Postoperative adjuvant EGFR-TKIs for resected EGFR-mutant NSCLC—opportunities and obstacles

Lung cancer remains the leading cause of cancer-related mortality, accounting for almost a fifth of all cancer deaths worldwide (1). If diagnosed at an early stage, complete surgical resection of non-small cell lung cancer (NSCLC) is the most favourable approach and is curative in over half of patients. However, in patients with pathological stage II–III disease, resection alone is associated with a high rate of recurrence and overall survival (OS) of 23–57% (2). Despite demonstrating only a 5% absolute improvement in 5-year OS, the addition of postoperative adjuvant chemotherapy has been standard of care since 2003 (3), but poor therapeutic compliance and high toxicities limit the long-term efficacy of this approach.

The identification of targetable genomic alterations has become increasingly essential to guide treatment of NSCLC. Patients with EGFR-mutated NSCLC represent approximately 40% of Asian and 10–20% of Caucasian patients (4,5) and are a therapeutically distinct subset of cancers linked to unique biological properties. In advanced stage EGFR-mutant NSCLC, outstanding survival outcomes attributable to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are observed in comparison to those achieved with conventional chemotherapy. The excellent outcomes of EGFR targeted treatment in the advanced disease setting has encouraged clinical trials of these agents in the adjuvant treatment of early-stage NSCLC harbouring EGFR mutations (6).

The recent consensus paper by Liang et al. outlines expert consensus statements and reviews current evidence and recommendations for the postoperative management of EGFR-mutant NSCLC (7). To date, six trials investigating EGFR-TKIs in the adjuvant setting have been completed. Heterogeneous trial design, with differences in patient populations and duration of adjuvant TKI treatment have led to inconclusive results. However, this postoperative management strategy has shown both significant disease-free survival (DFS) benefit, as well as the likelihood of increased compliance and reduced toxicity compared with chemotherapy regimens. This commentary will briefly highlight opportunities for clinical benefit as well as obstacles that require resolution before this mode of adjuvant treatment can become standard of care.

Opportunities

Molecular testing of resected NSCLC should be performed for all patients

Consensus 1 supports EGFR mutation testing of resected tissue to inform treatment strategy in the event of recurrence (7). In our opinion, molecular characterisation following surgical resection of non-squamous NSCLC is essential to plan adjuvant treatment. Reflex testing for EGFR at a minimum, and other targetable biomarkers where possible, has been recommended to aid clinical decision making in the event of treatment failure and postoperative disease recurrence. Multigene testing is employed in some institutions as coexisting mutations are not uncommon [38.8% of stage I–III resected NSCLC (8)], and may alter sensitivity to targeted agents (9). For example, coexistent TP53 mutations are a reported negative predictor of TKI efficacy and poor prognosis among patients with EGFR-mutated NSCLC (10,11). Patients with resected EGFR-mutant NSCLC with multiple mutations following EGFR-TKI treatment compared to those without other mutations (8,9). Clinical trials are needed to further evaluate the outcomes of adjuvant treatment with EGFR-TKIs in EGFR-mutated NSCLC where additional oncogenic mutations co-exist.

Risk prediction models to identify candidates for adjuvant therapy are useful in clinical decision making

Current guidelines recommend adjuvant therapy for patients with stage II–IIIA NSCLC with a high risk of recurrence. The ADJUVANT trial reported that EGFR-TKIs have shown most clinical benefit in patients with resected stage IIIA (12). Defining the “high-risk” subgroup is not easy. The cancer-specific survival (CSS) model from Zeng (eight variables derived from SEER data and validated in Chinese patients) showed very modest improvement in discrimination compared to UICC 8th edition staging (C-statistic 0.66 vs. 0.55 in the external validation dataset); although this is not high enough for clinical use (13). Young et al. validated a Chinese-derived OS model in the US National Cancer Database (NCDB) (n=57,313 resected stage I to IIIA, six variables) and found the UICC 7th edition was superior (C-statistic 0.804 vs. 8.833) (14). The two models only shared age, sex and examined lymph nodes as variables. Wu et al. moved away from the clinico-pathological paradigm to examine resected tumour genetic-features (15). Presented as an abstract at ESMO 2019, Wu et al. identified five predictive biomarkers using a Geneseeq 422-gene panel and specified a three-category model predicting significant OS hazard ratio (HR) in response to gefitinib or vinorelbine in resected EGFR-mutant stage II–IIIA NSCLC. As these three papers demonstrate, although clinico-pathological and genetic models promise enhanced predictive ability compared to the current UICC TNM standard in selecting patients for adjuvant therapy, further retrospective validation in diverse cohorts and prospective evaluation of clinical net benefit and cost-effectiveness in randomised controlled trials (RCTs) is required before they become relevant to the routine clinical setting.

