Osimertinib Achieves Longest OS as First-Line Monotherapy Among EGFR-TKIs, with One-Third of Patients Experiencing PFS Beyond 3 Years

On September 28, the overall survival (OS) data from the Phase III FLAURA study of osimertinib as first-line treatment for non-small cell lung cancer (NSCLC) were presented at the European Society for Medical Oncology (ESMO) 2019 Congress. Given that osimertinib has already been approved in 78 countries and regions worldwide for first-line treatment of EGFR mutation-positive NSCLC, particularly with its recent approval for this indication in China just last month, the release of these OS data was highly anticipated and long-awaited.

Overall Survival (OS) is defined as the time from randomization to death from any cause, whereas other clinical endpoints are based on tumor measurements. Therefore, OS is regarded as the “hard endpoint” in oncology drug clinical trials, and a significant improvement in OS best reflects the clinical value of an oncology drug. However, the collection of OS data is time-consuming, particularly in large-scale Phase III clinical trials. If new drug marketing applications were submitted only after complete OS data for all patients had been collected, it would substantially delay patient access to new therapies. Consequently, many oncology drugs are currently approved by regulatory authorities based on intermediate endpoints such as Progression-Free Survival (PFS) and Objective Response Rate (ORR) observed in clinical trials, with OS data obtained post-approval.

Osimertinib is a case in point. In April 2018, it was approved as a first-line therapy based on the significant improvement in progression-free survival (PFS)—delaying tumor progression—demonstrated in the FLAURA study. The mature overall survival (OS) data, which became available two years after the PFS results were released, further corroborated the clinical value of osimertinib in the first-line setting. According to data presented at this year’s ESMO Congress, osimertinib is the first EGFR inhibitor used as monotherapy in the first-line setting to achieve an OS of more than three years in patients with EGFR-mutated non-small cell lung cancer (EGFR+ NSCLC), thereby establishing its position as the standard of care for first-line treatment. Without further ado, let us examine the data.

Detailed Results of the FLAURA Study

The FLAURA study was a randomized, double-blind, active-controlled trial that enrolled 556 patients (60% Asian) with previously untreated locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer across 29 countries, to evaluate the efficacy and safety differences between osimertinib (80 mg, once daily) and standard EGFR-TKIs (erlotinib 150 mg, once daily, or gefitinib 250 mg, once daily). The primary endpoint of the trial was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR).

At the ESMO Congress in September 2017, AstraZeneca announced that the FLAURA study had met its secondary endpoint of improved progression-free survival (PFS) (18.9 vs. 10.2 months), with a 54% reduction in the risk of disease progression (HR=0.46, 95% CI: 0.37-0.57). Although overall survival (OS) data were not yet mature at that time, a 37% reduction in the risk of death compared to the control group was already observed. Furthermore, osimertinib as a first-line therapy demonstrated PFS benefits in patients both with and without central nervous system metastases.

FLAURA Study Data Released in September 2017

Note: The data cut-off date is June 12, 2017.

Osimertinib, as a first-line monotherapy for patients with EGFR mutations, achieved the longest progression-free survival (PFS) in history (18.9 months). Based on this data, it rapidly received Breakthrough Therapy Designation from the FDA after the ESMO 2018 Congress. Subsequently, regulatory agencies worldwide accepted marketing applications for osimertinib as first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC) and granted approvals based on the PFS data from the FLAURA study. The overall survival (OS) data from the FLAURA study has been a topic of significant interest to global regulatory authorities and a focal point for all pharmaceutical companies developing EGFR-TKI drugs.

On September 28, the ESMO 2019 Congress officially announced the overall survival (OS) data from the FLAURA study. The results demonstrated that osimertinib achieved the longest OS among all first-line monotherapies with EGFR-TKIs for patients with EGFR-mutated non-small cell lung cancer (NSCLC), extending survival by nearly 7 months compared to standard first-generation EGFR-TKI therapy (38.6 vs. 31.8 months), a difference that was both statistically and clinically significant. Notably, this outcome was attained despite the fact that up to one-third of patients in the first-generation EGFR-TKI arm crossed over to receive osimertinib. This crossover rate represents the highest proportion of patients receiving second-line osimertinib among all clinical trials of EGFR-TKIs to date, further underscoring the robustness of these findings.

FLAURA Study Data Released in September 2019

Note: The data cut-off date is June 25, 2019.

