REVIEW URRENT C OPINION
Epidermal growth factor receptor tyrosine kinase inhibitors in early-stage nonsmall cell lung cancer Johanna N. Spaans a and Glenwood D. Goss a,b,c
Purpose of review Targeted molecular therapy is playing an increasingly important role in the treatment of nonsmall cell lung cancer (NSCLC). Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the advanced disease setting. Preliminary findings suggest that EGFR-TKIs may also be beneficial as adjuvant therapy following complete resection in patients with EGFR-mutation-positive early-stage I–III NSCLC; however, many questions remain unanswered. Recent findings Single-arm trials of adjuvant EGFR-TKI therapy in patients with tumors harboring activating EGFR mutations show impressive 2-year disease-free survival (DFS). Phase III randomized trial data do not support adjuvant EGFR-TKI therapy in unselected completely resected stage I–III NSCLC, but show improved DFS in patients with completely resected EGFR-mutated NSCLC. Adverse events leading to treatment withdrawal and dose reductions are frequent with adjuvant EGFR-TKI therapy, and relapse following treatment withdrawal is common. Adjuvant EGFR-TKIs have not yet been shown to improve the overall survival (OS) in patients with tumors harboring activating EGFR mutations. Summary There are no data to support the use of adjuvant EGFR-TKIs in unselected early-stage NSCLC. Although EGFR-TKIs hold promise as adjuvant therapy in patients whose tumors harbor EGFR mutations, in the absence of definitive data confirming an OS benefit eligible patients should continue to receive adjuvant chemotherapy following complete resection. Keywords adjuvant, EGFR mutation, EGFR-TKI, toxicity
INTRODUCTION
disease setting and are currently being evaluated as adjuvant therapy in early-stage NSCLC [9 ,10 , 11,12]. Herein, we review the emerging data of the efficacy and safety of adjuvant EGFR-targeted therapy in stage IB–IIIA completely resected NSCLC and discuss the role of these agents in the management of early-stage disease. Unanswered questions regarding dose and treatment duration are discussed in the context of the toxicity of prolonged therapy. &
Surgical resection remains the primary modality of treatment in the management of early-stage I–III nonsmall cell lung cancer (NSCLC). Disease recurrence is common, with only 25–70% of stage I–III patients surviving 5 years [1,2]. As most recurrences occur distally [3], adjuvant chemotherapy in stage II and III disease has become the standard of care, with improvements in 5-year survival of 5–15% [4–6]. Improved survival in patients with stage IB disease with tumors greater than 4 cm has also been reported [7], albeit less consistently. Given the poor survival of patients with stage IB, II and III NSCLC and their low levels of compliance with adjuvant chemotherapy [8], alternate adjuvant therapies are required. Despite this need, the management of early-stage NSCLC has remained virtually unchanged for almost a decade. Molecular therapies targeting the epidermal growth factor receptor (EGFR) have demonstrated efficacy in the advanced www.co-oncology.com
&
a
Ottawa Hospital Research Institute, bOttawa Hospital Cancer Centre and cDepartment of Medicine, University of Ottawa, Ottawa, Ontario, Canada Correspondence to Dr Glenwood D. Goss, MD, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. E-mail: [email protected] Curr Opin Oncol 2015, 27:102–107 DOI:10.1097/CCO.0000000000000163 Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss
The optimal dose and duration of adjuvant EGFR-TKI therapy in EGFR-mutation-positive stage I–III NSCLC have not yet been defined.
patients with stage I–III NSCLC (n ¼ 183) found EGFR overexpression in more than 60% of surgical specimens [13]. Another retrospective study that included surgical specimens from more than 1000 patients with stage I–III adenocarcinoma NSCLC found an EGFR mutation prevalence of 20% [21], similar to those reported in the advanced disease setting [17]. The high proportion of stage IA patients whose tumors were found to harbor EGFR mutations in this, and other studies [22], also suggests that EGFR mutations in NSCLC are not stage dependent and supports the relevance of the EGFR pathway across all stages of NSCLC.
