progression. The primary endpoint was PFS per the investigator. Osimertinib showed greater efficacy, with median PFS significantly longer than chemotherapy (10.1 vs. 4.4 months; HR 0.30; 95% CI, 0.23 to 0.41).

The ORR was significantly better with osimertinib (71%) vs. chemotherapy (31%) (OR 5.39; 95% CI, 3.47 to 8.48). Interestingly, in the CNS involvement population, median PFS was 8.5 months for osimertinib vs. 4.2 months for chemotherapy (HR 0.32; 95% CI, 0.21-0.49). In a sub-analysis of 63 Japanese patients enrolled in the AURA 3 study (19), osimertinib demonstrated similar outcomes as the overall population, with a median PFS of 12.5 months (n=41) vs. 4.3 months with chemotherapy (n=22) (HR 0.27; 95% CI 0.13 to 0.56). Focus on CNS outcomes, a pooled analysis of the AURA 2 and the extension cohort has been recently reported, demonstrating the clinically significant CNS activity of osimertinib in T790M+ population (N=411) (20). Of 128 patients with CNS involvement, 50 were evaluable (≥1 measurable CNS lesion per RECIST 1.1 on baseline brain scan by BICR). Confirmed CNS ORR and disease control rate (DCR) were 54% (95% CI 39 to 68) and 92% (95% CI 81-98), respectively, regardless of prior brain radiotherapy. With a median follow-up of 11 months, the median CNS PFS was NR (95% CI, 7 to NR). Interestingly, the CNS activity of osimertinib has been specifically evaluated in leptomeningeal (LM) involvement, a neurological condition described up to 9% of EGFR-mutated patients, associated with very poor prognosis in cancer (21). In the BLOOM study (NCT02228369) (22), 41 patients with confirmed LM (LM+) (positive cerebrospinal fluid -CSF- cytology) involvement received osimertinib 160 mg once daily. Response was assessed by investigator in 2 cohorts: T790M unselected and T790M+ (centrally confirmed). Preliminary data of 32 patients (N=21 unselected; N=11 T790M+ patients) have been reported. Osimertinib demonstrated good penetrance through the blood-brain barrier (BBB), with a mean concentration in CSF was 7.51 nM (range 2.19–21.1 nM) at steady state (N=16). The median treatment duration was 6 months, with a longest duration of 17.5 months. In 23 evaluable patients, 10 had radiological improvement and 13 had stable disease (SD); only 2 had neurological deterioration in the clinical assessment (9%).

In addition, the preplanned subgroup analysis from the AURA 3 study, has very recently reported a higher CNS efficacy of osimertinib vs. chemotherapy (n=419) (23). Of 116 patients with CNS involvement, 46 patients had measurable CNS lesions (≥1 measurable CNS lesion per RECIST 1.1 on baseline brain scan by BICR). The CNS ORR in patients with measurable CNS lesions was 70% (21/30) with osimertinib vs. 31% (5/16) with chemotherapy (OR 5.13; 95% CI 1.44 to 20.64; P=0.015); and the median CNS PFS was 11.7 months and 5.6 months for osimertinib and chemotherapy respectively (HR 0.32; 95% CI, 0.15 to 0.69; P=0.004). The AURA studies demonstrated impressive efficacy, including impressive CNS activity, in EGFR- T790M+ patients after prior EGFR-TKI failure, with a manageable safety profile, leading to the approval of osimertinib at a dose of 80 mg orally, the fastest approval of a cytotoxic drug in the history of oncology. Osimertinib was designated as a breakthrough therapy in April 2014 based on the AURA phase 1 trial, and the drug was provisionally approved under the FDA accelerated approval program in November 2015 while the EMA accelerated program approval came in February 2016. Today, the clinical development of osimertinib has been extended to include early stage disease in the EGFR population. In the ongoing phase 3 ADAURA study (NCT02511106), initiated in August 2015, osimertinib (maximum duration of 3 years) is being explored in IB-IIIA stage disease as adjuvant therapy after complete resection (24). Results are expected in 2021.

