2024: ten years of progress in EGFRm NSCLC

1. Introduction

Lung cancer is a significant contributor to global cancer-related deaths. Over 1.2 million deaths each year are related with it, maintaining a disproportionately high mortality rate compared to other forms of cancer and standing as the foremost cause of cancer-related fatalities worldwide.

The most recent statistics for lung cancer are poor in comparison with other cancers, with a five-year survival rate of 10% to 20%. The five-year net survival rate, when age-standardized, typically falls within the range of 10% to 20%⁽¹⁾. Non-small cell lung cancer (NSCLC) is the most prevalent histologic type, being diagnosed in 84% of lung cancer patients.

1.1. Epidermal growth factor receptor (EGFR)

Somatic alterations in EGFR lead to constitutive activation of receptor tyrosine kinases (RTKs) signaling, and these occur in approximately 50% of Asian NSCLC patients and in 15% of Caucasian NSCLC patients. These mutations can result in overactivation of the EGFR protein, leading to uncontrolled cell proliferation, the development of cancer, and a worse prognostic for the patients⁽²⁾. Often, an EGFRm lung cancer is characterized by an aggressive phenotype with a faster disease progression. Despite an initial response to targeted therapy, many patients develop resistance to treatment, leading to decreased duration of response.

Moreover, patients are prone to develop brain metastases which complicates the treatment and worsens the prognosis⁽³⁾. A significant proportion of patients will not receive any further treatment due to clinical deterioration, and the second-line therapeutic options are very limited.

There are different types of EGFR mutations, including exon 19 deletions and the L858R mutation in exon 21, which are the most common in NSCLC, with over 90% of the known activating mutations. These mutations result in the continuous activation of the EGFR pathway, leading to the growth and survival of cancer cells⁽⁴⁾. Less common EGFR mutations include various exon 20 insertions and exon 18-point mutations. More­over, EGFRm patients usually develop resistance mutations like T790M⁽⁵⁾.

1.2. EGFR tyrosine kinase inhibitors

In the last couple of years, different EGFR tyrosine kinase inhibitors (TKIs) molecules have been developed and used in clinical practice. All these molecules have as main target the Ex19 and ex21 mutations, and can be classified into three generations of TKIs, according to their pharmacodynamic characteristics. First-generation drugs, such as gefitinib, icotinib and erlotinib, are binding the EGFR ATP in a reversible manner and have a strong affinity for both mutated and wild-type EGFR, leading to an increased number of adverse events. Also, their minimal ability to pass the blood-brain barrier leads to an insignificant response rate for patients with brain metastases⁽⁶⁾. Nonetheless, patients achieve resistance to the first-generation TKIs within 10-14 months, so the second generation of EGFR TKIs aimed at reducing the acquired resistance to the first generation of drugs⁽⁷⁾. Therefore, molecules like afatinib or dacomitinib have been developed with a slightly different mechanism of action that led to an irreversible EFGR ATP binding using covalent bonds and a smaller activity on the wild-type EGFR. The second generation of TKIs are limited by blood-brain barrier penetration and T790M tumor mutations. Still, the activity that crosses the blood-brain barrier remains minimal and, due to the different binding mechanism, second-generation TKIs bind the entire kinase active members of the HER family, with an increased adverse events profile⁽⁸⁾.

2. Osimertinib

In contrast, the third generation of EGFR TKIs brings again a different mechanism of action, binding irreversible only to the EGFR gene (Cys-797), with an increased selectivity for the mutant EGFR and with very low binding of the wild-type EGFR. Osimertinib, the most important molecule of this generation, has the ability to bind not only the ex-19 and ex-21 mutations but also the main acquired resistance mutation, T790M, decreasing substantially the time to progression and the ways of resistance to EGFR TKIs. Moreover, osimertinib is the first TKI that successfully crosses the blood-brain barrier, potentially having a meaningful impact for the patients developing brain metastases. The selectivity for EGFRm means a better safety profile compared with the first generations of TKIs, with rash and nausea being the most frequent adverse events observed in clinical studies⁽⁹⁾.

Moreover, osimertinib has a long-term half-life of 55 hours which provides a constant plasma concentration during a 24-hour cycle, supporting the once-daily administration and increasing the patients’ compliance to treatment. Furthermore, the chemical structure of osimertinib allows oral formulation and patients self-administration. Daily administration of osimertinib resulted in approximately threefold accumulation, with steady-state exposures achieved after 15 days of dosing⁽⁹⁾.

Today, third-generation TKIs, such as osimertinib, are widely regarded as the standard first-line treatment for advanced disease.

3. Osimertinib development program

The ongoing development program for osimertinib includes several key areas of investigation aimed at expanding its use and at improving outcomes for patients with NSCLC.

