Key Learning Points: ESMO Consensus Statement on EGFR Mutations in Non-small Cell Lung Cancer

An Expert Consensus Statement from the European Society for Medical Oncology Addresses Areas of Uncertainty in the Management of Non-small Cell Lung Cancers Driven by Epidermal Growth Factor Receptor Mutations; Dr Thomas Newsom-Davis Outlines Seven Key Learning Points from the Statement

Activating mutations in the epidermal growth factor receptor gene (EGFR) are key oncogenic drivers of non-small cell lung cancer (NSCLC).¹ The most common alterations occur in the tyrosine kinase domain of the EGFR gene, and include exon 19 deletions and exon 21 L858R substitution.¹ EGFR-mutant disease represents an estimated 10–15% of all NSCLC cases in the UK, and is considered to be a genetically distinct form of lung cancer.² It is most common in people with adenocarcinoma, non-smokers, females, and those of Asian descent.²

Management of EGFR-mutant NSCLC has evolved considerably over the past 15 years with the introduction of novel targeted therapies, notably EGFR tyrosine kinase inhibitors (TKIs), which have heralded a paradigm shift in treatment.³ Compared with traditional cytotoxic chemotherapy, EGFR TKIs have led to improved clinical outcomes and health-related quality of life in patients with advanced NSCLC, and are now positioned as first-line therapies in this setting.^4,5

Despite these advances in therapy, there are still areas of uncertainty and, in response, the European Society for Medical Oncology (ESMO) recently published an expert consensus statement³ to augment the ESMO guideline on NSCLC.⁶ This addresses controversial topics in the optimal management of EGFR-positive disease when evidence is limited or conflicting.^3,6 Four key areas are covered in the statement:³

• tissue and biomarker analyses
• early and locally advanced disease
• metastatic disease
• clinical trial design.

This article focuses on seven key learning points from the ESMO expert consensus statement on the management of EGFR-positive NSCLC.

1. Be Aware of Key ESMO Recommendations on Tissue and Biomarker Analysis

The consensus statement recommends comprehensive testing for all patients with non-squamous NSCLC, regardless of disease state, to accurately identify all EGFR mutations with clinical utility—including those considered atypical or uncommon, such as EGFR exon 20 insertion mutations.⁷ To achieve this, parallel testing with a broad next-generation sequencing (NGS) panel using tissue (or plasma/blood) is preferred to single-gene EGFR testing. 

Nearly all patients with EGFR-mutated NSCLC will eventually develop resistance to TKI therapy,¹ and tissue rebiopsy is advised at this stage to reveal actionable targets for further treatment. When no tissue is available for testing, ESMO suggests that circulating tumour DNA (ctDNA) be used as an alternative source for genomic profiling for EGFR alterations. Due to a reduced clinical response and greater potential for adverse reactions observed in patients with EGFR-positive tumours treated with immune checkpoint inhibitors,^8–11 the statement advises simultaneous screening for EGFR mutations and testing for programmed death ligand-1 expression to enable the selection of appropriate treatment. ESMO also recommends that testing for EGFR mutations should be expanded to encompass those patients with radically resected non-squamous NSCLC, given the introduction of EGFR TKI therapy into this therapeutic setting.³

2. Examine the Role of Osimertinib and Other EGFR Tyrosine Kinase Inhibitors in Early and Locally Advanced Disease

The international phase 3 ADAURA trial evaluated 3 years of treatment with the third-generation EGFR TKI osimertinib in patients with common EGFR mutations and completely resected stage IB–IIIA NSCLC, demonstrating a significant prolongation of disease-free survival (DFS) versus placebo.¹² The ESMO statement endorses the use of osimertinib in this setting, and indicates that adjuvant osimertinib may also be considered for patients who have undergone more limited lung cancer surgery to achieve complete resection. For patients who meet ADAURA inclusion criteria but may be intolerant of osimertinib (Box 1), ESMO suggests weighing up adjuvant use on a case-by-case basis. When recurrent disease occurs after adjuvant osimertinib, rechallenge can be attempted; however, if disease reappears during osimertinib administration, ESMO recommends stopping therapy and performing a rebiopsy to guide next treatment steps.³

There is no solid evidence to support the use of first- or second-generation EGFR TKIs as adjuvant treatment for surgically resected EGFR-positive NSCLC, according to the statement. ESMO also clarifies that there is currently no established therapeutic role for EGFR TKIs:³

• as concurrent or sequential treatment with stereotactic radiotherapy in patients with early-stage EGFR-mutated NSCLC not undergoing surgery
• as neoadjuvant therapy for operable stage IA–IIIA NSCLC, or borderline operable cases
• before, during, or after radiotherapy in patients with inoperable stage III EGFR-mutant NSCLC.