3.2 Osimertinib in the naïve EGFR-mutated population

Following the encouraging benefit demonstrated in pretreated population, osimertinib was then evaluated upfront, in untreated advanced NSCLC patients. In the randomized, double-blind, phase 3, FLAURA study (NCT02296125), 556 treatment-naïve patients with EGFR-mutation positive disease (exon 19 deletion or L858R) were randomized (1:1) to receive either osimertinib or a standard EGFR- TKI (gefitinib or erlotinib) (13). Crossover to the osimertinib arm was permitted after confirmation of progression. The primary endpoint was investigator-assessed PFS. Osimertinib showed efficacy superior to the standard EGFR-TKIs, with a median significantly longer PFS (18.9 vs. 10.2 months; 0.46; 95% CI, 0.37 to 0.57), but with comparable ORR in both groups (80% with osimertinib vs. 76% with standard EGFR-TKI). The immature survival (25% maturity) data showed a non-significant overall survival (OS) rate at 18 months of 83% (95% CI, 78% to 87%) with osimertinib vs. 71% (95% CI, 65% to 76%) with standard EGFR-TKIs (HR 0.63; 95% CI, 0.45 to 0.88; non-significant for interim analysis). In April 2018 the FDA and the EMA approved osimertinib for first-line. Interestingly, Planchard et al reported the exploratory post-progression outcomes of the FLAURA study (25); 29% of the osimertinib cohort and 47% of EGFR-TKI group received subsequent treatment. All time-to-event post-progression endpoints favored osimertinib, supporting the interim OS data. The median time to discontinuation was 20.8 months (95% CI 17.2 to 24.1) for osimertinib vs. 11.5 months (95% CI, 10.3 to 12.8) for standard of care; and the median time to discontinuation of an EGFR-TKI (including subsequent EGFR-TKI after study treatment) or death was 23.0 months (95% CI, 19.5 to NR) for osimertinib vs. 16.0 months (95% CI, 14.8 to 18.6) for standard of care groups.

3.3 Osimertinib in combination

Osimertinib is currently being evaluated in combination with several types of systemic therapies, including immune checkpoint inhibitors (ICI), antiangiogenics, and other targeted therapies. The limited information available comes from preliminary data reported in international meetings.

3.3.1. Osimertinib plus durvalumab
In the phase 1b TATTON study (NCT02143466) the combination of osimertinib plus the PD-L1 inhibitor durvalumab was explored in EGFR-mutated patients (26). The dose escalation part was conducted in TKI-pretreated EGFR patients and dose expansion in TKI-naïve patients. During dose escalation, 23 patients received 80 mg osimertinib once daily plus durvalumab 3 or 10 mg/kg every 2 weeks. In the expansion part, 11 patients received osimertinib plus durvalumab 10 mg/kg every 2 weeks. The ORR was 57% and 80% in the escalation (N=21) and expansion parts (N=10), respectively. However, due to pulmonary toxicity (see section 4.1.4) this arm was stopped prematurely.

3.3.2. Osimertinib plus antiangiogenics
EGFR-TKI in combination with antiangiogenics has been reported to be a synergic combination, improving PFS compared to EGFR-TKI alone in untreated EGFR-mutated NSCLC patients (27,28).

3.3.2.1. Osimertinib plus bevacizumab
The safety and efficacy of osimertinib plus bevacizumab is being assessed in a phase 1/2 study with 46 untreated EGFR-mutated advanced NSCLC patients (29). Preliminary data have been reported in 22 patients (N=17 evaluable for response). The primary endpoint for phase 1 was the maximum tolerated dose (MTD) for the phase 1 part and PFS rate at 12 months for the phase 2 part. The ORR was 76% (n=13) and the assessment of PFS at 12 months is ongoing. The combination osimertinib plus bevacizumab is also being evaluated vs. osimertinib alone in second line in the phase 2 BOOSTER study, with 154 pretreated EGFR-mutated T790M+ advanced NSCLC patients (NCT03133546), from the European Thoracic Oncology Platform (ETOP). The study is currently active and the end of the recruitment is expected for May 2022.

3.3.2.2. Osimertinib plus ramucirumab
Osimertinib plus ramucirumab, a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist, is being explored in a phase 1b study. Preliminary data were reported in the 2018 ASCO meeting by Planchard et al (NCT02789345). Twenty-five EGFR-mutated patients (exon 19 deletion or L858R exon 21) received osimertinib plus ramucirumab at 10 mg/kg i.v. every 2 weeks. The ORR was 76%, with a 12-month PFS rate of 57.5% (90% CI; 38.9 to 72.3).

