Implications of the success of EGFR-targeted therapy in advanced non–small cell lung cancer for its application to the adjuvant setting

Epidermal growth factor receptor gene (EGFR) kinase domain mutations are a driving force for a substantial proportion of non-small cell lung cancer (NSCLC) tumors. The prevalence of such mutations in individuals with such tumors differs among ethnic groups and geographic regions, ranging from ~10 to 15% in Caucasians up to ~40% to 60% in Asians. Monotherapy with 1st-generation (gefitinib, erlotinib) or 2nd-generation (afatinib) EGFR tyrosine kinase inhibitors (TKIs) had become the standard treatment option for patients with advanced or metastatic NSCLC harboring such mutations, with several randomized phase III studies having shown that front-line EGFR-TKIs confers an improved progression-free survival compared with platinum-based cytotoxic chemotherapy in this setting (1-4). However, the third-generation drug osimertinib has now been established as the preferred EGFR-TKI for chemotherapy-naïve EGFR-mutated NSCLC, given that the FLAURA study demonstrated its superiority over the first-generation agents gefitinib and erlotinib (5). The success of EGFR-targeted therapy for EGFR-mutated advanced NSCLC has allowed researchers to turn their attention to the potential of this approach for the adjuvant setting. Platinum-based doublet therapy has been the standard of care for patients with NSCLC of stage II or IIIA who undergo complete tumor resection regardless of EGFR mutation status. However, individuals who receive such adjuvant chemotherapy have shown an improvement of only 4 to 5 percentage points in 5-year overall survival rate compared with those receiving surgery alone (6).

Liang et al. have recently summarized the indications for EGFR-TKI therapy in patients with completely resected EGFR-mutated NSCLC (7). This expert consensus aimed to review the recent evidence and to offer recommendations on key issues relating to such treatment. The consensus was based largely on the results of several randomized phase II or III studies including the RADIANT, ADJUVANT, and EVAN studies. The RADIANT study investigated adjuvant erlotinib therapy administered for 2 years in patients with resected stage IB to IIIA NSCLC whose tumors were found to overexpress EGFR protein measured by IHC or to manifest EGFR gene amplification by FISH. It found that adjuvant erlotinib did not significantly improve disease-free survival (DFS) versus placebo in these biomarker-selected patients (8). Although subset analysis showed a trend toward a better DFS in favor of erlotinib in patients with activating mutations of EGFR, the difference was not statistically significant. In the ADJUVANT study, completely resected stage II to IIIA NSCLC patients positive for EGFR mutations were randomized to receive either gefitinib monotherapy for 2 years or cisplatin plus vinorelbine for four cycles. Median DFS was significantly longer for patients treated with gefitinib than for those treated with vinorelbine plus cisplatin (9). The EVAN study evaluated erlotinib therapy for 2 years compared with four cycles of vinorelbine plus cisplatin in patients with resected EGFR-mutated NSCLC of stage IIIA, finding that adjuvant erlotinib improved the 2-year DFS rate and had a better tolerability profile compared with the cytotoxic chemotherapy (10). In Japan, the WJOG6410L study, with a design similar to that of the ADJUVANT trial, is ongoing for evaluation of gefitinib monotherapy versus cisplatin in combination vinorelbine with in patients with surgically resected EGFR mutation–positive NSCLC of stage II or III.

On the basis of the results of these various randomized trials, EGFR-TKIs are now a adjuvant treatment option for patients with stage II to IIIA EGFR-mutated NSCLC, particularly for those at high risk for recurrence or will be associated with poor tolerance of chemotherapy, with an evidence level of 1 and strong recommendation. However, the Kaplan-Meier curves for DFS in the ADJUVANT study separated at ~12 months and then converged at ~36 months, with no apparent tail of nonprogressors in the gefitinib group, suggesting that adjuvant EGFR-TKI therapy in resected EGFR mutation–positive NSCLC patients might not have curative power, even though long-term remission was noted during such treatment.

Regarding the ideal duration of EGFR-TKI treatment in the adjuvant setting, the expert panel proposed that the postoperative therapy should last at least 2 years, with an evidence level of 2B and strong recommendation, given the results of the ADJUVANT study for evaluation of 2-year adjuvant treatment with gefitinib. However, the DFS curve for the gefitinib-treated patients showed a significant downward trend after 2 years, which would be associated with their discontinuation. The appropriate dosing duration therefore needs to be evaluated by further studies.

In summary, the effectiveness of EGFR-targeted therapy for advanced NSCLC has supported investigation of the potential of this approach for the perioperative setting. Several randomized trials have been published or are ongoing for evaluation of EGFR-TKI adjuvant therapy in patients with surgically resected EGFR-mutated NSCLC. The results to date, however, suggest that this approach may not increase the cure rate.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-2020-46). MT reports other from Boehringer Ingelheim, other from Chugai Pharmaceutical, other from AstraZeneca, other from Ono Pharmaceutical, other from Novartis, during the conduct of the study.

Ethical statement: The author is 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. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. [Crossref] [PubMed]
2. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. [Crossref] [PubMed]
3. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. [Crossref] [PubMed]
4. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. [Crossref] [PubMed]
5. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
6. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-60. [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. 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]
9. 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]
10. 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]