Evidence from resected early-stage non-small cell lung cancer with EGFR mutation: a literature review

Introduction

The presence of sensitizing mutation in the epidermal growth factor receptor (EGFR) gene is a major driver mutation in non-small cell lung cancer (NSCLC), with specific clinical and therapeutic implications (1).

In advanced-stage disease, EGFR mutations are present in 20–22% of NSCLC patients in Western countries and India and in 30% of patients in Japan while the rates observed in East Asia rise to 47–64% (2-4). First line targeted therapy with first generation EGFR-tyrosine-kinase inhibitors (TKIs) such as gefitinib and erlotinib showed better outcomes than chemotherapy (5,6). Subsequently, newer generation EGFR-TKIs such us afatinib and dacomitinib (second generation) and osimertinib (third generation) have further improved progression-free survival (PFS) compared with first-generation TKIs, with osimertinib demonstrating an overall survival (OS) advantage and a more favourable safety profile (7-10).

In early-stage NSCLC [i.e., stage I to resectable IIIA tumor-node-metastasis (TNM) 8^th American Joint Committee on Cancer (AJCC) edition], surgery and/or radiotherapy are usually performed with curative intent, with adjuvant or neoadjuvant chemotherapy being added in some cases to improve outcomes, regardless of molecular biomarker status. Since the development of targeted therapy in advanced-stage NSCLC, there has been increasing interest in the epidemiology, characteristics and therapeutic implications of EGFR mutation in early-stage NSCLC.

The aim of this review is to summarize the available evidence in early-stage EGFR mutant NSCLC, including epidemiological issues, clinical, radiological and pathological characteristics; and therapeutic implications of EGFR-TKIs in the adjuvant and neoadjuvant settings. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-35/rc).

Methods

We conducted a comprehensive review of the literature for information on NSCLC patients with either EGFR mutant or in early-stage NSCLC, including evidence published before 31^st December 2023.

Sources consulted included major international databases such as MEDLINE, PubMed, Scopus and Web of Science; as well as abstracts presented at major international lung cancer congresses such as the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) and the World Conference on Lung Cancer (WCLC) of the International Association for the Study of Lung Cancer (IASLC).

Information included was published in English and availability of full text (for papers) or full presentation (for congress communications) was required. Clinical trials, systematic reviews and observational studies were included, whereas clinical case reports and narrative reviews were excluded.

The search strategy is summarized in Table 1.

Diagnosis and epidemiology: clinical, radiological, pathological and molecular features

EGFR mutations are the most common driver mutations found in NSCLC. The most common variants are the exon 19 deletion and the L858R exon 21 mutation, being known as classical or sensitizing mutations (1). Other less common mutations include G719X, S768I and L861Q between exons 18 and 21 and exon 20 insertions (1,11). All these mutations cause a constitutive activation of the tyrosine kinase domain in the EGFR receptor, leading to uncontrolled cell growth; however, the sensitivity to TKI therapy differs, being greater in the classical mutations than in the uncommon ones. Genetic sequencing of EGFR exons 18 to 21 is required to diagnose these mutations, as this improves the sensitivity of mutation-specific based polymerase chain reaction (PCR) (12).

NSCLC is diagnosed at an early-stages (stage I to IIIA of the 8^th AJCC TNM edition) in approximately 30% of NSCLC cases (13). EGFR mutation rates vary between geographical regions, ranging from 13–17% in Western countries (14,15) to 53–58% in East Asian countries (16-18). Regardless of the geographic region, EGFR mutation rates appear to be slightly higher in early-stages than in advanced-stages, being higher in stage IA (14,15,17,18).

In terms of clinical characteristics, EGFR mutation is more common in women and in never-smokers than in men and smokers, like it is in advanced-stages (14-18). Radiologically, EGFR mutant early-stage NSCLC often presents with smaller solid consolidations and the presence of ground-glass opacities (17), with lower glucose uptake levels on positron emission tomography (PET) scan (18). In terms of histological pattern, EGFR mutations are more common in acinar or papillary pattern low-grade adenocarcinomas, and less common in tumors with sarcomatoid features, pleomorphic differentiation or in adenosquamous carcinomas (17,18).