3.3.3. Osimertinib plus savolitinib
Osimertinib plus savolitinib (volitinib, AZD6094; a highly selective MET tyrosine kinase inhibitor, which showed activity in MET-driver papillary renal cell carcinoma), is being explored in a phase 1b TATTON study (N=66). In 64 MET positive patients from the expansion cohort (confirmed by hybridation in situ by fluorescence FISH, immunohistochemistry or next generation sequencing), preliminary data showed encouraging activity, particularly interesting for T790M negative, with an ORR of 61% (30). The ORR for untreated T790M+ patients was 55% and for 3rd-gen TKI-pretreated T790M+ was 33%. The expansion cohort is currently ongoing in South Korea, Taiwan and United States.

4. Safety evaluation

The safety profile of osimertinib was consistent throughout the clinical trials, from phase 1 to 3. The data described below summarize common adverse reactions and laboratory abnormalities observed in osimertinib-treated patients. Table 2,3 summarizes the safety and tolerability data of osimertinib and Table 4 provides a comparison with other EGFR TKIs.

4.1 Preclinical safety data

The safety of osimertinib was preclinically evaluated in different animal models (31). The main findings observed in repeat-dose toxicity studies in rats and dogs comprised atrophic, inflammatory and/or degenerative changes in the corneal epithelium, gastrointestinal tract, skin, and reproductive tracts (female and male) with secondary changes in the spleen. These findings occurred at plasma concentrations lower than those found in patients after being treated with osimertinib at the therapeutic dose for one month. They were reversible within 1 month of stopping treatment, with the exception of corneal changes for which only partial recovery was seen. In mice and cynomolgus monkey, osimertinib was able to penetrate the intact blood-brain barrier.

4.2 Safety in clinical studies

Robust safety data are available for osimertinib monotherapy and data are emerging from combination trials. Table 2 summarizes the safety and tolerability profile of osimertinib in pretreated and TKI-naïve EGFR-mutated NSCLC patients.

4.2.1 Osimertinib in pretreated EGFR-mutated patients

Osimertinib safety was first assessed in 253 patients treated in the escalation and expansion cohorts from the AURA 1 study, with doses of osimertinib from 20 to 240 mg daily (17). No dose-limiting toxicities (DLT) were observed at any dose level and the maximum tolerated dose (MTD) was not defined. The most common adverse events (AEs) reported were diarrhea (47%), rash (40%), nausea (22%), and decreased appetite (21%). Grade ≥3 AEs were observed in 32% of patients and 6% had to discontinued osimertinib. Six cases of interstitial lung disease (ILD) were described and one case of pneumonia was fatal. QTc prolongation was reported in 11 patients, but did not require dose reduction or drug discontinuation. Despite not reaching an MTD, at the 160 mg and mainly at 240 mg dose levels there was an increase in both incidence and intensity of rash, dry skin, pruritus and diarrhea. Thus, the recommended phase 2 dose was designated to be 80 mg orally, once daily.
However, in the BLOOM study (22) osimertinib demonstrated a manageable tolerability with a daily dose of osimertinib was 160 mg. In first 32 patients reported, the most common AEs were skin effects (63%), diarrhea (40%), nausea (34%) and paronychia (28%), with only 1 case of grade 3 diarrea reported (3%).