HISTORY OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN ADVANCED NONSMALL CELL LUNG CANCER
RETROSPECTIVE STUDIES OF ADJUVANT EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN EPIDERMAL GROWTH FACTOR RECEPTOR-MUTANT NONSMALL CELL LUNG CANCER
KEY POINTS Unselected patients with early-stage NSCLC should not receive adjuvant EGFR-TKI following surgical resection. Preliminary results of adjuvant EGFR-TKI therapy in patients whose tumors harbor EGFR mutations are encouraging; however, until overall survival data are available, adjuvant chemotherapy should not be replaced by EGFR-TKI therapy in EGFR-mutation-positive disease.
The high prevalence of EGFR protein expression in NSCLC and its association with aggressive biology [13] provided the initial impetus to evaluate therapies targeting the EGF receptor in advanced disease, including small molecule EGFR tyrosine kinase inhibitors (EGFR-TKIs) and EGFR monoclonal antibodies. Although early reports did suggest higher response rates among patients overexpressing EGFR protein [14], activating mutations of exons 19 and 21 of the EGFR kinase domain have now been established as the most salient biomarkers predictive of EGFR-TKI efficacy [15–17]. Since the identification of these biomarkers, three EGFR-TKIs (erlotinib, gefitinib, and afatinib) have been approved in the first-line treatment of patients with EGFRmutant tumors, with response rates of approximately 60% [18–20]. Owing to the results of BR 21, a randomized trial showing improved progression-free survival (PFS) and overall survival (OS) in unselected patients with advanced NSCLC [14], erlotinib is also approved in advanced NSCLC following chemotherapy failure, regardless of EGFR mutation status.
EPIDERMAL GROWTH FACTOR RECEPTOR OVEREXPRESSION IN EARLY-STAGE NONSMALL CELL LUNG CANCER Activation of the EGFR pathway in early-stage NSCLC is supported by a number of studies showing EGFR protein overexpression and EGFR mutation rates in surgically resected tumors, comparable to those observed in patients with advanced NSCLC [13,21,22]. Specifically, a retrospective study of EGFR expression and copy number limited to
Early signals of the predictive significance of EGFR mutations in the adjuvant setting came from retrospective series that considered the impact of adjuvant EGFR-TKI therapy following surgery on relapse-free survival and OS among patients with activating EGFR mutations [23]. The first of these reports from the Memorial Sloan Kettering Cancer Center (MSKCC) included a cohort of 167 EGFR-mutant NSCLC patients treated between 2002 and 2008, a third of whom had received EGFR-TKIs [23]. In this study, among patients who received adjuvant EGFR-TKIs there was a trend toward improved 2-year diseasefree survival (DFS: 89 vs. 72%; P ¼ 0.06) [23]. It should be noted, however, that less than one-third of patients included in this study (28%) had received perioperative chemotherapy [23], which has now become the standard of care. In a subsequent 2012 publication of an expansion of this cohort (n ¼ 286), adjuvant treatment with erlotinib or gefitinib was found to improve the DFS (hazard ratio: 0.43, 95% CI: 0.26–0.72; P ¼ 0.001), with a trend toward improved OS (hazard ratio 0.50, 95% CI: 0.23–1.08; P ¼ 0.076) [21]. The better DFS in patients receiving adjuvant EGFR-TKIs in the expanded cohort, despite their higher disease stage (48 vs. 16% stage II/III), was intriguing enough to prompt further prospective investigations of EGFR-TKIs in the adjuvant setting.
