Real-world outcomes, treatment patterns and T790M testing rates in non-small cell lung cancer patients treated with first-line first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors from the Slovenian cohort of the REFLECT study

Lung cancer remains a major public health challenge worldwide, due to its diagnosis in advanced stages and high rate of mortality.^1,2 The discovery of sensitizing mutations to epidermal growth factor receptor (EGFR) has changed the treatment paradigm for lung cancer and has allowed for improved outcomes in patients with tumours harboring such actionable mutations.^3,4 Tyrosine kinase inhibitors (TKIs) targeting EGFR have proven efficacy for the treatment of EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) and are the treatment of choice when this sensitizing mutation is found.¹ Several generations of EGFR TKIs have been developed and have become gradually available – from the first-generation erlotinib and gefitinib, to second-generation afatinib and dacomitinib, and third-generation osimertinib.⁵

Initial treatment recommendations for metastatic EGFRm NSCLC relied on first- and second-generation (1G/2G) EGFR TKIs, but despite promising initial responses to these therapies, the disease inevitably develops resistance and the progression requires treatment change.⁶ In approximately half of cases, the resistance is mediated by the EGFR secondary mutation T790M^1,7, which is targeted by osimertinib in exon 20.⁸ Based on AURA3 study results, the standard of care is now testing for the T790M mutation in all patients whose disease has progressed on 1G/2G EGFR TKIs and treatment with osimertinib when the T790M resistance mutation is identified.^1,7,8 Based on the FLAURA study results, which showed significant survival benefit with osimertinib versus comparator EGFR TKIs, osimertinib received approval by the European Medicines Agency in 2018 and became the preferred first-line (1L) treatment option in advanced or metastatic EGFRm NSCLC.^1,9

The implementation of testing and treatment recommendations in clinical practice is not always a simple process. Access to new methods of molecular testing and novel therapies may be affected by lengthy local approvals and reimbursement processes, particularly in Central Eastern Europe (CEE).^10,11 Among countries in this region, Slovenia benefits from having a long tradition in cancer care and one of the oldest population-based cancer registries in Europe.^12,13 The advantage of having implemented a national cancer registry consists in the objective evaluation of the burden of disease and trends over time and is in direct conjunction with adequate setting and resource allocation at institutional level.^12,14

In Slovenia, the molecular testing of EGFRm is reflex and it was partially covered by pharmaceutical companies until July 2020, when it became fully reimbursed by the public health system.¹⁵ However, the reimbursement of innovative anti-cancer therapies is still not optimal, and it exceeds 2 years.¹⁶ For example, the newly approved osimertinib as 1L therapy was reimbursed only in October 2020.

In addition to patient and tumour characteristics, the treatment decisions in real-world (RW) practice are driven by clinical and cost-effectiveness, safety, and availability of treatments.¹⁷ As shown by the recent RW experience with 1L 1G/2G EGFR TKIs, the efficacy and safety of these agents proven in registration trials usually translate in real-life practice; yet, the testing rates of the resistance mutation T790M are not optimal.^{18, 19, 20, 21, 22, 23, 24, 25, 26} To what extent the same findings apply in the Slovenian population is unknown. For this reason, Slovenia participated in this multinational medical chart review with the overarching goals of understanding the outcomes of EGFRm NSCLC patients initiated on 1L 1G/2G EGFR TKIs, treatment and T790M testing patterns, and attrition rates in various locations from Europe and Israel.²⁷ Here we present the results of the Slovenian patients included in this study.

In total, 120 medical charts were included in this medical chart review from 3 study sites in Slovenia. The sites participating in the REFLECT study were also the only centres where lung cancer is being treated in Slovenia: 1 national cancer centre and 2 university hospitals.

First-line EGFR TKI therapy, progression and survival

The 1L EGFR TKI therapies initiated during the period of interest for the study had a balanced distribution: 37% of patients received erlotinib, 32% gefitinib and 31% afatinib. At the time of data collection, 94 patients (78%) discontinued 1L EGFR TKIs due to progression events or toxicities. Toxicities occurred in 9 cases (8%), with 5 of them (4%) not starting any further treatment line. A number of 26 patients (22%) continued 1L treatment.

In total, 89 progression events per protocol were reported: 47 radiological progression events (39%), 22 clinical progression events (18%), 16 deaths (13%) and 4 cases (3%) with start of a new therapy line without documented progression.

Median (95% CI) rwPFS was 15.6 (12.6, 19.2) months (Figure 1A). Estimated probabilities for rwPFS (95% CI) at 12, 24 and 36 months were 63% (54%, 71%), 39% (30%, 48%) and 18%% (10%, 28%), respectively. Median (95% CI) OS from start of 1L EGFR TKI was 28.9 (25.0, 34.3) months (Figure 1B). Estimated probabilities for OS (95% CI) at 12, 24 and 36 months were 83% (75%, 89%), 61% (51%, 69%) and 36% (27%, 46%), respectively.

