FLAURA in the real world: osimertinib in potentially trial-eligible and ineligible patients with EGFR-mutated advanced non-small cell lung cancer

Introduction

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR). It is effective against both EGFR-TKI-sensitizing mutations and EGFR T790M resistance mutations in patients with non-small cell lung cancer (NSCLC), including those with metastases in the central nervous system (CNS) (1).

In 2018, the Food and Drug Administration (FDA) approved osimertinib as the first-line treatment for patients with metastatic NSCLC who have EGFR exon 19 deletions or exon 21 L858R mutations. This decision was based on results of the FLAURA trial (NCT02296125), an international, multicenter, randomized, double-blind phase 3 study that assessed the efficacy and safety of osimertinib compared to gefitinib or erlotinib, both first-generation EGFR TKIs. A total of 556 patients with untreated advanced NSCLC and either EGFR exon 19 deletion or exon 21 L858R mutations were randomly assigned in a 1:1 ratio to receive either osimertinib 80 mg once daily or standard treatment with gefitinib at 250 mg or erlotinib at 150 mg once daily (1-3).

The trial demonstrated that patients treated with osimertinib experienced significantly longer progression-free survival (PFS) compared to those receiving gefitinib or erlotinib (both included in the comparator group), with median durations of 18.9 vs. 10.2 months, respectively [hazard ratio (HR) 0.46; P<0.001] for disease progression or death (2). In the final analysis, the osimertinib group had a median overall survival (mOS) of 38.6 months [95% confidence interval (CI): 34.5–41.8] while the comparator group had a mOS of 31.8 months (95% CI: 26.6–36), yielding an HR for death 0.80 (95% CI: 0.64–1.00; P=0.04) (1). Moreover, the safety profile of osimertinib was comparable to that of comparator EGFR-TKIs, although it exhibited a slightly lower incidence of grade 3 or higher adverse events, even with longer treatment durations, indicating better tolerability compared to the comparator EGFR-TKIs (1-3).

Despite the promising results from clinical trial results, there is limited information on the effectiveness of first-line osimertinib in real-world settings. Gathering such data is crucial, as it can reveal how osimertinib performs outside of controlled environments and whether its efficacy differs from that observed in clinical trials. Most recently, Connor Wells et al. studied real-world patient outcomes with osimertinib in individuals who would and would not have met the eligibility criteria for the original FLAURA trial. Their findings indicated significant discrepancies in the mOS between patients who would have qualified for FLAURA compared to those who would not have (4).

Design of real-world study of FLAURA

Patients were identified using the British Columbia (BC) Cancer Agency pharmacy database. Data on patients with advanced lung cancer with EGFR exon 19 deletions or exon 21 L858R mutations, who received at least one dose of osimertinib between January 1, 2020 and October 31, 2022 were collected retrospectively using a province-wide electronic health medical record system. Subjects who had previously received another EGFR inhibitor before switching to osimertinib due to funding or toxicity were excluded from the study (4).

Once patients were identified based on the specified criteria, they were categorized into two groups—FLAURA eligible and ineligible—according to five major ineligibility criteria used in the FLAURA clinical trial. These criteria included: (I) Eastern Cooperative Oncology Group (ECOG) performance status ≥2; (II) symptomatic brain metastases/remained on steroids or spinal cord compression; (III) hemoglobin <90 g/L; (IV) platelet <100×10⁹/L; or (V) creatinine >1.5× upper limit of normal with a clearance <50 mL/min (4).

The study’s co-primary endpoint focused on examining the mOS of patients using first-line osimertinib for advanced EGFR mutant NSCLC in the entire population and by trial eligibility.

Conduct of real-world study of FLAURA

Three hundred and eleven patients were included in the study, with 44% (137/311) deemed ineligible for the original FLAURA trial. The reasons for ineligibility were as follows: 120 patients had ECOG ≥2; 21 had symptomatic brain metastases or cord compression, 7 had anemia, 5 had thrombocytopenia, and 9 had low creatinine clearance. Twenty-five patients met multiple ineligibility criteria (4).

Overall, regarding baseline characteristics, FLAURA-ineligible patients exhibited significantly higher rates of de novo stage IV disease (characterized by distant metastasis at initial diagnosis) and were more likely to have stage IVB disease with metastases to more than three sites at time of treatment compared to FLAURA eligible patients. Additionally, a higher proportion of FLAURA ineligible patients had brain metastasis (43% vs. 17%, P<0.01), which is a major prognostic determinant. There were no significant differences in baseline age or comorbidities (4).