Combination therapies. Investigating resistance to front-line osimertinib is crucial for enhancing patients’ outcomes. Variability in clinical benefit and progression may be tied to EGFR mutation subtypes and other genetic factors. Trials are exploring the efficacy of osimertinib in combination with other therapies, such as chemotherapy (FLAURA 2), to enhance treatment outcomes and overcome resistance mechanisms^(10,11).

Brain metastases. Since brain metastases occur in up to one-third of patients with unresectable EGFR-mutated stage III NSCLC, the goals in these cases are to extend survival, prevent neurological dysfunction, and improve the quality of life. Studies are focused on evaluating osimertinib’s effectiveness in treating patients with NSCLC who have brain metastases, given its ability to penetrate the blood-brain barrier⁽¹²⁾.

Earlier stages of disease. Research is underway to assess osimertinib’s potential as a neoadjuvant (NEOADAURA trial⁽¹³⁾) and adjuvant therapy (ADAURA2 trial)⁽¹⁴⁾ in early-stage NSCLC, aiming to prevent recurrence and improve long-term survival or localized unresectable stages (LAURA trial)⁽¹⁵⁾.

These ongoing efforts are designed to broaden the application of osimertinib, improve patients’ outcomes, and address unmet needs in the treatment of NSCLC.

3.1. Resectable NSCLC

Traditionally, patients with resected tumors were treated with surgery followed by observation or, in some cases, with adjuvant chemotherapy. However, the risk of recurrence remained high, especially for those with EGFR mutations. The ADAURA trial was designed to address this significant unmet need in the treatment of early-stage EGFR-mutated NSCLC. The trial enrolled 682 patients with stages IB, II and IIIA EGFR-mutated NSCLC, specifically either exon 19 deletions or L858R mutations in exon 21, who were randomized to receive either osimertinib or a placebo for up to three years⁽¹⁶⁾.

In 2020, the initial results of the ADAURA trial were unveiled at the American Society of Clinical Oncology (ASCO) Annual Meeting. Data showed a significant improvement in disease-free survival (DFS), with the three-year DFS rate at 79% for the osimertinib group, compared to 28% in the placebo group. This translated to a hazard ratio of 0.20, showing an 80% reduction in the risk of recurrence or death. Moreover, the DFS benefit was seen across all prespecified groups⁽¹⁶⁾. In fact, these initial results led to the U.S. FDA and other global regulatory bodies approving osimertinib as adjuvant therapy for EGFR-mutated NSCLC⁽¹⁷⁾.

In 2023, the mature overall survival (OS) data revealed a significant improvement for patients treated with osimertinib. The hazard ratio was 0.49, showing a 51% reduction in the risk of death. The five-year overall survival rate was 88% in the osimertinib group, compared to 78% in the placebo group⁽¹⁸⁾.

The extended follow-up has confirmed the safety of osimertinib, with no new concerns emerging. The most common adverse events remain mild to moderate, with diarrhea, rash and paronychia being the most frequently reported. Importantly, the incidence of severe adverse events (grade 3 or higher) was low, and the overall tolerability of osimertinib was favorable⁽¹⁸⁾. Leading oncology organizations, such as the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), have incorporated osimertinib into their guidelines as the standard of care for adjuvant therapy in patients with resected stage IB-IIIA EGFR-mutated NSCLC⁽¹⁹⁾.

3.2. Unresectable NSCLC – stage III

In unresectable stage III NSCLC, following chemoradiotherapy (CRT) without progression, the current standard of care is consolidation durvalumab⁽²⁰⁾. However, patients with EGFRm⁽²¹⁾ draw limited benefit from immunotherapy, according to data from Pacific and Pacific-R studies^(22,23). Furthermore, patients with EGFRm have a higher risk of distant progression, especially brain metastases, that occur in 25-35% of patients after CRT, which supports the rationale of systemic therapy using a drug with central nervous system (CNS) penetration⁽²¹⁾.

At the ASCO 2024 conference, the phase-3 study LAURA outcomes were presented, showing that osimertinib significantly improved progression-free survival (PFS) in patients with unresectable stage III EGFRm NSCLC following chemoradiotherapy. The patients were randomized to receive either osimertinib or placebo until the Blinded Independent Central Review (BICR) assessed progression, toxicity, or other discontinuation criteria. The primary endpoint was PFS assessed by BICR per RECIST v1.1, with key secondary endpoints including OS, CNS PFS, objective response rate (ORR), duration of response (DOR), and safety⁽²⁴⁾. The results revealed a median PFS of 39.1 months for osimertinib, compared to 5.6 months for placebo, with an 84% reduction in the risk of progression or death. The PFS benefit was consistent across all prespecified subgroups, and osimertinib also proved a higher ORR and longer DOR compared to placebo. Additionally, new brain metastases were less frequent in the osimertinib group, indicating a protective effect against CNS progression⁽¹⁵⁾.