PROSPECTIVE TRIALS OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN EARLY-STAGE NONSMALL CELL LUNG CANCER Following the positive results of the EGFR-TKI erlotinib in the advanced disease setting (BR 21) [14], a
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
103
Lung and mediastinum
large phase III trial in unselected patients with stage IB–IIIA completely resected NSCLC was initiated to evaluate the role of another EGFR-TKI, gefitinib, in the adjuvant setting (BR 19) [24]. Despite its ambitious target accrual of 1242, only 503 patients were randomized prior to its early closure, based on the negative findings of the Iressa Survival Evaluation in Lung cancer (ISEL) trial of gefitinib in advanced disease [25]. In the final analysis of BR 19, treatment with gefitinib following surgery did not improve DFS or OS and, in fact, was potentially harmful (hazard ratio: DFS: 1.22, OS: 1.24; P ¼ ns) [26]. The limited time on gefitinib (median 4.8 months), the low EGFR mutation rate (4%) and the study’s early closure, however, limit the interpretation of these study results [26]. Given its established role in the advanced disease setting, erlotinib was subsequently evaluated in the adjuvant setting in patients with stage IB–IIIA disease in a randomized, placebo-controlled trial. The RADIANT trial selectively enrolled patients with EGFR overexpression to erlotinib or placebo (2 : 1), with planned EGFR mutation testing and subgroup analysis of the primary endpoint of DFS, the preliminary results of which were recently presented at the American Society of Clinical Oncology (ASCO) 2014 meeting [9 ,10 ,27]. Among the 973 patients randomized, adjuvant erlotinib vs. placebo did not improve DFS (median DFS: 50.5 vs. 48.2 months; P ¼ 0.32) [9 ]. Notably, for the full study set, the median treatment duration for adjuvant erlotinib (12 months) was half of the planned regimen (2 years), with adverse events leading to treatment termination in approximately one-third of patients [27]. In subgroup analysis, limited to patients whose tumors harbored EGFR mutations (n ¼ 161), longer DFS was noted in patients on erlotinib compared with placebo (46.4 vs. 28.5 months); however, these results were not statistically significant because of the hierarchical testing employed [10 ]. Of note, among study patients randomized to the control arm in the RADIANT trial (n ¼ 350), DFS in EGFR-mutant NSCLC patients has since been reported to be considerably shorter than their wildtype counterparts. Specifically, in exploratory analyses evaluating the prognostic significance of EGFR-mutant disease in RADIANT presented at the European Society for Medical Oncology (ESMO) 2014 meeting, the DFS in patients with activating EGFR mutations in the control arm was approximately half that of the wildtype population (28.5 vs. 55.1 months; P ¼ 0.23) [28 ]. Interpretation of these results and their impact on the efficacy analysis in the EGFR-mutant population in RADIANT is, however, limited by the small number of patients with EGFR-mutant NSCLC receiving placebo (n ¼ 59). &
&
&
&
&
104
www.co-oncology.com
Importantly, despite similar adverse-event-driven treatment withdrawals in the EGFR-mutant subgroup in the RADIANT trial, the median treatment duration (21 months) approached the prescribed regimen, highlighting the role of patient motivation in the adjuvant context [10 ]. Finally, as approximately half of the patients with EGFR-mutant NSCLC have received prior adjuvant chemotherapy (49%) [10 ], the results of the RADIANT trial provide some indication that adjuvant EGFR-TKI therapy may be beneficial in patients with activation EGFR mutations who receive adjuvant chemotherapy. The subgroup results in the EGFR-mutant population of the RADIANT trial are consistent with the emerging data from single-arm prospective trials in this population, which have reported impressive long-term DFS with the use of adjuvant EGFR-TKIs following surgical resection in stage I–III NSCLC [29,30 ]. For example, a trial in Surgically resected EGFR mutant Lung cancer with adjuvant Erlotinib Cancer Treatment (SELECT) which prospectively enrolled patients with EGFR-mutation-positive NSCLC to 2 years of adjuvant erlotinib following any prescribed chemotherapy or radiation, reported 2-year DFS of 90% in 100 EGFR-mutation-positive patients, over half of whom had stage II or III disease [30 ]. Notably, although two-thirds of patients in this study completed at least 22 months of therapy, treatment toxicity continued to be a problem, with 40 and 16% of patients requiring dose reductions to 100 and 50 mg, respectively [30 ]. Despite the encouraging DFS results in both EGFR-mutation-positive NSCLC single-arm trials and subgroup analyses in randomized studies in early-stage disease, adjuvant EGFR-TKIs have not yet been shown to improve OS. RADIANT was only powered to detect an improvement in DFS and the limited follow-up in this trial precludes an evaluation of adjuvant EGFR-TKI therapy on OS. The recently initiated Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) study [31] (clinicaltrials.gov identifier: NCT02193282) is a large randomized trial of adjuvant erlotinib or placebo in patients with activating EGFR mutations powered to detect an improvement in OS (HR¼0.67), the results of which are not expected until 2017. It should be noted that a number of other adjuvant studies in Asia limited to EGFR-mutant NSCLC are also underway, evaluating the efficacy of immediate EGFR-TKI therapy in head-to-head comparisons with four cycles of standard cisplatin-based chemotherapy [32,33]. The results of these studies may further define the role of EGFR-TKIs in the adjuvant setting. &