Figure 1

Second and subsequent therapy lines

Of the 89 patients with disease progression on 1L EGFR TKIs, 66 (74%) initiated 2L treatment. In the Slovenian cohort of patients, 16 (13%) patients who discontinued 1L died before receiving 2L treatment, while 12 (10%) patients alive of the time of 1L discontinuation did not receive any further line. The 2L treatments included osimertinib (82%), chemotherapy (17%) and other targeted therapy (1%). At the time of data collection 18 patients (28%) were still receiving 2L treatment (Figure 2).

Figure 2

Of the 48 patients discontinuing 2L, 19 (40%) received third-line (3L) treatment, which consisted of chemotherapy (53%), targeted therapy (26%), osimertinib (16%), or immuno-oncological therapy (5%) (Figure 2). At the end of data collection, 1 patient (5%) was still on 3L treatment. Attrition rates on 1L, 2L, and 3L treatment are shown in Figure 3.

Figure 3

Of the 18 patients discontinuing 3L, 5 (28%) received fourth-line (4L) treatment, which consisted of targeted therapy (60%) or osimertinib (40%). All patients discontinued 4L, with one case of death being registered, while the remaining 4 patients received the fifth-line of treatment (5L), which consisted of targeted therapy (50%), chemotherapy (25%), and osimertinib (25%) (Figure 2). All patients discontinued 5L treatment.

This is the first comprehensive analysis of the outcomes, treatment patterns, and testing rates in metastatic EGFRm NSCLC patients who received 1L 1G/2G EGFR TKI therapy in Slovenia over 3.5 years, from 2015 to 2018. This is a nationally representative dataset for our clinical practice because all 3 large-volume centers from Slovenia that ensure an integrated oncology care of lung cancer patients, with national coverage, participated in the REFLECT study.

Considering the real-life setting, the unselected population of patients with EGFRm NSCLC and the relatively equal distribution of 1G/2G EGFR TKIs (37% erlotinib, 32% afatinib, 31% gefitinib), our findings indicate positive treatment outcomes with 1L EGFR TKIs with a median rwPFS of 15.6 months. In the overall cohort from the REFLECT study (n=896), the median rwPFS was 13.0 (95% CI 12.3, 14.1) months and more patients received afatinib (45%).²⁷ In clinical trials of 1G/2G EGFR TKI therapy, the acquired resistance developed after a median of 9.2–14.7 months of targeted treatment.⁶ Other European RW studies that partially overlap with the limits of the data collection set for the REFLECT study, but with a different distribution of the 1G/2G EGFR TKI therapies have shown PFS ranging from 7.6 to 11.0 months.^{18, 19, 20,22,26} The enhanced rwPFS outcomes observed in the Slovenian cohort may be the result of more standardized and homogenous cancer care across centers, including established pathways for EGFR and T790M mutation testing, as well as effective control policies. Furthermore, in many cases the treatment may have continued beyond radiological progression, a common approach in patients with genetic actionable alterations.¹ Another observational study specifically exploring the continuation of EGFR TKIs beyond radiological progression showed that patients continued treatment without clinical deterioration for a median of 5.1 months and had a median PFS of 15.3 months.²⁸

The median OS from the start of the 1L 1G/2G EGFR TKI therapy was 28.9 months in the Slovenian cohort and 26.2 (95% CI 23.6, 28.4) months in the overall REFLECT study cohort.²⁷ In general, the median OS reported in RW studies with 1L 1G/2G EGFR TKIs varies greatly, due to timelines set for the analysis, factors related to the healthcare system and access to EGFR TKIs, patient characteristics and data quality. Our findings are in line with those of other reports and are relevant for the period under study, when third-generation EGFR TKI osimertinib was not yet approved as 1L treatment.^{18,20,22,24,26} Following osimertinib 1L approval and subsequent market entries, more data on the effectiveness of osimertinib in various geographies are awaited.

Upon progression on 1L 1G/2G EGFR TKIs, Slovenian national guidelines for the treatment of NSCLC, in accordance with European guidelines, recommend testing for resistance mutation T790M and, in patients with positive test results initiation of osimertinib.^1,29 In this cohort, 82% of patients were tested for the presence of T790M upon progression on 1L; the resistance mutation was identified in two-thirds (68%) of these patients, thereby providing an opportunity for treatment that is effective against disease with T790M mutation. Expressed at the level of the overall Slovenian cohort (42%), this positive rate of T790M is in line with other RW data from European cohorts.^21,23,30,31 Additionally, in most patients (n=66) receiving 2L treatment in our cohort, post-progression treatment consisted of osimertinib (82%), preponderantly in patients with the T790M mutation. These results support a unified approach to T790M testing and subsequent treatment at the national level, consistent with guidelines recommendations.^1,29 In current local practice, when a clinical progression is suspected (even before radiologic progression), an active search with minimally invasive liquid biopsy for the presence of resistance T790M mutation is begun. This approach allows for early initiation of 2L systemic therapy with the goal of improving patient outcomes.