The safety profile of osimertinib after chemoradiotherapy was consistent with its established profile, with manageable adverse events. The combination of EGFR-TKIs and chemoradiotherapy or radiotherapy can increase the risk of radiation pneumonitis, but the incidence of grade 3 radiation pneumonitis was low in the LAURA trial, with no grade 4 or 5 events reported^(15,25). As a conclusion of these first results, osimertinib after CRT can become the new standard of care for patients with unresectable stage III EGFRm NSCLC who have not progressed after definitive chemoradiotherapy.

3.3. Metastatic NSCLC

The role of osimertinib in mNSCLC was highlighted by the AURA clinical trials. The AURA clinical trial program played a pivotal role in establishing the efficacy and safety of osimertinib in this setting⁽²⁶⁾. The AURA program comprised multiple single-arm phase I and II trials, which demonstrated the promising activity of osimertinib in patients with EGFR T790M mutation-positive advanced NSCLC, including those who had progressed on prior EGFR TKI therapy. Furthermore, in the phase III AURA3 trial, osimertinib compared with platinum-pemetrexed showed a significant improvement in PFS for patients with mNSCLC who had disease progression after first-line EGFR-TKI therapy and a resistance T790M mutation, leading to the first ever approval of osimertinib in this setting^(26,27).

A further step is represented by the FLAURA trial, a landmark in the management of EGFR-advanced or mutated NSCLC. This phase III trial compared osimertinib with standard-of-care EGFR TKIs (erlotinib or gefitinib) as first-line treatment in patients with EGFRm NSCLC. FLAURA demonstrated significantly prolonged OS (38.6 versus 31.8 months) with a HR for death of 0.80 and a favorable safety profile with osimertinib compared to standard EGFR TKIs, leading to its approval as a first-line treatment for this patient population. The results of FLAURA have consolidated osimertinib’s role as a standard of care in the first-line treatment of advanced EGFR-mutated NSCLC, marking a significant advancement in the management of this disease⁽²⁸⁾. Despite the good response to osimertinib, most patients progress through different resistance mechanism. Some phase II and III studies have shown superior efficacy results with first-generation EGFR-TKI gefitinib plus carboplatin-pemetrexed compared to gefitinib alone. These data support the hypothesis that adding a platinum-based agent and pemetrexed to osimertinib may prolong the benefit of osimertinib in monotherapy⁽¹¹⁾. This was proven in the FLAURA 2 clinical trial, an open-label, randomized 1:1 clinical trial that enrolled patients with EGFRm (exon 19 deletion or L858R mutation) diagnosed with advanced NSCLC, who had not previously received treatment for advanced disease. The patients received osimertinib (80 mg once daily) with chemotherapy, pemetrexed plus cisplatin or carboplatin, versus the comparator arm that received the current standard-of-care, osimertinib as monotherapy (80 mg once daily). The primary endpoint was investigator-assessed progression-free survival. Overall survival and safety profile were also evaluated.

First-line treatment with osimertinib in combination with chemotherapy demonstrated significantly longer PFS versus osimertinib monotherapy in patients with advanced NSCLC and EGFR mutation. The safety profile of osimertinib plus platinum-pemetrexed was consistent with the known profiles for these individual treatments.

Investigator-assessed PFS was significantly prolonged in the osimertinib plus chemotherapy group compared to the osimertinib group (HR 0.62). At 24 months, 57% of patients in the osimertinib plus chemotherapy group and 41% of those in the osimertinib group were alive and without disease progression. Mature OS data are expected; however, a favorable trend is to be noticed for the osimertinib-chemotherapy combination⁽¹¹⁾. Moreover, a significant improvement in CNS efficacy was seen for the combination arm, central nervous system progression being delayed irrespective of the CNS metastases baseline status⁽²⁹⁾.

4. Conclusions

Lung cancer is a leading cause of cancer-related deaths globally, and EGFR mutations offer an even poorer prognosis. Osimertinib has proven efficacy across different stages of NSCLC with EGFRm, from early resectable disease to advanced and metastatic stages. Clinical trials such as ADAURA, LAURA and FLAURA have demonstrated significant improvements in both progression-free and overall survival, establishing osimertinib as a standard of care in these settings. The drug is generally well tolerated, with a manageable safety profile, making it suitable for long-term use in various treatment settings. Ongoing trials are exploring the benefits of combining osimertinib with other therapies to further enhance its efficacy and address resistance mechanisms, potentially broadening its application in the NSCLC treatment. 

Autori pentru corespondenţă: Alexandru C. Grigorescu E-mail: alexgrigorescu2004@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.