&
&
&
&
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss
DISCUSSION Given the results from BR 19, and more recently RADIANT, unselected early-stage NSCLC patients should not receive adjuvant EGFR-TKIs, particularly given the toxicity of long-term therapy. Among earlystage NSCLC patients whose tumors harbor activating EGFR mutations, preliminary data suggest that EGFR-TKIs may prolong the DFS. This is supported by the results of the single-arm SELECT trial and confirmed in the subgroup analysis of the RADIANT trial. The worse prognosis of the EGFR-mutant population on the placebo arm in RADIANT is, however, counterintuitive and contrary to our current understanding of EGFR-mutation-positive disease. Indeed, much controversy exists on the prognostic and predictive significance of EGFR mutation status in early-stage NSCLC [21,22,34,35]. The poor prognosis of the EGFR-mutant comparator in RADIANT may not be representative of the mutant population in earlystage NSCLC because of small numbers (n ¼ 59) and cannot be dismissed as a factor contributing to the positive results for treatment with EGFR-TKIs in the EGFR-mutant population. Consequently, efficacy of adjuvant EGFR-TKI therapy in patients with mutant-positive disease requires confirmation in ALCHEMIST. Among patients with EGFR-mutation positive NSCLC given 2 years of adjuvant EGFR-TKI therapy, there are few recurrences on treatment, with the majority of disease recurrence occurring within a year of treatment cessation [30 ]. These results compare favorably with the disease recurrence patterns observed in adjuvant chemotherapy trials, which all show a steady decline in DFS in the first 2 years [4,5,36]. Progressive worsening of DFS in the 2 years following surgery is also a pattern observed in patients with EGFR-mutant NSCLC with adjuvant chemotherapy [10 ]. Although extending the duration of adjuvant EGFR-TKI treatment in the EGFR-mutant NSCLC might be a tempting option to delay disease progression, the feasibility of this approach from a tolerability perspective is uncertain. In both the single-arm trials and the randomized RADIANT trial, dose reductions and early treatment termination were common, with only 34–69% of patients receiving 22 months of the planned 24 months of adjuvant EGFR-TKI therapy [9 ,30 ]. Given the above, the excellent tolerability and safety profile of the newer third-generation EGFRTKIs is particularly relevant in the adjuvant setting. Early results of both CO-1686 and AZD9291, selective inhibitors of activating EGFR mutations and T790M mutations, have shown rates of diarrhea, rash, and fatigue in the range of 20–30% [37,38], roughly half the rates observed with first-generation EGFR-TKIs. &
&
&
&
To date, dose-limiting toxicities for these novel agents are uncommon and dose reductions infrequent [37,38]. Given their improved safety profile, these new EGFR-TKIs may replace erlotinib and gefitinib in the adjuvant setting in patients with EGFRmutant NSCLC, assuming comparable efficacy, and may also afford prolonged administration of adjuvant therapy beyond the current 2-year regimen. Finally, the improved safety profile of the thirdgeneration EGFR-TKIs may also allow for combination regimens with chemotherapy, a therapeutic approach that has met with some success in advanced NSCLC [39,40]. The prevention of disease recurrence through preoperative induction therapy has a long history in early-stage NSCLC [41,42]. In the case of induction chemotherapy, the potential for down staging of the disease and increased rates of resection must be weighed against treatment toxicity that may preclude surgery [43,44], which is why it continues to remain controversial in early-stage NSCLC [42]. Given their better tolerability, adjuvant EGFR-TKIs may represent an attractive alternative in the induction setting. In support of this approach, induction EGFR-TKIs have demonstrated good tumor penetration in a recent study by Haura et al. [45], who found drug concentration in resected tumors to be 40-fold higher than in plasma [45]. Given their poor prognosis and resection rates [46], induction therapy with EGFR-TKIs maybe a particularly attractive therapeutic option in patients with stage III disease. There are currently a number of clinical trials underway evaluating EGFR-TKIs as induction therapy in EGFR-mutant stage II and III NSCLC (clinicaltrials.gov identifiers: NCT01843647, NCT01407822, and NCT01470716), which may further help tailor adjuvant treatment in this population. Importantly, the feasibility of tailoring adjuvant treatments based on the molecular characteristics of the tumor, including EGFR status, has recently been demonstrated in both the adjuvant setting [47] and the neoadjuvant setting [48], and may become the standard of care.