EGFR-TKIs are associated with improved compliance and quality of life

We must also consider both the increased toxicities and the low compliance rate (<60%) reported in patients receiving standard adjuvant chemotherapy. For appropriately selected patients at high risk of recurrence, EGFR-TKIs may be preferable to chemotherapy because of improved quality of life and compliance rate, as demonstrated in the ADJUVANT trial in which compliance among patients receiving EGFR-TKIs was 95.5% compared to chemotherapy (78.4%) (12).

Obstacles

Carefully designed clinical trials are essential to establish clear indications for treatment

The conflicting results shown in the three landmark studies RADIANT, ADJUVANT and EVAN are likely due to heterogeneous study design. In the negative RADIANT trial, a large proportion of stage IB patients were reported in the erlotinib arm, and more patients in the placebo arm having stage IIIA disease. Furthermore, inaccurate screening of EGFR status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) rather than DNA testing misrepresented the target population. Prolonged DFS was not seen in the EGFR-mutant treated with erlotinib (16). In the ADVJUANT and EVAN trials, patients with stage II–IIIA (N1–N2) EGFR-mutant NSCLC treated with EGFR-TKIs showed lower toxicities and significantly longer DFS (12,17). A recent meta-analysis reported that EGFR-TKIs significantly improved DFS in studies with <50% patients with stage I and >30% patients with stage IIIA NSCLC (18). Not surprisingly, the data did not support of the use of adjuvant EGFR-TKIs in patients with stage I NSCLC where DFS was not significantly improved.

In advanced NSCLC, prolonged use of TKIs typically results in the emergence of acquired resistance via a variety of mechanisms, notably T790M secondary mutations. Therefore, mature OS data is essential for understanding long term EGFR-TKI efficacy in the adjuvant setting to clarify treatment strategy. Despite improved DFS demonstrated in ADJUVANT, EVAN, SELECT and EMERGING trials, OS data was not reported (7). OS benefit is a necessary indication before altering the course of clinical practice, as DFS benefit may be a transient effect that may fail to translate directly into improved OS. The ALCHEMIST-EGFR trial of erlotinib versus placebo is ongoing with OS as a primary outcome (19). We await OS data from this trial and further ongoing studies along with reports of patterns of drug-resistance at the time of disease recurrence e.g., presence of the T790M mutation. Mature OS data from head-to-head comparison trials of EGFR-TKI versus chemotherapy followed by EGFR-TKIs in selected patient cohorts are eagerly awaited.

Identification of the most effective EGFR-TKI agent, optimal timing and duration in the adjuvant treatment strategy is yet to be defined

Residual uncertainties include whether to administer EGFR-TKI alone or in combination with chemotherapy, and if in combination, the optimal scheduling of TKI in relation to chemotherapy. The P-C-G trial showed significant DFS benefit in EGFR-mutated patients treated with gefitinib following chemotherapy in stage IIIA-N2 NSCLC (20). However, the Chinese trial of icotinib in combination with chemotherapy in stage IB–IIIA patients showed no statistical DFS benefit (21).

Additionally, the appropriate duration of treatment is yet to be defined. First-generation TKIs have shown a median DFS of 10 months in advanced NSCLC (22) and TKI sensitive cells have been shown to reach their maximal inhibition after 3 months. The ADJUVANT study is the only trial so far to directly compare gefitinib with chemotherapy among over 200 patients treated for up to 2 years. Trial data reported DFS Kaplan-Meier curves for each arm separated at 12 months are merged again at 36 months, proposing that gefitinib maintained clinical benefit for up to 12 months following TKI cessation (12). A similar trend was reported in the RADIANT trial of erlotinib versus placebo, suggesting that TKI treatment might not be curative but sustain DFS by delaying recurrence by 10–12 months compared to chemotherapy (16). Extended treatment regimens have shown long-term clinical benefit from imatinib and tamoxifen for gastrointestinal stromal tumour (GIST) and breast cancer respectively (23). The phase III ADAURA trial of osimertinib versus placebo in stage IB–IIIA resected NSCLC has the longest duration of treatment to date (3 years). OS results from these trials are eagerly awaited and will provide further insight on the appropriate selection and duration of TKI treatment (24).

Ethnic diversity in study cohorts will broaden the translational potential of EGFR-TKI trials

It is well established that EGFR mutations occur in a higher proportion of NSCLC among Asians than in Caucasians. The positive ADJUVANT, EVAN and EMERGING trials reported on Chinese patients only, limiting generalisability to the broader NSCLC population (12,17,25). The early RADIANT trial reported on an ethnically diverse group including Asian, East- and West-European, Latin- and North American patients. However, this was a negative trial, likely due to the inclusion of patients unselected for EGFR status (16). Future trials incorporating more diverse patient groups will be welcomed.