A 28% of the patients required dose interruption and 13% had dose reductions to 80 mg once daily. The toxicity profile in the AURA 2 study (N=210) was similar to that of the AURA 1 study (11), with a low incidence of grade ≥3 AEs. Diarrhea, rash, dry skin and paronychia were the most common AEs. QTc prolongation was reported in 13 patients (6%), 11 related to osimertinib (four of which were grade 3). ILD was reported in 2% (N=4). Hematologic toxicities were reported in this phase 2 trial, including thrombocytopenia and neutropenia, which were not observed in the phase 1 study (11). In the phase 2 extension cohort (N=201) (NCT01802632) reported by Yang et al (18), the most common AEs were diarrhea (43%; <1% grade ≥3) and rash (40%; <1% grade ≥3). ILD was reported in 8 patients (4%; two grade 1; three grade 3), including fatal events for three patients. In the CNS pooled analysis from the AURA 2 population, osimertinib did not show any difference on incidence or severity of toxicities in patients with CNS metastasis (20,32). In the AURA 3 study, the proportion of patients with grade ≥3 AEs was lower with osimertinib (23%) than with chemotherapy (47%). As expected, toxicity in the osimertinib arm was comparable with previous AURA studies, with diarrhea (41%), rash (34%), dry skin (23%) and paronychia (22%) as most common AEs. Four percent of patients (N=10) developed ILD, one of which was fatal, and QTc prolongation was reported in 4% of patients (N=10), with only 1 grade 3. (12). In the sub-analysis of 63 Japanese patients enrolled in the AURA 3 study, as with efficacy, safety results were consistent with the overall population (19). 4.2.2 Osimertinib in naïve EGFR-mutated patients In the FLAURA study, 279 patients received osimertinib and 55 crossed over to osimertinib from the standard EGFR-TKI arm (13). Fewer grade ≥3 AEs (34%) were reported with osimertinib compared to standard EGFR-TKIs (45%), with a similar overall toxicity profile and a lower serious adverse event (SAE) rate. This was consistent with previous studies, with the most common AEs being diarrhea (58%), rash (58%), and dry skin (36%). QTc prolongation was reported in 10% of patients (N=29, one grade ≥3) and ILD in 4% (N=11, six grade ≥3), with no fatal events. In the osimertinib group, 7 of 11 patients recovered from ILD and the other four were recovering. In the osimertinib group, the rate of permanent discontinuation was lower than with standard EGFR-TKIs (13% vs. 18%), however the rate of dose interruption (24-25%) and dose reduction (4%-5%) due to AEs was similar in both groups. 4.2.3 Osimertinib in combination 4.2.3.1 Osimertinib plus durvalumab In the TATTON study (NCT02143466) AEs were significantly more frequent with the durvalumab plus osimertinib combination, particularly a higher incidence of ILD. The most common AEs were nausea/vomiting (39%), anemia (35%), and diarrhea (35%) during dose escalation, and ILD (64%), diarrhea (55%) and nausea (45%) during expansion (26). Six patients developed ILD (26%, two grade ≥3) in the dose escalation and seven patients (three grade ≥3 cases) in the expansion parts; most patients were manageable with corticosteroids. However, considering the high incidence of ILD observed, this arm was stopped. Consequently, the phase 3 CAURAL trial (NCT02454933) with osimertinib plus durvalumab vs. osimertinib alone in EGFR-T790M+ patients was also prematurely closed. 4.2.3.2. Osimertinib plus antiangiogenics 4.2.3.2.1. Osimertinib plus bevacizumab The preliminary of osimertinib plus bevacizumab reported in 22 patients from a phase 1/2 study (29), did not show any dose limiting toxicity (DLT); the MTD, primary endpoint for the phase 1 part, was determined at the orally daily dose of 80 mg and bevacizumab at the dose of 15 mg/kg q3 weeks. The most frequent AEs were rash (52%), hypertension (43%), thrombocytopenia (38%), fatigue (38%), and diarrhea (33%). All SAEs were hypertension (19%), with no discontinuation reported for AEs. 4.2.3.2.2. Osimertinib plus ramucirumab In the phase 1b study with osimertinib plus ramucirumab, preliminary data demonstrated a safety profile consistent with monotherapy, without additive toxicities. While no DLTs were observed, all patients (N=25) had ≥1 AE, most commonly hypertension (44%), diarrhea (32%), or stomatitis (24%). The SAEs (all grade 3) reported were hypertension (8%), platelet count decreased (8%), anemia (4%), congestive heart failure (4%), and neutrophil count decreased (4%). No grade 4 AEs were reported. 4.2.3.3. Osimertinib plus savolitinib In the TATTON trial, the safety was assessed in 66 MET-amplified EGFR-mutated advanced NSCLC patients. With the combination osimertinib plus savolitinib, the most common AEs were nausea (44%), vomiting (35%), fatigue (30%), and decreased appetite (30%), which were consistent with the known toxicities of both drugs. The SAEs were reported in 50% of the patients, mainly vomiting (8%), rash (65) and AST/ALT elevation (6%). 