CAUTIONS The impact of previous exposure to EGFR-TKIs in early-stage disease on the future effectiveness of EGFR-TKIs is currently unknown. EGFR-TKIs have an established role in advanced NSCLC in patients whose tumors harbor activating EGFR mutations, with response rates of greater than 60% and improvements in PFS of 5–10 months over chemotherapy alone [49]. The third-generation EGFR-TKIs have been specifically engineered to target the most common resistance mutation (T790M), which may
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
105
Lung and mediastinum
further improve the long-term prognosis of advanced EGFR-mutant NSCLC. Although preliminary reports suggest that patients with EGFRmutant NSCLC who recur following adjuvant EGFR-TKI therapy do remain sensitive to EGFR-TKIs [29], the possibility that prior exposure could breed resistant clones and worsen long-term OS cannot be ignored. Further, the newer T790M-specific EGFRTKIs may also not be as efficacious in patients previously exposed in the adjuvant setting, given data showing a low frequency of T790M mutations among patients who recur after adjuvant EGFR-TKI therapy [30 ]. What implications these differing patterns of resistance will have on the overall effectiveness of EGFR-TKI therapy in NSCLC is unclear. In addition, enthusiasm for adjuvant EGFR-TKI therapy should be tempered by the fact that, to date, there is no evidence that treatment with EGFR-TKIs leads to disease cure in either the advanced disease setting or in early-stage NSCLC. As most lung cancers are multiclonal, targeted therapies which only inhibit a narrow set of oncogenic pathways are unlikely to ever successfully eliminate residual cancer, even in early-stage disease. &
CONCLUSION Currently, there are no data to support the use of adjuvant EGFR-TKIs in unselected early-stage NSCLC. Data showing improved DFS with adjuvant EGFR-TKIs in stage I–III NSCLC patients whose tumors harbor activating EGFR mutations, although encouraging, are not definitive. In the absence of data showing improved OS in early-stage mutantpositive NSCLC treated with adjuvant EGFR-TKIs, adjuvant chemotherapy must remain the gold standard for eligible populations. Whether EGFRTKIs after adjuvant chemotherapy will become the standard of care in the adjuvant setting in EGFRmutant-positive NSCLC will depend largely on the OS results of the EGFR-mutation-positive subgroup in RADIANT and the OS results of the ALCHEMIST trial. It is uncertain whether EGFR-TKIs will replace chemotherapy as adjuvant therapy following surgical resection. This will only be answered by the ongoing trials in Asia. Collectively, if these trials are able to establish a role for adjuvant EGFR-TKIs in early-stage EGFR-mutant NSCLC, then future studies should focus on optimizing EGFR-TKI dose and duration and tailoring therapeutic approaches, including the possible inclusion of neoadjuvant EGFR-TKIs in patients with poorer prognosis. Acknowledgements There are no acknowledgements.
106
www.co-oncology.com
Financial support and sponsorship The authors have no support or sponsorship to declare. Conflicts of interest Although G.D.G. has previously received honoraria from AstraZeneca, Roche, Pfizer, and Boehringer Ingelheim, with regard to this review there is no conflict of interest. J.N.S. has no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumors. J Thorac Oncol 2007; 2:706–714. 2. Ravdin PM, Davis G. Prognosis of patients with resected nonsmall cell lung cancer: Impact of clinical and pathologic variables. Lung Cancer 2006; 52:207–212. 3. Uramoto H, Tanaka F. Prediction of recurrence after complete resection in patients with NSCLC. Anticancer Res 2012; 32:3953–3960. 4. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall-cell lung cancer. N Engl J Med 2004; 350:351–360. 5. Winton T, Livingston R, Johnson D, et al., National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected nonsmall-cell lung cancer. N Engl J Med 2005; 352:2589– 2597. 6. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation (LACE): a pooled analysis of five randomized clinical trials including 4584 patients. J Clin Oncol 2006; 24 (18s):7008. [abstract] 7. Strauss GM, Herdone JE, Maddau S, et al. Adjuvant chemotherapy in stage IB nonsmall cell lung cancer (NSCLC): update on Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 2006; 24:. (no. 18 suppl): abstract 2007. 8. Uramoto H, Nakanishi R, Nagashima A, et al. A randomized phase III trial of adjuvant chemotherapy with bi-weekly carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with completely resected nonsmall cell lung cancer. Anticancer Res 2010; 30:4695–4699. 