At the molecular level, classic sensitizing mutations reach close to 90% EGFR mutations in early-stages (both exon 19 deletions and L858R exon 21 mutation); L858R mutations show a higher proportion than the observed in advanced-stages (15,17-20). TP53 co-mutation, which is a negative prognostic feature, is less common in early-stage than in advanced-stage disease (27% versus 65%) (15). Among the uncommon mutations, exon 20 insertions are less frequent than in advanced disease (15).

According to patient cohorts treated without adjuvant targeted therapy (before adjuvant EGFR-TKIs were evaluated), the prognosis in low risk resected EGFR mutant early-stage NSCLC is similar to non-mutant early-stage NSCLC: recurrence-free survival (RFS) rates and median RFS are close (14,17,18). However, according to the control arms of recent clinical trials, a higher risk of recurrence is suggested particularly in stage II–IIIA and 5 years after surgical treatment (18,21,22). Local recurrence and systemic recurrence rates are similar in EGFR mutant and non-mutant NSCLC, although brain metastases at recurrence are more common in EGFR mutant patients (9–16% versus 6–12%) (17-20). OS may be better in EGFR mutant early-stage NSCLC due to the availability of targeted therapy in the advanced-stage setting, in the event of progression, which improves outcomes in cases with distant recurrence (14,17,18).

Local treatment, adjuvant chemotherapy and immunotherapy

Regardless of the presence of an EGFR mutation, the standard local treatment of early-stage NSCLC requires complete tumor resection with an anatomical resection (mainly lobectomy) with systematic mediastinal lymph node dissection (23,24).

Clinical trials evaluating sub lobar resection for small and peripheral tumors have not reported subgroup results according to the presence or absence of driver mutations (25,26). However, the benefit seen in the overall population results may translate to the same benefit in EGFR mutant population given the similar local and locoregional recurrence rates observed (17,18).

In all commers, after resection, adjuvant chemotherapy with four cycles of cisplatin-based doublet is recommended after resection for resected high-risk stage IB (mostly tumors larger than 4 cm), stage II and stage III (7^th AJCC TNM edition) NSCLC, achieving a 5% OS improvement at 5 years after surgery, with a number needed to treat (NNT) of 20–25 (27-30). This means that 20 to 25 patients should be treated with chemotherapy to prevent one death. The role of neoadjuvant chemotherapy (i.e., before surgery) shows similar OS results (31,32).

Recently, the combination of immunotherapy with anti-PD-(L)1 immune checkpoint inhibitors with chemotherapy has improved outcomes in both the adjuvant and the neoadjuvant settings. However, immunotherapy has not been shown to be beneficial in advanced EGFR-mutant NSCLC (33-37). Therefore, the presence of an EGFR mutation is often an exclusion criterion (or at least a stratification factor) in the major clinical trials of immunotherapy in early-stage disease, and major regulatory agencies exclude EGFR mutated [and anaplastic leukemia kinase (ALK), altered] NSCLC in the approval of these treatments. Adjuvant immunotherapy with atezolizumab improved outcomes in the overall population in the Impower010 clinical trial, but did not appear to improve outcomes in the EGFR-mutant subset of patients; similarly, the PEARLS clinical trial of adjuvant therapy with pembrolizumab did not include enough EGFR mutant cases to draw conclusions (22,38). In the neoadjuvant or perioperative setting, the presence of an EGFR mutation was an exclusion criterion in many trials [NADIM, NADIM2, Checkmate-816, Checkmate-77T and AEGEAN (39-43)], while in others its detection and reporting was not mandatory and the number of patients with mutation status reported was very limited to draw conclusions [Keynote-671 (44)].

Therefore, most clinical practice guidelines do not recommend the use of immunotherapy in the treatment of patients with early-stage EGFR mutant NSCLC (30,45,46).

