Targeting minimal residual disease after surgery with molecular targeted therapy: the real path to a cure?

Stage II–IIIA non-small cell lung cancer (NSCLC) affects a highly heterogeneous group of patients with differences in the extent and localization of the disease, and the definition of stage II–IIIA disease has changed over time. The 5-year survival for completely resected stage II–IIIA NSCLC patients is poor (36–60%) (1). Indeed, at least one-third of patients show recurrences after surgery.

Clinical trials of adjuvant chemotherapy have been conducted to lower the recurrence rate and improve the prognosis by targeting minimal residual disease (MRD), which is considered a factor of relapse. A meta-analysis by the NSCLC collaborative group in 1995 revealed that postoperative adjuvant chemotherapy showed a 5% improvement in the 5-year survival rate (2). A meta-analysis (LACE) including five studies [ALPI (3), BLT (4), IALT (5), JBR 10 (6), ANITA (7)] comparing surgery alone and cisplatin (CDDP)-based chemotherapy showed a significant improvement in the 5-year survival rate, and the survival effect was particularly observed at stage II–IIIA in the sub-group analysis (8). Among those studies, the analysis of 1,888 cases evaluated for comparison between surgery alone and vinorelbine plus CDDP showed an improvement of 5.9% in the 5-year survival rate (9). These findings suggest that adjuvant chemotherapy by using platinum-based chemotherapy (vinorelbine plus CDDP) is currently the standard of strategy for patients with completely resected stage II-IIIA NSCLC (10,11). However, 0.8% of treatment-related deaths has been reported for CDDP-based adjuvant therapy (9).

Target therapy is not indicated outside of a clinical trial as an adjuvant therapy in this setting. For patients with or without driver mutations, the use of adjuvant target therapy including cetuximab, erlotinib and crizotinib is under evaluation (Table 1), and preliminary results have not suggested a survival benefit (13,14). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the recommended first-line treatments for EGFR-mutant advanced NSCLC. There is implicit evidence that particularly NSCLC patients harboring EGFR activating mutations at resected IIIA N2 stage have a superior recurrent-free survival with erlotinib. However, whether this evidence is applied to an improvement in overall survival or merely delays recurrence remains unknown (15). Evidence is also scarce for EGFR-TKIs as adjuvant therapies for EGFR-mutant completely resected stage II–IIIA NSCLC patients. The BR 19 study retrospectively assessed the adjuvant gefitinib in genotype-nonspecific patients with completely resected stage IB–IIIA NSCLC, and no survival benefit was reported in the gefitinib-treated group (16). Two prospective trials [RADIANT (15) and SELECT (17)] showed promising survival benefit in patients with EGFR-mutant stage I–III NSCLC who received the adjuvant erlotinib. In the SELECT phase II trial (17), the 2-year disease-free survival (DFS) is 73% at stage II and 92% at stage III and in the RADIANT phase III trial (15), among the 161 patients in the EGFR mutant subgroup, DFS favored erlotinib.

Table 1 Ongoing randomized phase III trial of an EGFR-TKIs as adjuvant treatment for patients with NSCLC harboring EGFR activating mutations (12)
Full table

Zhong et al. initiated a randomized phase III trial (ADJUVANT/CTONG1104) to evaluate the efficacy of gefitinib compared with that of CDDP-based chemotherapy in Chinese patients who underwent complete resection for EGFR-mutant stage II–IIIA NSCLC (18). The median DFS was significantly longer with gefitinib (28.7 months) than with vinorelbine plus CDDP (18.0 months), with reduced toxicity (no interstitial lung disease) and improved quality of life. Based on these findings, these authors concluded that the adjuvant gefitinib could be a potential therapeutic choice compared with adjuvant cytotoxic chemotherapy in these patients. As a limitation, the overall survival data, which was predefined secondary endpoint, is not mature and the 3-year DFS rate does not show a significant difference between the two groups (34% vs. 27%, respectively). Although DFS may be a suitably valid surrogate for overall survival in the adjuvant setting, this parameter might not prove the benefit of using EGFR-TKI as a postoperative adjuvant therapy until the survival benefit is proved after a sufficient observation period, because EGFR-TKI is expected to be used in patients receiving CDDP-based adjuvant therapy. Next, the basis of the two-year administration period of gefitinib is uncertain, which may follow the trial design of the phase III trial to assess the utility of uracil-tegafur as adjuvant therapy for completely resected stage I lung adenocarcinoma (19). Although not observed in this ADJUVANT trial, gefitinib has a fatal complication of ILD, and there are many complications that degrade QOL, such as liver dysfunction and skin rash when compared to uracil-tegafur. There is no criterion to judge whether the 2-year dosing period of gefitinib is long, short or appropriate, and it is also necessary to consider the risk of disease flare particular to EGFR-TKI after gefitinib discontinuation (20).