The clinical success of first-line treatment with EGFR-TKIs in advanced EGFR-mutant NSCLC has led to keen interest in the use of these agents for patients with early-stage disease. The BR.19, RADIANT, ADJUVANT, EVAN, SELECT and EMERGING trials investigated adjuvant use of EGFR-TKIs in resected NSCLC, with four of these six trials reporting improved DFS. The recent consensus by Liang et al. presents eight key recommendations to aid clinical management of resected EGFR-mutant NSCLC. However, adoption of these recommendations will ultimately depend on each jurisdictions’ healthcare funding/reimbursement systems and applicable standards of clinical care. Future clinical trials together with a rigorous scientific approach to evidence analysis will define the harms and benefits of adjuvant EGFR-TKIs in the postoperative setting, address remaining uncertainties, and help to redefine therapeutic options for patients with resectable lung cancer. Moreover, the potential of immunotherapeutics is also envisaged to significantly change the therapeutic landscape in the near future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-2020-133). Dr. KMF reports grants from Various competitive funding bodies, non-financial support from Industry, other from Various Universities, other from Various international funding bodies, other from UpToDate, other from Cochrane Clinical Answers, outside the submitted work. 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. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30. [Crossref] [PubMed]
2. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016;11:39-51. [Crossref] [PubMed]
3. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:vi89-98. [Crossref] [PubMed]
4. Yang W, Gao Y, Li X, et al. Postoperative survival of EGFR-TKI-targeted therapy in non-small cell lung cancer patients with EGFR 19 or 21 mutations: a retrospective study. World J Surg Oncol 2017;15:197. [Crossref] [PubMed]
5. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015;5:2892-911. [PubMed]
6. Sim EH, Yang IA, Wood-Baker R, et al. Gefitinib for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2018;1:CD006847 [Crossref] [PubMed]
7. Liang W, Cai K, Chen C, et al. Society for Translational Medicine consensus on postoperative management of EGFR-mutant lung cancer (2019 edition). Transl Lung Cancer Res 2019;8:1163-73. [Crossref] [PubMed]
8. Jao K, Tomasini P, Kamel-Reid S, et al. The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer. Lung Cancer 2018;123:22-9. [Crossref] [PubMed]
9. Blakely CM, Watkins TBK, Wu W, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 2017;49:1693-704. [Crossref] [PubMed]
10. Canale M, Petracci E, Delmonte A, et al. Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin Cancer Res 2017;23:2195-202. [Crossref] [PubMed]
11. VanderLaan PA, Rangachari D, Mockus SM, et al. Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes. Lung Cancer 2017;106:17-21. [Crossref] [PubMed]
12. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018;19:139-48. [Crossref] [PubMed]
13. Zeng Y, Mayne N, Yang CJ, et al. A nomogram for predicting cancer-specific survival of TNM 8th edition stage I non-small-cell lung cancer. Ann Surg Oncol 2019;26:2053-62.
14. Young KA, Efiong E, Dove JT, et al. External validation of a survival nomogram for non-small cell lung cancer using the National Cancer Database. Ann Surg Oncol 2017;24:1459-64. [Crossref] [PubMed]
15. Wu YL, Liu SY, Wang Q, et al. A comprehensive model of genetic-features predicts outcome of personalized adjuvant treatment in resected EGFR-mutant stage II-IIIA NSCLC: results from a phase III trial (CTONG 1104-ADJUVANT). Ann Oncol 2019;30:v586, abstr 1441PD.
16. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol 2015;33:4007-14. [Crossref] [PubMed]
17. Yue D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018;6:863-73. [Crossref] [PubMed]
18. Lu D, Wang Z, Liu X, et al. Differential effects of adjuvant EGFR tyrosine kinase inhibitors in patients with different stages of non-small-cell lung cancer after radical resection: an updated meta-analysis. Cancer Manag Res 2019;11:2677-90. [Crossref] [PubMed]
19. Kim WJ, Lim JH, Lee JS, et al. Comprehensive analysis of transcriptome sequencing data in the lung tissues of COPD subjects. Int J Genomics 2015;2015:206937 [Crossref] [PubMed]
20. Li N, Ou W, Ye X, et al. Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: a randomized, phase II study. Ann Surg Oncol 2014;21:2091-6. [Crossref] [PubMed]
21. Feng S, Wang Y, Cai K, et al. Randomized adjuvant chemotherapy of EGFR-mutated non-small cell lung cancer patients with or without icotinib consolidation therapy. PLoS One 2015;10:e0140794 [Crossref] [PubMed]
22. Normando SR, Cruz FM, Del Giglio A. Cumulative meta-analysis of epidermal growth factor receptor-tyrosine kinase inhibitors as first-line therapy in metastatic non-small-cell lung cancer. Anticancer Drugs 2015;26:995-1003. [Crossref] [PubMed]
23. von Mehren M, Joensuu H. Gastrointestinal Stromal Tumors. J Clin Oncol 2018;36:136-43. [Crossref] [PubMed]
24. Wu YL, Herbst RS, Mann H, et al. ADAURA: Phase III, double-blind, randomized study of osimertinib versus placebo in EGFR mutation-positive early-stage NSCLC after complete surgical resection. Clin Lung Cancer 2018;19:e533-6. [Crossref] [PubMed]
25. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]