3. Implement Effective Strategies for Dealing with Osimertinib Failure

Third-generation EGFR TKIs such as osimertinib are ESMO’s preferred first-line option for metastatic NSCLC tumours harbouring common EGFR mutations, and should also be prioritised as initial therapy for those patients with central nervous system (CNS) metastases and/or with leptomeningeal involvement. But what is the optimal management approach after osimertinib failure? In this context, treatment decisions hinge on patient and disease characteristics, genomic factors, and access to therapy or ongoing clinical trials.³ According to ESMO, standard platinum chemotherapy should still be considered the standard of care in clinical practice post-osimertinib—although promising new approaches are emerging. As such, alternative on-target therapies, such as TKIs, monoclonal antibodies (mAbs), and antibody–drug conjugates, can be viewed as preferred therapeutic options upon the development of resistance to osimertinib treatment, in the context of clinical trials.^13–15 ESMO also adds that patients with osimertinib-resistant tumours should be prioritised for access to molecularly-driven clinical trials of specific agents targeting resistance alterations. For patients with no targetable alterations after osimertinib progression, ESMO advises that osimertinib can be continued if disease progression/clinical deterioration is slow—but other management options may also be considered. For patients with histological transformation to small cell lung cancer, chemotherapy with platinum etoposide remains the recommended treatment after standard EGFR TKI therapy.³

4. Manage Uncommon EGFR Mutations and More Unusual Clinical Scenarios

EGFR exon 20 insertions are non-classic alterations that display documented resistance to treatment with standard EGFR TKIs.¹ For metastatic patients carrying these EGFR exon 20 insertions, ESMO recommends platinum-based chemotherapy as first-line treatment—preferably without concomitant immune checkpoint inhibitors, due to the potential risk of toxicity with later lines of therapy. Targeted agents, such as the bispecific mAb amivantamab or the dual-targeted oral TKI mobocertinib, should be considered in the second line for EGFR exon 20 insertion mutant lung cancer. 

For patients with other uncommon sensitising EGFR mutations (p.G719X, p.L861Q, p.S768I) or compound mutations, either afatinib or osimertinib should be considered as monotherapy, based on a tailored approach including all emerging data.³ Chemotherapy can also be contemplated when a strength of recommendation in favour of TKI is limited or missing. 

In the presence of two or more concomitant targetable alterations, ESMO suggests a comprehensive NGS analysis should be carried out to pinpoint the potential dominant clone, with selection of TKI determined by the results. If different alterations are confirmed to be copresent, then the use of platinum-based chemotherapy should be prioritised, with or without TKIs.³

5. Take a Broad Approach to EGFR Mutation Testing 

The ESMO consensus statement reinforces the importance of ensuring that all suitable patients, both those with metastatic and early/locally advanced stage (IB–IIIA) disease, are tested for EGFR mutations. Implementation of this broad testing approach in UK practice will require reflex testing to be built into existing diagnostic pathways.³ Current NICE recommendations on EGFR mutation testing date from 2013,² and refer to polymerase chain reaction (PCR) based assays. This advice was not revised when guidance for the diagnosis of lung cancer was updated in 2022 (and earlier this year),⁵ and is therefore at odds with the ESMO consensus statement, which highlights the need for comprehensive NGS-based testing, given that single gene PCR-based testing may miss some EGFR mutations, particularly the rarer ones.³ Ultimately, oncologists and local diagnostic services must be familiar with all EGFR mutations, and methods of detection and treatment, because they are not all the same. 