The mOS for the FLAURA-eligible group was significantly longer at 34.2 months [95% CI: 28.9–not reached (NR)] compared to 15.8 months (95% CI: 11.9–20.2) for the ineligible group (P<0.001) (Table 1). At the time of analysis, 36% (63/174) of eligible patients had died while 70% (96/137) of ineligible patients had died. The adjusted HR of death after controlling for baseline factors of EGFR mutation type, elevated lactate dehydrogenase (LDH), asymptomatic brain metastases at diagnoses, bone metastases and stage [8^th edition tumor-node-metastasis (TNM) classification] at treatment initiation, was 2.03 (95% CI: 1.14–3.6, P=0.016) for ineligible patients. The adjusted HR for progression or death was 1.80 (95% CI: 1.06–3.05, P=0.029) for the ineligible group (4).

Furthermore, disease control (complete response + partial response + stable disease) was lower in ineligible patients compared to eligible patients, 78% vs. 91% (P=0.001). The rates of toxicity were similar between the two groups, with no significant difference in percentage of patients requiring dose reduction or treatment cessation due to toxicity (20% for eligible patients vs. 26% for ineligible patients, P=0.16) (4).

Discussion

This study aimed to reveal the efficacy of first line osimertinib in advanced EGFR mutant NSCLC in the real world. Notably, Connor Wells et al. provided data highlighting significant differences in outcomes between patients who would have been ineligible vs. eligible for the original FLAURA clinical trial. Specifically, the mOS for real-world patients deemed ineligible for FLAURA was about 18 months shorter than that of those who met the eligibility criteria. Meanwhile, the mOS for real-world patients who qualified for FLAURA was similar to the mOS observed in the FLAURA clinical trial.

It is not uncommon that real-world studies reveal significantly worse outcomes for patients classified as trial-ineligible compared to those who could potentially qualify for trials, whose outcomes often align with those observed in clinical trials. This pattern was also noted in real-world studies of KEYNOTE-024 and -042 in which patients with metastatic NSCLC were treated with immune checkpoint inhibitor pembrolizumab and were evaluated based on whether they were KEYNOTE trial-ineligible or potentially trial-eligible. In the trial-ineligible group, the mOS decreased by approximately 10 months (P=0.004) (5).

Interestingly, about 40% of patients in Connor Wells et al.’s study would have been ineligible for FLAURA, mostly due to poor performance status (ECOG ≥2). Additionally, patients who were FLAURA ineligible had higher burden of disease with greater rates of de novo stage IV disease and metastases to more than three sites at time of treatment compared to FLAURA eligible patients. These factors suggest a poorer functional baseline and likely contribute to the shorter mOS and the lower response rate in the FLAURA ineligible patients in this real-world study.

OSI-FACT and FLOWER, two studies that also studied the real-world efficacy of first line osimertinib in EGFR mutant advanced NSCLC, showed median time to treatment discontinuation (mTTD) that was similar to that of FLAURA eligible population in Connor Wells et al.’s study (Table 2) (6,7). Importantly, only approximately 16% of patients in OSI-FACT and FLOWER studies had an ECOG ≥2. Another study of 224 patients with advanced EGFR-mutated NSCLC in Germany treated with first line osimertinib demonstrated a median OS of 39.3 months in the FLAURA-like cohort (n=138), similar to osimertinib arm mOS of FLAURA trial. Meanwhile, the mOS in all patients (n=224) was slightly lower at 30.1 months though specific patient characteristics have not been published (Table 2) (8). Another small study of 56 patients with poor performance status, defined as ECOG 2–4, who were treated with osimertinib by Takamizawa et al. revealed that patients with ECOG of 2 had mOS of 14.5 months (n=36) while patients with ECOG of 3 or 4 had mOS only of 5 months (n=20) (9). These results further implicate that baseline performance status strongly influences the prognostication of patients.

Other factors that may contribute to the discrepancy of mOS duration between ineligible and eligible patients are increased tumor burden. The FLOWER study also demonstrated that the presence of metastases to 3 or more sites was associated with decreased OS (4,7). Moreover, the ineligible group had a higher frequency of L858R mutations (4), which has been associated with a worse prognosis (4,10,11).

Limitations of this real-world study of FLAURA to consider include the fact that data was retrospectively obtained and assessed, which allows for selection biases and possible missing information given that the parameters of the research project were not outlined at the time of patient chart documentation. Moreover, data was collected only in BC, which has a different healthcare system and may present a different patient population.

