Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain: OSIREX-Spanish Lung Cancer Group

Background AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Methods Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016–December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. Results 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. Conclusion This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Trial registration Clinical trial registration number: NCT03790397.


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Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Trial registration: Clinical trial registration number: NCT03790397.

Background
In Spain occur about 27,351 new lung cancer cases per year and the disease was responsible for 22,896 deaths in 2018 [1,2]. Most non-small cell lung cancer (NSCLC) patients are diagnosed with unresectable disease and around 40% with advanced disease.
The identification of oncogenic driver alterations that can be targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI: erlotinib, gefitinib, afatinib, dacotinib) for EGFR mutated tumors has improved median progressionfree survival (PFS), overall response rates and quality of life in metastatic NSCLC patients, making EGFR TKIs the first-line treatment of choice in patients with EGFR mutation (EGFRm) advanced NSCLC [3]. Unfortunately, however, even these patients eventually develop resistance.
Until recently, treatment options in the post-EGFR-TKI second-line setting were limited, with low rates of response to platinum-based doublet chemotherapies [6][7][8].
Osimertinib (AZD9291) is a potent oral irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations with activity in the central nervous system (CNS) [9,10]. In the phase 1 component of the phase 1/2 AURA trial (ClinicalTrials.gov number, NCT01802632), objective response rate (ORR) for osimertinib in patients with T790M-positive NSCLC was 61% and median PFS was 9.6 months [11].
The publication of the FLAURA study, which obtained a significantly longer PFS and overall survival (OS) than with standard EGFR-TKI in first-line (18.9 months vs. 10.2 months), led to the approval of osimertinib for standard first-line treatment.
Osimertinib has been approved in Europe and commercialized in Spain for the treatment of patients with EGFR T790M-positive (EGFR/T790M+) advanced NSCL C and in first line regardless the T790M mutation status.
Then, just after the ASTRIS study had closed recruitment [12], the Foreign Medication Program was opened. This is a Special Use Medication Program (SUMP) from the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) to access osimertinib in Spain for the patient population without other treatment options for pretreated patients with EGFR/T790M+ advanced NSCLC.
Based on the lack of real-world results in this setting, and the experience with osimertinib in Spain since 2015, we proposed a retrospective study to describe the experience in terms of efficacy and safety in EGFR/T790M+ NSCLC.

Study population
This was a post-authorization-other-designs, noninterventional, multicenter, retrospective study that in no way interfered with physicians' normal clinical practice. The study is based on collection of data about those patients treated with osimertinib within the SUMP and therefore did not involve any diagnostic or therapeutic procedures beyond normal clinical practice. The results provide some insights into the clinical efficacy of osimertinib treatment and consumption of hospital primary care resources.
Eligible patients had histologically or cytologically confirmed stage IIIb/IV EGFR/T790M+ NSCLC and had received osimertinib treatment within the osimertinib Spanish Special Use Medication Program (SUMP).
Living patients had to have signed and dated an Independent Ethics Committee/Institutional Review Board (IRB/EC)-approved written informed consent form following regulatory and institutional guidelines. This had to be obtained before the performance of any protocolrelated procedures that were not part of normal care.

Assessment
The primary objective was to estimate PFS to osimertinib. Secondary objectives were to establish osimertinib toxicity profile, estimate duration of response (DOR), ORR by RECIST v1.1 and report on the consumption of hospital and primary care resources.
All clinical efficacy objectives were to be assessed depending on treatment line (first, second, third or further lines).
Date of progression, type of progression, DOR defined as time from documentation of tumor response until disease progression or death, and ORR by RECIST v1.1 were measured.
Adverse events (AEs) related to osimertinib treatment received within the SUMP in Spain were filed in a Remote Data Capture system (RDC)/Case Report Form (CRF). Type and severity of AEs were classified according to the NCI CTCAE Version 5.0. The causal relationship to the study drug was determined by the physician and should be used to assess all AEs. The casual relationship may be either "related" or "not related".

Independent ethics committee (IEC) or institutional review board (IRB)
The study was evaluated by the Ethical Committee of Hospital Universitario Puerta de Hierro de Majadahonda, Madrid.
The study was also classified by the Spanish Health Authority as "EPA-OD" (post-authorization study, other designs). The ethical committees of other hospitals also reviewed the study as per local practice. The study was carried out following the Declaration of Helsinki on Good Clinical Practices and Organic Law 3/2018, 5th December on Protection of Personal Data and digital rights that were guaranteed during the study. The study was coordinated and monitored by the Spanish Lung Cancer Group (SLCG) and financed by AstraZeneca following the specifications in the protocol. This funding included the cost of submitting the study for approval to an accredited IEC; submission for classification to the AEMPS; database design, maintenance and management; monitoring activities; statistical analysis and corresponding statistical report.

Data quality assurance
The application used for data collection had safety margins and internal coherence rules to avoid input of incorrect data or anomalous or incoherent values. Data quality and queries were revised and dealt with by the SLCG Data Management Department. All patient information required was included in a Remote Data Capture system (RDC)/Case Report Form (CRF).

