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Editorial |

Adjuvant Epithelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer: Yes, No, Maybe So? FREE TO VIEW

Mellar P. Davis, MD, FCCP; Vamsidhar Velcheti, MD; Nathan A. Pennell, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: V. V. is on the advisory board of Clovis Inc and serves as a consultant for Foundation Medicine, Novartis. N. A. P. has served as a consultant for AstraZeneca and Boehringer Ingelheim. None declared (M. P. D.).

CORRESPONDENCE TO: Mellar P. Davis, MD, FCCP, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave, T34, Cleveland, OH 44195


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):1357-1359. doi:10.1016/j.chest.2016.01.032
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Dr Huang et al performed a systematic review of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected lung cancer. The studies largely comprised patients unselected for sensitive tyrosine kinase mutations (exon 19 deletions and point mutations replacing leucine for arginine at codon 858 in exon 21 [L858R]), and the trials had significant heterogeneity that limited conclusions. Patients receiving adjuvant TKIs (erlotinib or gefitinib) had a disease-free survival (DFS) benefit of 3% at 3 years, and benefits were greater for those receiving ≥ 18 months of TKI therapy. Overall survival was not improved. In the subset with sensitizing EGFR mutations, there was a DFS benefit of 9.5% at 3 years, with evidence of reduced distant relapse (hazard ratio, 0.71 [95% CI, 0.56-0.92]).

FOR RELATED ARTICLE SEE PAGE 1384

Given the marginal benefit of EGFR TKIs in unselected patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), TKIs should not be used in unselected populations with early-stage cancer., The Adjuvant Erlotinib vs Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Cancer (RADIANT) trial selected patients on the basis of cancers that overexpressed EGFR according to immunohistochemistry markers and/or copy numbers according to fluorescent in situ hybridization. Patients with stage IB to IIIA lung cancers that were surgically resected were randomized (2:1) to receive either erlotinib or placebo after adjuvant chemotherapy. There was no difference in DFS (50.5 months vs 48 months). Median duration of adjuvant erlotinib therapy was 12 of the planned 24 months. Significant dropout occurred with the full dose (150 mg) of erlotinib, and 17% of patients had EGFR-sensitive mutations. DFS was longer in the group treated with erlotinib compared with the group taking placebo (46.4 months vs 28.5 months; hazard ratio, 0.61 [95% CI, 0.38-0.98]); according to the statistic used (hierarchical analysis), this outcome was not significant.

The first trial to prospectively investigate TKIs as adjuvant therapy for patients with EGFR-sensitive mutations was the SELECT trial, which was a single-arm study. Patients with resected stage IA to IIIA cancer underwent 2 years of treatment with erlotinib 150 mg daily after adjuvant chemotherapy. The primary end point was DFS at 2 years, which was compared with that of historical control subjects. DFS was > 86% at 2 years, and this outcome was better than that of the historical control subjects. Of the 100 patients receiving erlotinib, 69% completed 22 months of therapy but 40% required dose reductions. Only four patients recurred on therapy, and most (n = 25) recurrences were after TKI therapy was stopped. Most relapses responded to the reintroduction of erlotinib. Importantly, only one resistant mutation (T790M) was found, based on the results of a repeat biopsy.