Over the course of the lung cancer disease, many patients develop CNS metastases, which confer a poor prognosis and present additional treatment challenges.³² CNS metastases are often identified in patients with adenocarcinoma and molecular alterations, and their incidence is significantly correlated with the presence of EGFR-activating mutations.^1,33,34 In this cohort, 38% of patients had CNS metastases, most of them present at the time of diagnosis of the metastatic stage of lung cancer (28%). In a local retrospective analysis exploring the cumulative incidence of brain metastases in 629 patients with adenocarcinomas tested for EGFRm, those with the EGFR activating mutation had a longer time to CNS progression (25.9 vs. 11.9 months, p=0.002).³⁵ In this REFLECT study cohort, the time to CNS progression was 19.8 months, with a median OS of 24.3 months in patients with CNS metastases at the start of 1L 1G/2G EGFR TKI therapy. The difference may be due to advances in radiological techniques used to identify CNS metastases, as well as practice changes. The dynamic landscape of technology, improved local control and reduced morbidity are reflected in the current management of CNS metastases as stereotactic radiosurgery has become the foremost treatment modality in patients with “limited” intracranial disease.³⁶

REFLECT was primarily a study of attrition rates between treatment lines. In this cohort, of the 78 patients who started 1L 1G/2G EGFR TKIs and were alive at the time of treatment discontinuation, 12 (15%) did not receive 2L treatment. The trend of not receiving further treatment was sustained in subsequent lines, although the number of patients alive at the time of treatment discontinuation progressively decreased. The rate of patients not receiving 2L treatment after the 1L EGFR TKIs was initially reported in clinical trials and it was approximately 35%, whereas in RW studies the rate varies more widely (10–62%).^25,37,38 Although the REFLECT study did not explore the reasons why patients did not receive further treatment lines, data reported in the literature suggest various causes, including lack of genetic testing, low T790M mutation rate, poor performance status and even patient’s preference not to receive the next line of treatment, which would be chemotherapy in many cases.³⁷ In our cohort we noticed that 18% patients progressing on 1L EGFR TKI were not tested for presence of T790M mutation. The rationale behind the lack of T790M testing at progression was not investigated, but such finding might be explained by rapid deterioration of clinical status followed by death on 1L EGFR TKI, presence of exon 20 insertion, which is associated with limited efficacy of common EGFR TKIs and unfavorable prognosis or poor performance status at the time of disease progression rendering patient ineligible for any further systemic therapy.^37,39,40 Hence, the true T790M positivity rate and proportion of patients eligible for targeted 2L may be different in real-life. Beyond possible differences in healthcare setting and availability of effective treatment options, exploring locally in more depth the reasons behind attrition rates is crucial to further improve patient outcomes.

The real-life character of this study confers both strengths and limitations. With a minimal set of inclusion and exclusion criteria, and a representative dataset for Slovenia, this study allowed for building RW evidence on 1L 1G/2G EGFR TKI therapy at the national level based on a 3.5-year data review (2015–2018). The fact that data collection relied entirely on information existing in patients’ records, which sometimes have insufficient or missing data, is a key limitation in such designs. Nevertheless, Slovenia benefited from the participation of all 3 of the country’s institutions in which lung cancer is treated. As a result, data availability was very good, with minimal cases of unknown information in patients’ histories. In general, secondary data collection may be subject to selection bias, including of sites and patients. To reduce site selection bias and potential patients’ spreading between sites, all 3 Slovenian comprehensive cancer centers were included in the study. To reduce patient selection bias, the ethics review package submitted has requested an informed consent waiver, which was granted by the National Ethics Committee. Thus, all medical records of eligible patients were considered, irrespective of the vital status at the time of data collection and patients were enrolled consecutively in the electronic data collection form in the chronological order of starting the 1L 1G/2G EGFR TKI therapy. In contrast to clinical trials design, disease progression was not confirmed through a standardized, objective method, and the study definition reflects the RW situation (start of a new line of therapy or any other records indicative of progression, besides radiological tests). Finally, the study was not powered to compare the individual 1G/2G EGFR TKIs, and therefore outcomes could not be further characterized by molecule.

This real-world study, performed in a representative dataset for Slovenian clinical practice, provides insights into the effectiveness of 1G/2G EGFR TKIs and T790M testing patterns in EGFRm NSCLC patients receiving routine care. The survival outcomes and reduced attrition rate reported in this real-life setting from our country are encouraging. Newer 1L treatment options require follow-up studies to reflect the dynamic changes in clinical practice.