Statistical analysis
A total of approximately 156 patients were included from several Spanish sites. The observation period was from August 2016 and December 2018.
The following descriptive statistics were used. Frequency statistics for categorical variables: number and percentage. Mean, standard deviation, median (interquartile range) and categorical distribution for quantitative variables (e.g. number of exacerbations, hospital admissions, emergency unit visits, prescriptions, primary care visits). In addition, two-sided 95% confidence intervals (CI) were presented for the specified study outcomes.
PFS was defined from initiation of osimertinib treatment until radiological and/or clinical progression or death from any cause, whichever occurred first. OS was defined from initiation of osimertinib to death from any cause.
Progression was ideally measured by RECIST v 1.1; patients with unknown progression status at time of data collection were censored at the date they were last known to be free of radiological and/or clinical progression. DOR was defined as time from documentation of tumor response to disease progression or death.
PFS and DOR were estimated using Kaplan-Meier analysis.
ORR, defined as percentage of patients achieving complete or partial response, was evaluated based on RECIST v 1.1 response criteria.
Clinical efficacy variables were assessed for patients (squamous vs non-squamous) depending on whether they received first, second, third or subsequent lines of treatment. Safety of osimertinib administration was described by tabulation of the CTCAE version 5.0. No inferential analyses were foreseen. No interim analyses were predefined. All study results were considered exploratory and descriptive by design. All statistical analyses were performed using R software.

Protocol deviations
There were no major protocol deviations as this was not a clinical trial and data collection was carried out in a timely manner and according to protocol. One hundred and fifty-six patients were included but only 155 were valid since 1 patient was an inclusion error.
Regarding chemotherapy, 152 of the 155 patients included (98.1%) received chemotherapy during follow up.

Efficacy results
According to RECIST v 1.1, best response to osimertinib was distributed thus: 2 (1.3%) patients with complete response (CR), 63 (40.6%) with partial response (PR), 48 (31%) with stable disease (SD), 18 (11.6%) with progression and 24 (15.5%) without registered response. Of the 131 patients with registered response to osimertinib treatment, estimated objective response (PR or CR reached) was 42%. Regarding comparison of response rates between treatment lines when osimertinib was administered, no statistically significant differences were observed among the 75 patients who received osimertinib in first or second line with registered response (of the 35 that responded, 46.7%) and the 56 patients who received osimertinib in third or fourth line with registered response (of the 30 that responded, 53.6%) (pvalue = 0.482). Table 2 shows the drugs administered as first, second and third lines prior to osimertinib. Table 3 shows a summary of AEs on osimertinib classified according to the CTCAEv5.0. One hundred and fifty-five patients received treatment and were included in the study. Of these, 76 (49.0%) did not show AEs; 29 (18.7%) showed AEs with a maximum grade of 1; 32 (20.6%) showed AEs with a maximum grade of 2; 14 (9%) showed AEs with a maximum grade of 3; 2 (1.3%) with a maximum grade of 4; and 2 (1.3%) with a maximum grade of 5.

Adverse events (AEs)
Osimertinib dose was adjusted in 26 patients (16%) and was due to toxicity in 18 of these (11.6%). Treatment was discontinued in 4 patients (2.6% of the total treated) due to toxicity.

Follow up and survival
Patients were monitored from the beginning of osimertinib treatment until time of death, loss to follow up or study closure while they were still alive. Median follow up for all patients was 11.7 months (range 0.4-32.0 months), while the median for those patients that were alive was 14.9 months (range 1.8-32.0 months).
Of the 155 patients included, 89 (57.4%) progressed during follow up, 16 (10.3%) died before progression and 50 (32.3%) were still alive without progression at the trial's closure. Figure 2 shows the estimated median PFS curve for this type of patients, with a median PFS of 9.4 months (95% CI, 7.3-11.6 months).
PFS can be compared by treatment line. Of the 87 patients that received osimertinib as first or second line, 61 progressed or died during follow up (70.1%). Of the 68 patients who received osimertinib as third or further line, 44 progressed or died during follow up (64.7%). No statistically significant differences were observed between the PFS curves of both groups of patients (p-value = 0.113).   Table 3 Adverse events on treatment with osimertinib
No significant differences were observed when comparing OS according to presence or absence of CNS metastases at the initiation of osimertinib treatment (p-value = 0.365). Median OS was 18.3 months (95% CI, 14.9-21.7 months) and 13.8 months (95% CI, 11.0-16.6 months) for those patients without and with brain involvement prior to osimertinib initiation, respectively.

Follow up of patients that received osimertinib as last treatment
Overall survival for the 134 patients that received osimertinib as last treatment (no posterior treatment registered) was compared with that of the 21 patients that received subsequent chemotherapy and no significant differences were observed (p-value = 0.411).
Of the 134 patients, whose last treatment was osimertinib, the end date was not registered for 52 of them, so they continued on treatment at the date of treatment data collection closure (31/12/2018).
The small number of these subgroup of patients does not lend itself to precise estimates, making it difficult to detect potential differences. Estimated median OS for Table 3 Adverse events on treatment with osimertinib (Continued)   Of the 6 patients included in this group that had received previous treatment, 3 (50%) died during follow up. Estimated median OS for these patients was 15.6 months, while estimated median PFS was 9.4 months.