Targeted therapy in the adjuvant setting

The treatment benefit of EGFR-TKIs in advanced disease has resulted in the study of their role in early stages (5-9).

First generation EGFR-TKI

The main clinical trials investigating adjuvant treatment with first generation inhibitors are summarized in Table 2. These trials included only patients with classic sensitizing EGFR mutations and their inclusion criteria were based on the 7^th edition of the AJCC TNM.

The role of adjuvant erlotinib was evaluated in the RADIANT trial, which compared 2 years of erlotinib versus placebo after complete resection and adjuvant chemotherapy (47). Although a benefit in RFS was demonstrated, this did not translate into a benefit in OS. Likewise, the role of adjuvant gefitinib was evaluated in the ADJUVANT and IMPACT, both compared to chemotherapy (48,49). In these trials, a benefit in RFS was observed but again there were no differences in OS. The lack of OS benefit in first generation TKI trials may be due to therapeutic options at relapse, as 55–83% patients in these trials received an EGFR-TKI at disease recurrence.

The lack of benefit in OS with adjuvant first generation TKIs was confirmed in two meta-analyses that included data from these previously mentioned trials and several single-arm earlier phase studies (53,54).

Subsequently, two clinical trials investigated the role of icotinib, another first generation TKI. The EVIDENCE trial enrolled patients with stage II to IIIA disease and compared icotinib with chemotherapy, while the CORIN trial enrolled patients with stage IB disease and compared icotinib with placebo (51,52). Both trials observed an RFS benefit but no OS differences, although OS data may still not be mature yet, as the phase 2 ICOMPARE trial in stage II to IIIA patients treated with icotinib showed an RFS and OS benefit with 2 years of adjuvant treatment compared to 1 year of treatment (55).

Finally, the EVAN trial, which included patients with resected stage IIIA who were treated with erlotinib versus placebo for 2 years in China, observed both an RFS and an OS benefit in the experimental arm (50). However, adjuvant treatment may would have had a greater effect due to the inclusion of higher-risk patients, the lack of chemotherapy in the control arm and the low rate of EGFR-TKI treatment at progression (32%, lower than in the previous trials).

Third generation EGFR-TKI

The ADAURA clinical trial evaluated the adjuvant therapy with third generation TKI osimertinib (21,56-59). Previously, osimertinib had demonstrated an advantage over first-generation TKIs in terms of efficacy [including in central nervous system (CNS) disease] and toxicity in advanced disease (8,10,60).

ADAURA was a randomized phase 3 clinical trial that enrolled 682 patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with a classic sensitizing EGFR mutation (19 exon deletion or 21 exon L858R mutation) in stages IB to IIIA (7^th AJCC TNM edition), after complete resection with or without adjuvant chemotherapy. Patients were randomized 1:1 to receive osimertinib or placebo for 3 years. The primary endpoint was RFS in patients with stage II to IIIA disease. In the study population 64% of patients were from East Asia, 64% were women and 70% were never smokers. The stage distribution was 32%, 34% and 34% for IB, II and IIIA respectively. Prior to trial treatment, 60% of patients received chemotherapy at investigator’s decision. All patients were required to have a basal brain imaging study prior to enrolment.

Table 3 shows the main efficacy results of ADAURA study.

Osimertinib treatment significantly improved RFS compared to placebo in stage II to IIIA (primary endpoint) and in the overall population (stage IB to IIIA, secondary endpoint). In subgroup analysis, the benefit was maintained regardless of age, gender, race, smoking history, stage, EGFR mutation and chemotherapy administration (21).

In terms of the pattern of relapse, both local and distant recurrences were lower in patients treated with osimertinib, with fewer recurrences in the most common sites (lung, CNS, lymph nodes and bone). Specifically, for CNS recurrence, osimertinib treatment showed an absolute risk reduction of 11% at 4 years follow up [from 92 with placebo to 81% with osimertinib, hazard ratio (HR) 0.36] (56).