Despite the results of the real-world study of FLAURA showing worse outcomes in ineligible patients with EGFR mutant NSCLC, osimertinib will likely remain the first-line treatment for advanced EGFR mutant NSCLC even for “ineligible patients”, for the time being, given there are limited, if any, alternative therapies for such patients and those with poor performance status are often excluded from clinical trials. The less favorable prognosis for “ineligible patients” should not discourage clinicians from offering the best available therapy for those expected to live sufficiently long to derive benefit from osimertinib as patients will still likely benefit from symptom control due to responses observed in 60% of the patients. Additionally, a small minority still had a 36-month plus survival (4).

It is evident that additional studies and treatments are required to enhance outcomes for patients with poor baseline performance statuses. Recently, FLAURA-2 revealed improved progression-free survival (PFS) with combination therapy of osimertinib and platinum-based chemotherapy compared to osimertinib alone (12). However, the study was limited to patients with adequate performance status, adequate organ function, as well as controlled brain metastases. Furthermore, many oncologists may be reluctant to administer combination treatments to patients with compromised health due to concerns about increased toxicity and potentially poor outcomes. At this time, osimertinib remains the optimal and only treatment option for both FLAURA-eligible and ineligible patients.

Conclusions

The real-world study of FLAURA clinical trial demonstrated that mOS of patients deemed FLAURA-ineligible was about 18 months shorter than that of real-world patients who met FLAURA eligibility criteria. In contrast, the mOS of real-world patients who qualified for FLAURA was similar to that observed in the FLAURA clinical trial. Further analysis suggests that poorer performance status and functional baseline likely contribute to the shorter mOS in the FLAURA-ineligible patients. Additional studies are required to improve the outcomes of patients with poor baseline performance statuses and EGFR-mutated NSCLC. However, the less favorable prognosis for “ineligible patients” should not discourage clinicians from offering the best available therapy as of now.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-108/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-108/coif). S.I.O. has received honoraria from AnHeart Therapeutics, Pfizer, JNJ/Janssen, Daiichi Sankyo, Lilly, DAVA Oncology LLP; was on the Data Safety Monitoring Board or Advisory Board of Elevation Oncology; and has Stock/stock options in Turning Point Therapeutics, Elevation Oncology, MBrace Therapeutics. M.N. has received consulting fees from Caris Life Sciences (molecular tumor board), speakers bureaus from Mirati, Takeda, Janssen, and Blueprint Medicine, travel support from AnHeart Therapuetics; was on the Advisory Board of AstraZeneca, Daiichi Sankyo, Novartis, Lilly, Pfizer, EMD Serono, Genentech, Regeneron and BMS; and has Stock/stock options in MBrace Therapeutics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
3. FDA approves Osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations, Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations. Accessed April 24, 2024.
4. Connor Wells J, Mullin MM, Ho C, et al. Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial. Lung Cancer 2024;190:107529. [Crossref] [PubMed]
5. Griesinger F, Sebastian M, Brueckl WM, et al. Checkpoint Inhibitor Monotherapy in Potentially Trial-Eligible or Trial-Ineligible Patients With Metastatic NSCLC in the German Prospective CRISP Registry Real-World Cohort (AIO-TRK-0315). JTO Clin Res Rep 2024;5:100626. [Crossref] [PubMed]
6. Sakata Y, Sakata S, Oya Y, et al. Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation-positive non-small-cell lung cancer in a real-world setting (OSI-FACT). Eur J Cancer 2021;159:144-53. [Crossref] [PubMed]
7. Lorenzi M, Ferro A, Cecere F, et al. First-Line Osimertinib in Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Outcome and Safety in the Real World: FLOWER Study. Oncologist 2022;27:87-e115. [Crossref] [PubMed]
8. Griesinger F, Zacharias S. Long-term survival and treatment (tx) patterns in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive (m) advanced NSCLC treated with first-line (1L) osimertinib (osi): German cohort of a global real-world (rw) observational study. ESMO Open 2024;9:102607. [Crossref]
9. Takamizawa S, Okuma Y, Kato Y, et al. First-line osimertinib in EGFR mutation-positive non-small cell lung cancer patients with poor performance status. Future Oncol 2022;18:291-300. [Crossref] [PubMed]
10. Hong W, Wu Q, Zhang J, et al. Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer. Oncol Lett 2019;18:3887-95. [Crossref] [PubMed]
11. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:839-44. [Crossref] [PubMed]
12. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023;389:1935-48. [Crossref] [PubMed]