Health service resources
Data on use of health service resources during treatment with osimertinib (from first dose to last) was collected. It was assumed that all 155 patients had finished treatment with osimertinib, so none were censored.
The use of health service resources is described according to previous characteristics before osimertinib treatment. Table 4 shows the main number of resources used according to different characteristics. A comparison between the values observed using the Mann-Whitney U test is also shown. The results show that stage T3-T4 patients consumed more resources, with a significant difference in R13 (other imaging tests). Similarly, nonsmokers and those who had more previous chemotherapy lines also required more resources.

Discussion
Obtaining real-life data is a very important factor in understanding drug efficacy. Typically, clinical trials include a highly selected population that is not always representative of real-world clinical practice. Our study consolidates information about the efficacy of osimertinib in any line of treatment, thus over 40% of our patients received the drug beyond third line, and in 78% of cases patients had some type of comorbidity.
In fact, PFS was 9.4 months (95% CI, 7.5-11.6), which does not show significant differences even in fourth line, according to the literature [13].
It should be remembered that standard treatment with chemotherapy in these patients does not reach more than 5-6 months PFS, at best [14]. Other real-world studies with osimertinib [15] have reached PFS of 10.1 months (95% CI, 9.2-11.0 months), including a recently published pooled analysis [16] with median PFS of 9.9 months (95% CI, 9.5-12.3), very similar to our own.
Similarly, for the other objective measure of efficacy, ORR, significant differences were not observed by treatment line. Our study obtained ORR of 50%, very similar to other retrospective studies [17] and to pivotal studies with osimertinib in these patients, bearing in mind they are mostly Caucasian, and Asian populations have higher response rates and, usually, longer PFS [18].
As well as efficacy, one of the most important factors is the excellent tolerance and minimal side effects with osimertinib. Of 155 patients that received treatment and were included in the study, 76 (49.0%) did not experience AEs. Only 2 (1.3%) had AEs with a maximum grade of 4, 2 patients (1.3%) had AEs with a maximum grade of 5, and discontinuation due to toxicity was just 2.6%, in line with the pivotal clinical trials published. CNS involvement, both at time of initial diagnosis and at disease progression, is common in these patients [19] and is an indicator of poor prognosis. It should be noted that among patients with brain metastases at the start of osimertinib treatment, the majority had been previously treated (58%) and, despite this, response rate with osimertinib was 40%-rising to almost 70% if we include stabilizations-confirming the drug's activity in this setting [8]. Notably, all this was achieved outside the framework of a clinical trial in which only asymptomatic patients with stable disease and not requiring steroids were included in the previous 4 weeks [20].
Since the publication of the results of the FLAURA study, which demonstrated clearly improved median PFS in patients treated with osimertinib (18.9 months) versus first-generation TKIs (10.2 months) [21], it seems that the debate about the role of osimertinib now no longer focuses on its activity in second lines, when the patient develops the resistance mutation, but on the treatment sequence.
It is important to note that the greatest use of resources occurs when more lines of treatment have been given prior to osimertinib. Therefore, in addition to the clear benefit of early-line osimertinib, toxicity is reduced and the economic benefit is increased.

Conclusion
Given all of the above, we believe that it is important to report real-world data from patients treated with osimertinib in any line. Our results with 155 patients are similar to those of real-world studies in China with 77 patients [22], Germany with 51 [15], or France with 205 patients [23] and demonstrate that real-world data closely agrees with that obtained in pivotal clinical trials, even without patient selection.
Abbreviations AEs: Adverse events; CNS: Central nervous system; CRF: Case report form; DOR: Duration of response; EPA-OD: Post-authorization study, other designs; IEC: Independent ethics committee; NSCLC: Non-small cell lung cancer; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RDC: Remote data capture system; SD: Stable disease; SLCG: Spanish lung cancer group; SUMP: Special use medication program; TKI: Tyrosine kinase inhibitors

Funding
The study was coordinated and monitored by the Spanish Lung Cancer Group (SLCG) and financed by AstraZeneca following the specifications in the protocol. This funding included the cost of submitting the study for approval to an accredited Independent Ethics Committee (IEC); submission for classification to the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS); database design, maintenance and management; monitoring activities; statistical analysis and corresponding statistical report.

Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Ethics approval and consent to participate The study was evaluated by the Ethical Committee of Hospital Universitario Puerta de Hierro de Majadahonda, Madrid. The study was also classified by the Spanish Health Authority as "EPA-OD" (post-authorization study, other designs). The study was carried out following the Declaration of Helsinki on Good Clinical Practices and Organic Law 3/2018, 5th December on Protection of Personal Data and digital rights that were guaranteed during the study. Alive patients have signed and dated an Institutional Review Board/Independent Ethics Committee (IRB/IEC)approved written informed consent form in accordance with regulatory and institutional guidelines.

Consent for publication
Not applicable.

Competing interests
A summary conflict of interest statement in a separate document.
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