The final OS analysis was then reported and showed a benefit with osimertinib treatment with an absolute risk reduction of 10% for death at 5 years (88% with placebo versus 78% with osimertinib, HR 0.49). The OS benefit was consistent in all pre-specified subgroups, including stage (although the magnitude of the benefit appeared to be greater in stage IIIA than in IB) and chemotherapy use (59).

Osimertinib treatment also prolonged time to subsequent oncological treatments (59). Among placebo-treated patients who received subsequent treatment, 88% of them received an EGFR-TKI: this proves that the OS benefit is not due to the lack of active treatment at relapse. The most common TKI was osimertinib (43%), followed by first generation TKIs (gefitinib 30%, erlotinib 13%, icotinib 8%), second generation afatinib (16%) and dacomitinib (1%) as well as other third generation TKI (aumolertinib 2%, furmonertinib 1%).

Osimertinib-related toxicity was 91% of any grade and 23% of grade 3 or higher (21,56). The toxicity profile was similar to that seen in advanced disease, with diarrhoea (47%), paronychia (27%) and dry skin (25%). Interstitial lung disease and cardiac events occurred in 3% and 6% of patients, respectively. Dose reduction, interruption and discontinuation rates were 12%, 27% and 13%, respectively: dose reduction and interruption rates were higher than those reported in advanced disease (while discontinuation rates were similar), suggesting differences in disease and toxicity perception and in reporting between different disease settings (8). Despite this, osimertinib did not adversely affect quality of life compared with placebo (57).

Based on these results, osimertinib has been approved by the major regulatory authorities in the US, Europa and China [Food and Drug Administration (FDA), European Medicines Agency (EMA) and National Medical Products Administration (NMPA)], among others, and its use is recommended as adjuvant treatment in patients with IB–IIIA NSCLC after complete resection with or without adjuvant chemotherapy (30,45,46). This is the first approval and recommendation of a targeted therapy treatment in early-stage NSCLC, which makes it necessary to test for EGFR mutations in these stages (as do the recommendation against prescribing adjuvant or neoadjuvant immunotherapy in the presence of an EGFR mutation).

Following the recent publication of these findings, some concerns have been raised about adjuvant treatment with osimertinib.

Firstly, the optimal duration of the treatment is unclear. Kaplan-Meier RFS curves appear to show an increase in recurrence in the osimertinib arm after 3 years (the duration of treatment) (21,56). In addition, EGFR mutation is associated with a later pattern of relapse (18). It has been suggested that a longer adjuvant treatment with osimertinib may improve the efficacy outcomes of this treatment. Therefore, the TARGET trial (NCT 05526755) is ongoing, evaluating 5 years of adjuvant treatment with osimertinib. Further follow-up in the ADAURA trial may provide more information on this issue.

Secondly, the role of adjuvant chemotherapy is unclear. In the ADAURA trial, subgroup analyses suggest that the benefit of osimertinib is independent of the use of chemotherapy (21,56,58). The use of chemotherapy was at the discretion of the investigator and it was more common in patients younger than 70 years and with stage II to IIIA disease (58). While this supports the use of adjuvant osimertinib in patients who are not fit enough to receive chemotherapy or in tumors for which there is no indication of adjuvant chemotherapy, it does not mean that chemotherapy can be safely omitted in other subgroups and so it is still recommended according to tumor stage and patient characteristics. Recent clinical trials also suggest a benefit in combining chemotherapy with osimertinib in advanced disease (61,62), but whether if this benefit translates to adjuvant therapy (and in which patients) is still unclear.

Thirdly, prognostic and predictive biomarkers are needed. Since in the ADAURA trial 30% of patients in the osimertinib arm had a recurrence at 4 years, risk stratification may select candidates for treatment intensification (56). Thus, persistence of circulating tumoral DNA (ctDNA) or minimal residual disease (MRD) after surgery, the presence of concomitant mutations in TP53 or RB1 genes and the presence of PD-L1 expression have been suggested as negative prognostic factors (63-66).