The excellent systematic review by Dr Huang et al leaves us grappling with questions about the role of adjuvant EGFR TKIs in lung cancer. Have we chosen the right TKI? Neither gefitinib nor erlotinib has shown a survival advantage in advanced NSCLC; however, the irreversible inhibitor afatinib demonstrated a survival benefit in advanced NSCLC with exon 19 deletions. What is the optimal duration of adjuvant TKI therapy? Is 2 years enough time to see the full benefits? Recurrences largely occurred while not receiving TKI treatment in the SELECT study, suggesting that 2 years may be inadequate. Most recurrences were still sensitive to reversible TKIs, which suggests that TKIs suppress sensitive clones but do not eliminate them. Will adjuvant TKI therapy require continuous dosing, similar to imatinib for chronic myelogenous leukemia, or will benefits be seen within a limited time frame, such as occurs with adjuvant tamoxifen treatment for breast cancer? What is the optimal dose that most patients will tolerate or do adjuvant TKIs need to be given at full dose? Although the incidence of T790M mutations account for one-half of acquired resistance with the reversible TKIs, T790M mutations are not the major reason for relapse off of TKI adjuvant therapy. Are third-generation TKIs (eg, osimertinib), which target T790M, appropriate or better choices for adjuvant therapy? The improved tolerability of third-generation TKIs could increase compliance even if T790M is not a major cause for relapse. With the rapid advances in cell-free DNA technologies, we are able to detect somatic mutations in blood with a high degree of sensitivity and specificity. We could use highly sensitive platforms to monitor patients postoperatively to detect minimal residual disease. These assays could be used in designing clinical trials for monitoring recurrence postoperatively to modify therapy at the time of molecular recurrence. The use of such methods to detect minimal residual disease could potentially better select patients postoperatively for adjuvant EGFR TKI therapy.

Ongoing Trials

Multiple trials are in progress to answer questions regarding adjuvant TKI use. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an enrichment enrollment trial of adjuvant erlotinib vs placebo for EGFR mutation-positive cancers and crizotinib vs placebo for cancers with anaplastic lymphoma kinase rearrangements. Patients with stage IB (> 4 cm) to stage IIIA disease with completely resected cancers have been randomized to receive targeted therapy vs placebo after adjuvant chemotherapy. The NCTO 1746 251 trial is comparing adjuvant afatinib 40 mg for 3 months vs 3 years for patients with resected stage IA to IIIB NSCLC with EGFR mutations., The RTOG 1210/Alliance 31101 is analyzing adjuvant TKI therapy after chemoradiation in patients with EGFR mutation-sensitive cancers. A Chinese trial (C-TONG 1104) is comparing adjuvant TKI agents after resection of stage II to IIIA (N1 or N2) cancers with EGFR-sensitive mutations. Gefitinib is given for 2 years vs four cycles of chemotherapy. The Japanese trial WJOG 6410L is comparing adjuvant gefitinib vs chemotherapy for resected stage II to IIIA lung cancer with EGFR-sensitive mutations. Gefitinib is given for 2 years and chemotherapy is administered for four cycles. Ultimately, however, as these trials are designed, we will not be able to determine if an adjuvant TKI alone is superior or equivalent to sequential or concurrent TKI treatment and chemotherapy. The ALCHEMIST trial lacks a TKI-only arm, and the Chinese and Japanese studies lack a combined chemotherapy and TKI adjuvant arm.

Should adjuvant TKIs be used for patients with resected lung cancers with EGFR- sensitive mutations? This treatment is perhaps appropriate for those at significant risk for recurrence (stage IB to IIIA) who medically cannot tolerate adjuvant chemotherapy. It could be considered based on improved DFS. Should TKIs be added routinely outside of a clinical trial for at-risk individuals? The answer is no. Will TKIs improve DFS and, more importantly, the survival of patients with resected EGFR-mutant lung cancers? Maybe so, but we will have to wait.

Huang Q. .Li J. .Sun Y. .Wang R. .Cheng X. .Chen H. . Efficacy of EGFR tyrosine kinase inhibitors in the adjuvant treatment for operable non-small cell lung cancer by a meta-analysis. Chest. 2016;149:1384-1392 [PubMed]journal
 
Kelly K. .Chansky K. .Gaspar L.E. .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;26:2450-2456 [PubMed]journal. [CrossRef] [PubMed]
 
Goss G.D. .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;31:3320-3326 [PubMed]journal. [CrossRef] [PubMed]
 
Kelly K. .Altorki N.K. .Eberhardt W.E. .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;33:4007-4014 [PubMed]journal. [CrossRef] [PubMed]
 
Riely G.J. .Miller V.A. .Pao W. .et al Clinical characteristics and natural history of patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations treated with erlotinib or gefitinib. J Clin Oncol. 2005;23:641s- [PubMed]journal
 
Pennell N.A. .Neal J.W. .Govindan R. .et al The SELECT trial: a multicenter phase II trial of adjuvant erlotinib (E) in patients with resected, early-stage non-small cell lung cancer (NSCLC) and confirmed mutations in the epidermal growth factor receptor (EGFR). J Clin Oncol. 2011;29:TPS209- [PubMed]journal
 