Despite the initial improvement in patients with EGFR mutant who received EGFR-TKIs, acquired resistance was observed in almost all cases. Although many resistance mechanisms have been elucidated, the EGFR T790M mutation in exon 20 accounts for about 50% of all acquired resistance, making testing for this alteration a key factor in determining treatment strategies using second- and third-generation EGFR-TKIs (21,22). However, in this ADJUVANT trial, the EGFR T790M status of patients who received gefitinib as adjuvant therapy and relapsed after surgery is unknown. Thus, it may be necessary to compare gefitinib adjuvant therapy in patients who received CDDP-based adjuvant therapy and apply EGFR-TKI at the time of relapse to ascertain the influence of T790M on the treatment strategy of the ADJUVANT trial. Additionally, considering that osimertinib showed better efficacy than gefitinib and erlotinib in the first-line treatment of EGFR mutant advanced NSCLC, with a similar safety profile and lower rates of serious adverse events in the FLAURA trial (23), is also likely that other EGFR-TKIs including osimertinib, are better for EGFR-TKI in an adjuvant setting (12).

The strongest evidence that the treatment of MRD can prevent relapse as a measurable surrogate for cure comes from the experience of treating completely resected NSCLC patients by using adjuvant therapy, which is fundamentally intended to eradicate MRD not resected with surgical modalities (6). However, not all MRD cells seem to contribute to a disease recurrence, so the term MRD is somewhat nonspecific (24). Thus, it remains unclear whether MRD lower than the minimum detectable threshold indicates a cure. In a preoperative setting, CDDP-based therapy confers response rates that are superior to the rates achieved in advanced NSCLC (25), which may reflect the fact that early stage and advanced stage tumor cells are fundamentally different in susceptibility to chemotherapy. However, since chemotherapy does not fundamentally indicate total cell kill in the treatment of epithelial tumors, whether EGFR-TKI intervention should be performed in an adjuvant setting or at the time of relapse remains a problem. In the case of other driver mutations, such as ALK, ROS1, RET, NTRK rearrangement and the BRAF mutation, the usefulness of molecular targeted therapy as adjuvant treatment should also be examined.

Zhong and colleagues showed that adjuvant gefitinib led to 28.7 months [95% confidence interval (CI), 24.9–32.5] of DFS, compared with 18.0 months (95% CI, 13.6–22.3) with vinorelbine plus CDDP in patients with completely resected stage II–IIIA EGFR-mutant NSCLC. Based on this result, it is possible to apply gefitinib as standard therapy of an adjuvant therapy; however, considering the unknown influence of T790M and a fatal complication ILD, it is necessary to ascertain the appropriate timing of intervention and confirm whether targeting MRD with molecular targeted therapy is the real path to a cure.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Non-Small Cell Lung Cancer Survival Rates, by Stage: AMerican Cancer Society. Available online: https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/survival-rates.html
2. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899-909. [Crossref] [PubMed]
3. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 2003;95:1453-61. [Crossref] [PubMed]
4. Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg 2004;26:173-82. [Crossref] [PubMed]
5. 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]
6. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-97. [Crossref] [PubMed]
7. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719-27. Erratum in: Lancet Oncol 2006;7:797. [Crossref] [PubMed]
8. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9. [Crossref] [PubMed]
9. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-51. [Crossref] [PubMed]
10. Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017;15:504-35. [Crossref] [PubMed]
11. Pisters KM, Evans WK, Azzoli CG, et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 2007;25:5506-18. [Crossref] [PubMed]
12. Tazza M, Metro G. Adjuvant treatment of non-small cell lung cancer: focus on targeted therapy. J Thorac Dis 2017;9:4064-9. [Crossref] [PubMed]
13. Eaton BR, Pugh SL, Bradley JD, et al. Institutional Enrollment and Survival Among NSCLC Patients Receiving Chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617. J Natl Cancer Inst 2016;108:djw034. [Crossref] [PubMed]
14. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26:2450-6. [Crossref] [PubMed]
15. 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]
16. Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013;31:3320-6. [Crossref] [PubMed]
17. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. Proc Am Soc Clin Oncol 2014;32:abstr 7514.
18. 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]
19. Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713-21. [Crossref] [PubMed]
20. Akamatsu H, Ono A, Shukuya T, et al. Disease flare after gefitinib discontinuation. Respir Investig 2015;53:68-72. [Crossref] [PubMed]
21. Yu HA, Riely GJ, Lovly CM. Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 2014;20:5898-907. [Crossref] [PubMed]
22. Stinchcombe TE. Novel agents in development for advanced non-small cell lung cancer. Ther Adv Med Oncol 2014;6:240-53. Erratum in: Ther Adv Med Oncol 2015;7:237. [Crossref] [PubMed]
23. 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]
24. Luskin MR, Murakami MA, Manalis SR, et al. Targeting minimal residual disease: a path to cure? Nat Rev Cancer 2018;18:255-63. [Crossref] [PubMed]
25. Scagliotti GV, Pastorino U, Vansteenkiste JF, et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol 2012;30:172-8. [Crossref] [PubMed]