5. Post-marketing data Following FDA and EMA approval for T790M+ advanced NSCLC, an international single-arm real- world treatment study is being conducted (ASTRIS study) (33,34). Since September 2015, 1217 patients have been treated in Canada, Australia, South America, Europe and Asia, with 3500 patients planned. A preliminary safety report was presented after 1 year. Any grade AEs was reported in 234 patients (19%), and 30 patients (2%) had a ‘special interest’ event. IDL was reported in 25 cases (2%) while QTc prolongation was present in nine cases (1%). There were no unexpected toxicities in this real-life population compared to the reported clinical studies, with a similar safety profile was similar. A total of 364 patients were enrolled in the French expanded access program (35). Out of 350 patients evaluable for safety, ≥1 AEs were reported in 36 patients (10.3%); 13 patients (3.7%) had AEs leading to discontinuation and 9 (2.6%) had dose reductions due to treatment. 6. Safety in special populations including pharmacogenomic data No dosage adjustment is required for patient age, body weight, gender, ethnicity or smoking status (31). In the 1367 patients included in pharmacokinetic analyses, no clinically significant relationships were identified between predicted steady-state exposure (AUCss) and age (range: 25 to 91 years), gender (65% female), ethnicity (including White, Asian, Japanese, Chinese and non-Asian-non-White patients), therapy line and smoking status (N=34 current smokers, N=419 former smokers) With regards to hepatic impairment, in a pharmacokinetic analysis of 142 patients with hepatic impairment (N=134 mild, N=8 moderate) compared with 1216 patients with normal hepatic function, osimertinib exposure was similar. Pharmacokinetic analysis of osimertinib exposure showed similar outcome for the 847 patients with renal impairment (N=593 mild, N=254 moderate) and the 502 patients with normal renal function. Patients with severe hepatic and renal impairment were not included in the clinical trials. The QTc prolongation seen with osimertinib was evaluated in 210 patients from the AURA 2 study. Serial ECGs were performed following a single dose and at steady state to assess the effect of osimertinib. A pharmacokinetic /pharmacodynamic analysis predicted a drug-related QTc prolongation of 14 msec with an upper limit of 16 msec (90% CI). 7. Comparison with safety of other drugs Globally, the safety and toxicity profile of osimertinib is considered very similar to other EGFR-TKI, as expected. However the difference with other EGFR-TKI lies in the incidence and severity of the treatment-related AEs, with a tolerance that favors osimertinib. Table 4 summarizes the safety profile of osimertinib and other EGFR-TKIs. Compared to first-generation EGFR-TKI, osimertinib showed a lower rate of ≥1 grade of rash, with similar rates of diarrhea, dry skin or paronychia, as most common AEs reported (13). However, patients exposed to osimertinib had a lower SAEs rate (32% vs. 41%): mainly rash (1% vs. 7%) and transaminase elevation (1% vs. 8%). Additionally, the EGFR-TKI discontinuation was lower in the osimertinib group (13% vs. 18%). The toxicity profile of second-generation EGFR-TKI was consistent with other EGFR-TKI, but the incidence and severity of AEs reported have been generally higher compared to first- and third- generation EGFR-TKI. The phase 3 studies evaluating afatinib (36) vs. chemotherapy and dacomitinib vs. gefitinib (34), reported high rates of diarrhea (78-95%), rash/dermatitis acneiform (35-89%), paronychia (37-54%) and stomatitis (40-72%), with high incidence of SAEs (63% for dacomitinib). However, the discontinuation for both drugs was only 10%. The ILD is an important pulmonary toxicity reported related to EGFR-TKI. Osimertinib studies have reported ILD rates between 2% (early studies) and 4% (phase 3 studies). Compared to other EGFR- TKI, ILD is slightly higher in osimertinib-exposed patients (4% vs. 2%) (13), but ILD is usually reversible with corticosteroids and manageable, with no fatal event. However, in the patients exposed to osimertinib in combination with durvalumab, up to 64% of patients experienced ILD, with 13% of SAEs (26) not previously seen with other EGFR-TKIs (37), which determined the early stop of this arm in the TATTON study. Other toxicity more related to osimertinib is the QTc prolongation, which has been reported in 4% of the patients treated with osimertinib from the AURA studies, but up to 10% in the FLAURA study. This rate was slightly higher than the 4% reported for other EGFR-TKI. However, the SAEs related to QTc prolongation were very low is both groups (2% for osimertinib vs. 1% for other EGFR-TKIs), with no fatal events. Globally, the safety, toxicity profile and tolerability favor osimertinib compared to EGFR-TKIs. Only the slightly higher ILD and QTc prolongation rates are different from other EGFR-TKIs, being most of them manageable with no fatal events associated. This suitable profile together with the efficacy data, is a key argument than can tip the balance in favor of osimertinib. 