Furthermore, the newly released data show that 28% of patients in the osimertinib group remained on first-line osimertinib treatment at year 3, compared with only 9% in the control group who continued receiving first-generation EGFR-TKI therapy. The proportion in the osimertinib group was three times that of the control group, indicating that nearly 30% of patients receiving first-line osimertinib achieved a progression-free survival (PFS) exceeding 3 years, thereby remaining free from disease progression-related distress during this period. This raises an important question: how to identify patients who derive long-term PFS benefit from osimertinib. Further prospective or retrospective clinical studies are awaited to address this issue.

The safety profile of osimertinib was consistent with the results observed in previous clinical trials. Despite the duration of treatment with osimertinib being nearly twice that of standard EGFR-TKIs, the incidence of grade ≥3 serious adverse events (AEs) was comparable between the two groups (42% vs. 47%), as was the proportion of patients who discontinued treatment due to AEs (15% vs. 18%).

Clinical Value of Osimertinib as First-Line Therapy

Lung cancer is the leading cause of cancer-related mortality both globally and in China, with approximately 653,000 new cases and 600,000 deaths annually in China. Even in an era marked by the continuous emergence of targeted therapies and immunotherapies, the five-year survival rate remains only 16%–18%, largely because most Chinese patients are diagnosed at advanced stages. From a clinical perspective, the primary goal for patients with early-stage (Stage I–II) lung cancer is to improve cure rates, whereas for those with advanced-stage (Stage III–IV) disease, where curative treatment is challenging, the main objectives are to prolong overall survival and enhance quality of life.

Prior to the advent of EGFR-TKIs, lung cancer patients were limited to surgery or chemoradiotherapy, which were associated with significant adverse effects and short survival periods. Subsequently, it was recognized that tumor initiation and progression are driven by specific genes. By effectively inhibiting these driver genes with targeted therapies, tumor progression can be suppressed and delayed, thereby improving survival outcomes. This understanding led to the development of EGFR-TKIs, which have significantly extended the survival of patients with advanced EGFR mutation-positive lung cancer and ushered in an era of precision medicine in the clinical management of lung cancer. EGFR mutations are a very common type of genetic alteration in lung cancer patients. The mutation rate is approximately 10%–15% among NSCLC patients in Europe and the United States, whereas it reaches as high as 30%–40% in Chinese NSCLC patients, with some epidemiological data indicating rates exceeding 50%. Thus, EGFR-TKIs have brought substantial benefits to Chinese lung cancer patients, positioning the clinical diagnosis and treatment of EGFR-positive NSCLC in China at the forefront of international practice.

The current challenge is that resistance to EGFR-TKI therapy is inevitable. In terms of treatment strategies, beyond the use of next-generation EGFR inhibitors capable of overcoming resistance, the primary focus is on optimizing and enhancing the long-term efficacy of existing EGFR-TKIs, thereby delaying the onset of resistance and recurrence. Clinical trials are exploring diverse combination regimens involving EGFR-TKIs, including combinations with anti-angiogenic agents, immune checkpoint inhibitors, and poly(ADP-ribose) polymerase (PARP) inhibitors. As a third-generation EGFR-TKI used as monotherapy, osimertinib not only provides a last line of defense for patients who have developed resistance to first- and second-generation EGFR-TKIs (such as gefitinib and erlotinib), but also demonstrates significant clinical value by extending patient survival when used as a first-line treatment compared to current standard EGFR-TKIs.

In fact, based on real-world medication data and outcome reports following the FLAURA study, fewer than one-quarter of patients with advanced non-small cell lung cancer (NSCLC) who develop resistance to EGFR-TKIs harbor the T790M mutation and are suitable for second-line treatment with osimertinib. In other words, the population benefiting from osimertinib as a second-line therapy remains quite limited. Elevating osimertinib to first-line therapy is therefore more critical, as it provides greater survival benefits for patients with EGFR-mutated advanced NSCLC compared to first- and second-generation EGFR-TKIs, while also reducing the risk of brain metastases. Approximately 25% of patients with EGFR-mutated advanced NSCLC already have brain metastases at diagnosis, and this proportion increases to 40% within two years after diagnosis. The median overall survival for these patients with brain metastases is typically less than 8 months. Due to its superior blood-brain barrier penetration compared to first- and second-generation EGFR-TKIs, osimertinib demonstrates excellent efficacy in patients with advanced NSCLC and central nervous system metastases.