Fourth and finally, several settings are not assessed in the ADAURA trial, such as tumors smaller than 4 cm, the presence of affected surgical margins or tumors treated with ablative radiotherapy. Some studies are evaluating the role of osimertinib after complete resection in stage IA2–IA3 EGFR NSCLC, where the frequency of EGFR mutation is higher (ADAURA2, NCT-05120349), or after radical chemoradiotherapy in unresectable locally advanced NSCLC (LAURA, NCT-03521154). Patients with positive surgical margins who require adjuvant radiotherapy and patients with incidental stage IIIB–IIIC after complete resection are likely to benefit from adjuvant treatment with osimertinib, although this was not represented in the clinical trial (21).

Other clinical trials investigation adjuvant treatment with third generation TKIs are ongoing, including trials comparing furmonertinib with placebo (NCT-04853342, FORWARD trial); aumolertinib with placebo (NCT-04687241) or aumolertinib with chemotherapy versus aumolertinib alone versus chemotherapy alone (NCT-04762459, APEX trial).

Targeted therapy in the neoadjuvant setting

The evidence for EGFR-TKIs as neoadjuvant therapy is limited, so their use is not recommended in routine clinical practice and is restricted to the investigational setting.

With regard to first generation TKIs, the EMERGING clinical trial (CTONG-1103) enrolled patients with confirmed N2 EGFR mutated NSCLC. They received erlotinib for 6 weeks preoperatively followed by 1 year postoperatively, or chemotherapy (cisplatin-gemcitabine) for two cycles preoperatively and two cycles postoperatively that. Radiological response rates and RFS favored erlotinib, but there were no pathological complete responses and major pathological responses (less than 10% tumor remaining at resection) were 10% in the erlotinib group. There were no differences in OS (67,68).

Two single-arm clinical trials have been reported with osimertinib. The NEOS trial (ChiCTR-1800016948) evaluated 6 weeks of treatment before surgery in 88 patients; radiological responses were encouraging but pathological responses were only 15% (4% major and 11% complete responses) (69). The UCSF trial evaluated treatment with osimertinib for 4–8 weeks in 27 patients and reported a major pathological response rate of 15% (70).

The phase 3 randomized NeoADAURA clinical trial is also ongoing (NCT-04351555), comparing osimertinib versus osimertinib with chemotherapy versus chemotherapy for 9 weeks prior to surgery. There are other ongoing phase 2 trials with first generation TKIs (icotinib monotherapy, NCT-03749213, or with chemotherapy, NCT-05104788, NeoIpower trial), with second generation TKIs (afatinib, NCT-04201756) and with third generation TKIs (aumolertinib, NCT-04455594, Answer trial).

Conclusions

EGFR mutant early-stage NSCLC has a variable incidence according to geographical location, and its clinical and molecular features are diverse. Determination of EGFR mutation status in early-stage patients is necessary for optimal therapeutic decision-making, as the presence of an EGFR mutation implies lack of benefit from adjuvant or neoadjuvant immunotherapy and EGFR-TKIs are available. In fact, adjuvant treatment with osimertinib for 3 years after surgery, with or without chemotherapy, has improved RFS and OS in these patients, without compromising quality of life.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-35/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-35/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-35/coif). S.M.R. reports taking part as an invited speaker for Sanofi, BMS and Takeda; receiving support from Merck, Sanofi, Lilly, BMS, and Pfizer for meeting registration, accommodation and/or travel expenses, all outside the present manuscript. A.B. reports taking part as invited speaker for BMS, MSD, Pfizer, Sanofi, Pierre Fabre, Novartis, Takeda and Astra Zeneca; receiving support from BMS, MSD, Sanofi, Pfizer and Astra Zeneca for meeting registration, accommodation and/or travel expenses; and taking part in an Advisory Board for BMS, MSD and Sanofi, all outside the present manuscript. M.M. reports receiving grants from Roche and Astra Zeneca; taking part as invited speaker for Roche, MSD, Pfizer, Sanofi, Pierre Fabre, Novartis, Takeda and Astra Zeneca; and receiving support for attending meetings and/or travel from Astra Zeneca, MSD, Sanofi, all outside the present manuscript. The authors have no other 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/.

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