8. Conclusion Osimertinib is an oral third-generation EGFR-TKIs, specifically designed to inhibit EGFR sensitizing mutations and the acquired T790M-mutation. Osimertinib showed greater efficacy, with an extraordinary CNS activity, compared to chemotherapy with a manageable safety profile in pretreated T790M+ EGFR-mutated patients. In untreated EGFR-mutated patients, osimertinib has demonstrated improved PFS compared to other EGFR-TKIs with similar toxicity profile, but lower rate of SAEs; OS mature data are still ongoing. Preliminary data of osimertinib in combination with antiangiogenic drugs or targeted therapies (MET-driver) shows encouraging activity, with no significant adding toxicities. 9. Expert opinion Osimertinib is a third-generation EGFR-TKI that can overcome acquired resistance due to T790M- mutation while also remaining effective against sensitive EGFR-mutations, with minimal activity on wild-type EGFR tumors. The safety and tolerability profile has been characterized and is considered acceptable. Osimertinib has demonstrated greater efficacy, highlighting the CNS activity, compared to chemotherapy with a manageable safety profile in T790M+ patients, and was approved by the FDA in 2015, in less than three years. It is currently the standard of care after failure to prior EGFR- TKI if T790M+ mutations are detected either in tissue or ctDNA. However, the therapeutic strategy is changing due to the FLAURA study. In untreated EGFR-mutated patients, osimertinib improved PFS by more than 8 months compared to other EGFR-TKIs with a similar toxicity profile, but with a lower SAE rate. In April 2018, the FDA and EMA approved osimertinib in the first-line setting. Although the OS data from FLAURA study are not yet mature, post-progression data revealed that all time-to-event post-progression endpoints favored osimertinib. Final OS data will establish the true benefit of osimertinib as frontline therapy compared to the sequential strategy guided by T790M status. Novel resistance mechanisms post-osimertinib such as EGFR C797S mutation and other bypass mechanisms can also play a role on the management of this population. Even though the question of the optimal strategy remains unanswered, osimertinib is already approved and available for untreated and pretreated (T790M+) EGFR-mutated patients. The tolerability and safety profile are clearly favorable for osimertinib with lower SAEs rates, except for the slightly higher rate of ILD, which remains manageable. Osimertinib is being explored in combination with other drugs. Preliminary data with durvalumab showed increased IDL, but further studies are needed evaluating the activity and safety of ICIs in the EGFR+ population to establish whether ICIs should be in the EGFR+ therapeutic scenario. Preliminary data of osimertinib plus antiangiogenic drugs and MET-driver therapy shows encouraging activity, without added toxicities. Finally, osimertinib is also being assessed in early stages after complete resection. No data are available for the EGFR population and currently the standard of care is adjuvant platinum-based chemotherapy, regardless of the molecular status. The ADAURA study will allow us to determine whether targeted therapy benefit is limited to advanced disease. Over the next few years, osimertinib will be consolidated as standard therapy in the advanced EGFR population, either in untreated patients as upfront therapy or in pretreated patients, depending on the mature OS data from the FLAURA study in combination with the CNS activity and safety; and probably in early stage disease also, as the results of the ADAURA study are as encouraging and optimistic as expected. 2. Advanced EGFR-mutated NSCLC patients, after failure on prior EGFR TKI, if T790M resistance mutation is present Pharmacology description/mechanism of action Osimertinib is an irreversible EGFR inhibitor for tumors harboring sensitizing and T790M TKI-resistance mutations. It is a mono- anilinopyrimidine compound that is less potent at inhibiting phosphorylation in EGFR-wild-type cell lines, with ~200-fold greater potency against L858R/T790M than EGFR-wild-type. Route of administration Oral. Funding This paper was not funded Disclosure statement The authors have no relevant affiliations or financial involvement wi h any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.” Acknowledgements The authors thank Sarah MacKenzie for English language editing. References *=of importance, **= of considerable importance 1. Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, et al. European cancer mortality predictions for the year 2017, with focus on lung cancer. Ann Oncol. 2017;28(5):1117–23. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018: Cancer Statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. 3. Hirsh V. 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