In addition to the FLAURA study, at the European Lung Cancer Congress held from April 10 to 13 this year, AstraZeneca announced the final analysis results of two expansion cohorts from the Phase I AURA study, providing further evidence of the benefits of osimertinib as first-line treatment for advanced NSCLC with EGFR mutations. Sixty untreated patients with locally advanced or metastatic EGFR mutation-positive NSCLC received either 80 mg or 160 mg of osimertinib once daily until disease progression or other criteria for discontinuation were met. The median follow-up time was 19.1 months. Results showed that the ORR (Objective Response Rate) for osimertinib 80 mg and 160 mg was 67% and 87%, respectively, with a duration of response (DoR) of 19.3 and 16.7 months, respectively. The median PFS (Progression-Free Survival) reached 22.1 and 19.3 months, respectively. The most common adverse reactions included diarrhea, stomatitis, paronychia, etc. Adverse reactions observed in the 80 mg group were consistent with previous study findings, with no new adverse reactions identified.

What Should Be Done for Resistance to First-Line Osimertinib Treatment?

For patients with EGFR mutations, should first- or second-generation EGFR-TKIs be used as first-line therapy, followed by sequential treatment with third-generation EGFR-TKIs such as osimertinib upon resistance? Or should third-generation EGFR-TKIs be used directly? Currently, there is no consensus on these two treatment strategies. The controversy may not lie in the evidence of survival benefits from using osimertinib as first-line therapy, but rather in how to manage resistance after its initial use. This scenario of having no further therapeutic options may be the greatest concern for both physicians and patients.

In reality, eventual resistance to osimertinib is inevitable, and such cases have already been observed. The primary strategy to address this involves investigating the mechanisms underlying third-generation EGFR inhibitor resistance to develop fourth-generation EGFR inhibitors. The predominant resistance mutation identified for third-generation EGFR-TKIs is the C797S mutation. On October 19, 2018, AstraZeneca announced that the main mechanisms of osimertinib resistance were associated with MET amplification and EGFR C797S mutations, rather than acquired resistance mediated by EGFR T790M. On the same day, AstraZeneca also announced the initiation of ORCHARD, an open-label, multicenter Phase II study, enrolling patients with advanced non-small cell lung cancer (NSCLC) who had experienced disease progression following first-line osimertinib therapy.

Furthermore, AstraZeneca has conducted a Phase II study, codenamed SAVANNAH, in patients with locally advanced or metastatic EGFR+/MET+ non-small cell lung cancer (NSCLC) who have developed resistance to osimertinib, to evaluate the efficacy of osimertinib in combination with savolitinib (a c-MET inhibitor from Hutchison China MediTech). In early April, interim data from two cohorts of the Phase Ib TATTON study were presented at the American Association for Cancer Research (AACR) Annual Meeting. Among these, the analysis of the expansion cohort treated with osimertinib plus savolitinib for MET-amplified, EGFR-mutant NSCLC that had progressed after first-line osimertinib therapy showed that the combination had an acceptable safety profile, with an objective response rate of 25% and a median duration of response of 9.7 months. The AACR 2019 Annual Meeting also featured multiple poster presentations on mechanisms of resistance to osimertinib, exploring the relationship between osimertinib resistance and signaling pathway proteins such as AXL, MERTK, AKT3, and MEK/ERK.

In summary, osimertinib is the first EGFR inhibitor used in the first-line setting that enables overall survival (OS) to exceed three years in patients with advanced EGFR-positive non-small cell lung cancer (NSCLC). It demonstrates a significant improvement in OS compared to current standard EGFR-TKI therapies and reduces the risk of brain metastases, underscoring its undeniable clinical value. First-line osimertinib therapy has been listed as a preferred recommended treatment for advanced EGFR mutation-positive NSCLC by major international guidelines, including the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Non-Small Cell Lung Cancer, the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines, the Pan-Asian Adapted Clinical Practice Guidelines for the Management of Metastatic Non-Small Cell Lung Cancer, and the Japanese Lung Cancer Guidelines. To address potential resistance to osimertinib, two approaches are warranted: first, exploring combination regimens involving first-line osimertinib to maximize the duration of survival benefit; and second, conducting further mechanistic studies and clinical trials to identify effective therapeutic strategies for managing resistance and to define patient populations likely to achieve long-term benefits.