ESMO further emphasises the need to biopsy at the point of disease relapse, especially after first-line TKI use, to inform on next treatment lines, as well as possible clinical trials. It also reminds clinicians of the importance of regular cranial imaging in patients with fully resected EGFR-mutated lung cancer, recommending 6-monthly brain magnetic resonance imaging; patients with EGFR-mutated NSCLC have a higher risk of developing brain metastases.¹⁶ For EGFR-positive patients who have CNS metastases, work with a specialist neuro–oncology multidisciplinary team, and liaise closely for advice on management. Treatment for these patients is typically focused on stereotactic radiotherapy, and whole brain radiotherapy is largely avoided.³

Finally, ESMO provides important clarification on the optimal treatment for patients who have an EGFR exon 20 insertion—recommending first-line chemotherapy, followed by mobocertinib or amivantmanab, as approved by NICE.^17,18 Clear advice is also given on the management of uncommon EGFR mutations, for example, the recommendation to use afatinib for patients with G719X, S768I, and L861Q mutations, and for rare scenarios such as in the presence of comutations.³

6. Address Dilemmas in Cases of Limited or Conflicting Evidence

In accordance with the overall aims of the document, the ESMO consensus statement provides important clarification on managing EGFR-mutant NSCLC when evidence is limited or conflicting. For example, the precise advantages of adjuvant osimertinib in resected stage IB–IIIA disease are still unclear. Although it is known that treatment confers a significant advantage on disease free survival, evidence of the effect on overall survival (OS) is limited;¹² however, a recent update from ADAURA indicates that osimertinib demonstrated a statistically significant improvement in OS compared to placebo.¹⁹ The ESMO consensus recommendations add weight to the validity of using adjuvant osimertinib while further pivotal OS data is awaited.

The statement also reinforces the importance of using adjuvant chemotherapy—when indicated by stage of disease—before adjuvant osimertinib. Osimertinib is not a substitute for chemotherapy in this setting. Similarly, osimertinib is not recommended after radical stereotactic radiotherapy for early or locally advanced disease, nor is it recommended after radical chemoradiotherapy for the same patient group.³ Although there is considerable interest in neoadjuvant strategies at present, particularly chemoimmunotherapy (as evaluated in the Checkmate 816 trial),²⁰ neoadjuvant osimertinib is not currently endorsed by ESMO for resectable or borderline resectable NSCLC.

Addressing another clinically challenging scenario, ESMO outlines practical advice on the management of relapse on or after adjuvant osimertinib—with the recommendation for osimertinib rechallenge if relapse occurs after adjuvant osimertinib; but, it advises switching to a different therapy if relapse occurs during adjuvant osimertinib. Helpful guidance is also provided on how to manage patients whose disease has progressed on first-line osimertinib. This includes what to do in the event of small cell transformation and the more common resistance mechanisms, as well as possible future treatments (and current trials) relevant to this. Finally, ESMO discourages the use of single agent immunotherapy for patients with EGFR-positive NSCLC, due to the lack of confirmed clinical benefit. ³

7. Recognise Key Similarities and Differences Between the ESMO Statement and the NICE Guideline on Lung Cancer 

An update to the NICE guideline on the diagnosis and management of lung cancer in September 2022 incorporated new treatment pathways for advanced NSCLC with specific targetable alterations (Figure 1).⁵ 

For EGFR-TK positive non-squamous NSCLC, NICE recommends afatinib,²¹ dacomitinib, erlotinib, gefitinib, osimertinib, or platinum doublet chemotherapy as initial therapy.⁵ Osimertinib is the only treatment recommended by NICE for T970M-positive patients who experience disease progression after initial therapy with afatinib, dacomitinib, erlotinib, or gefitinib. Similarly, erlotinib is the only recommended treatment option for patients whose disease progresses following first-line platinum doublet chemotherapy. 

For disease progression that occurs after any of the recommended first-line options (or after follow-up treatment with osimertinib), NICE advises using one of the following regimens: 

• platinum doublet chemotherapy
• pemetrexed plus cisplatin
• pemetrexed plus carboplatin
• immunotherapy with atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel.⁵

Figure 1: NICE Treatment Pathway for EGFR-TK Positive Non-squamous NSCLC

For oncologists treating NSCLC, it is important to understand where the ESMO consensus statement aligns with, or is in conflict with, existing NICE recommendations for the UK. A summary of key points of difference and similarity is provided in Box 2.

Summary

The ESMO expert consensus statement aims to resolve issues of uncertainty in the treatment of EGFR-mutations in NSCLC, and to inform practice in this area. It provides detailed information to reinforce existing NICE guidance, despite some areas of contradiction, and—used in combination with ESMO guidance on lung cancer—is a useful road map for oncologists to follow.