Yang J.C. .Wu Y.L. .Schuler M. .et al Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141-151 [PubMed]journal. [CrossRef] [PubMed]
 
Walter A.O. .Sjin R.T. .Haringsma H.J. .et al Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3:1404-1415 [PubMed]journal. [CrossRef] [PubMed]
 
Gerber D.E. .Oxnard G.R. .Govindan R. . ALCHEMIST: bringing genomic discovery and targeted therapies to early-stage lung cancer. Clin Pharmacol Ther. 2015;97:447-450 [PubMed]journal. [CrossRef] [PubMed]
 
Lampaki S. .Lazaridis G. .Zarogoulidis K. .et al Defining the role of tyrosine kinase inhibitors in early stage non-small cell lung cancer. J Cancer. 2015;6:568-574 [PubMed]journal. [PubMed]
 
Milovancev A. .Stojsic V. .Zaric B. .et al EGFR-TKIs in adjuvant treatment of lung cancer: to give or not to give? Onco Targets Ther. 2015;8:2915-2921 [PubMed]journal. [PubMed]
 
Chuang J.C. .Neal J.W. .Niu X.M. .Wakelee H.A. . Adjuvant therapy for EGFR mutant and ALK positive NSCLC: current data and future prospects. Lung Cancer. 2015;90:1-7 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Huang Q. .Li J. .Sun Y. .Wang R. .Cheng X. .Chen H. . Efficacy of EGFR tyrosine kinase inhibitors in the adjuvant treatment for operable non-small cell lung cancer by a meta-analysis. Chest. 2016;149:1384-1392 [PubMed]journal
 
Kelly K. .Chansky K. .Gaspar L.E. .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;26:2450-2456 [PubMed]journal. [CrossRef] [PubMed]
 
Goss G.D. .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;31:3320-3326 [PubMed]journal. [CrossRef] [PubMed]
 
Kelly K. .Altorki N.K. .Eberhardt W.E. .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;33:4007-4014 [PubMed]journal. [CrossRef] [PubMed]
 
Riely G.J. .Miller V.A. .Pao W. .et al Clinical characteristics and natural history of patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations treated with erlotinib or gefitinib. J Clin Oncol. 2005;23:641s- [PubMed]journal
 
Pennell N.A. .Neal J.W. .Govindan R. .et al The SELECT trial: a multicenter phase II trial of adjuvant erlotinib (E) in patients with resected, early-stage non-small cell lung cancer (NSCLC) and confirmed mutations in the epidermal growth factor receptor (EGFR). J Clin Oncol. 2011;29:TPS209- [PubMed]journal
 
Yang J.C. .Wu Y.L. .Schuler M. .et al Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141-151 [PubMed]journal. [CrossRef] [PubMed]
 
Walter A.O. .Sjin R.T. .Haringsma H.J. .et al Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3:1404-1415 [PubMed]journal. [CrossRef] [PubMed]
 
Gerber D.E. .Oxnard G.R. .Govindan R. . ALCHEMIST: bringing genomic discovery and targeted therapies to early-stage lung cancer. Clin Pharmacol Ther. 2015;97:447-450 [PubMed]journal. [CrossRef] [PubMed]
 
Lampaki S. .Lazaridis G. .Zarogoulidis K. .et al Defining the role of tyrosine kinase inhibitors in early stage non-small cell lung cancer. J Cancer. 2015;6:568-574 [PubMed]journal. [PubMed]
 
Milovancev A. .Stojsic V. .Zaric B. .et al EGFR-TKIs in adjuvant treatment of lung cancer: to give or not to give? Onco Targets Ther. 2015;8:2915-2921 [PubMed]journal. [PubMed]
 
Chuang J.C. .Neal J.W. .Niu X.M. .Wakelee H.A. . Adjuvant therapy for EGFR mutant and ALK positive NSCLC: current data and future prospects. Lung Cancer. 2015;90:1-7 [PubMed]journal. [CrossRef] [PubMed]
 
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