9. Kelly K, Altorki NK, Eberhardlt WEE, et al. A randomized, double-blind & phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with and without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) nonsmall cell lung cancer (NSCLC): RADIANT results. J Clin Oncol 2014; 32 (5s); suppl.; abstract 7501. The results of the RADIANT trial in the full study population provided definitive confirmation that EGFR-TKI therapy should not be used in unselected early-stage NSCLC. 10. Shepherd FA, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus & placebo (P) in nonsmall cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitive mutations from the RADIANT trial. J Clin Oncol 2014; 32 (5s); suppl.; abstract 7513. The subgroup analysis in the EGFR-mutation-positive NSCLC population has provided some of the most convincing evidence to date on the treatment effect of adjuvant EGFR-TKI therapy in patients with activating EGFR mutations. 11. Wang SY, Ou W, Li N, et al. Pemetrexed–carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA–N2 nonsmall cell lung cancer harbouring EGFR mutations: A randomized phase II study. J Clin Oncol 2013; 31:suppl.; abstract 7519. 12. Guangdong Association of Clinical Trials. Gefitinib versus vinorelbine/platinum as adjuvant treatment in stage II–IIIA (N1–N2) NSCLC with EGFR mutation (ADJUVANT). ClinicalTrials.gov Available at http://clinicaltrials. gov/ct2/show/NCT01405079?term=NCT01405079&rank=1. [Accessed 29 September 2014] 13. Hirsch FR, Varella-Garcia M, Bunn PA, et al. Epidermal growth factor receptor in nonsmall cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21:3798– 3807.
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss 14. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated nonsmall cell lung cancer. N Engl J Med 2005; 353:123–132. 15. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129–2139. 16. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefinitib therapy. Science 2004; 304:1497– 1500. 17. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 2005; 353:133– 144. 18. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive nonsmall-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735–742. 19. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for nonsmall cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–2388. 20. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327–3334. 21. D’Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFRmutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 2012; 7:1815– 1822. 22. Izar B, Sequist L, Lee M, et al. The impact of EGFR mutation status on outcomes in patients with resected stage I nonsmall cell lung cancer. Ann Thorac Surg 2013; 96:962–968. 23. Janjijian YY, Park BJ, Zakowski MF, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor epidermal growth factor (EGFR) mutations. J Thorac Oncol 2011; 6:569–575. 24. Goss SD, Tsao MS, O’Callaghan CJ, et al. A phase III randomized, doubleblind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB–IIIA nonsmall cell lung cancer (NSCLC): NCIC CTG BR 19. J Clin Oncol 2010; 28 (18s); suppl.; abstract LBA 7005. 25. Thatcher N, Chang A, Pariku P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall cell lung cancer: results from a randomized placebo-controlled multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005; 366:1527–1537. 26. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected nonsmall cell lung cancer: results of the NCIC CTG BR 19 study. J Clin Oncol 2013; 31:3320–3326. 27. O’Brien MER, Eberhardt WEE, Altorki NK, et al. Analysis of treatment duration and safety of adjuvant erlotinib versus placebo after surgery in patients (pts) with nonsmall cell lung cancer (NSCLC): RADIANT trial. J Clin Oncol 2014; 32 (5s); abstract 7535. 28. Altorki N, Kelly K, O’Brien M, et al. EGFR del19/L858R activating mutation & (Mþ) subgroup in RADIANT. Baseline characteristics, prognostic role, and disease-free survival (DFS) by stage. In: ESMO 2014 Congress, Madrid, Spain; 26–30 September; abstract 1177PD. The poor prognosis of EGFR-mutant NSCLC patients on placebo reported by Altorki at ESMO 2014 may provide an alternate explanation for the impressive results of RADIANT in the EGFR-mutant population. Validation studies will therefore be required to confirm the benefit of adjuvant EGFR-TKIs in EGFR-mutant NSCLC. 29. Neal JW, Pennell NA, Govindan R, et al. The SELECT study: a multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC). J Clin Oncol 2012; 30:suppl.; abstract 7010. 30. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of & adjuvant erlotinib in resected early-stage EGFR mutant-positive NSCLC. J Clin Oncol 2014; 32 (5s); abstract 7514. This large single-arm prospective trial has demonstrated impressive 2-year disease-free survival in stage I–III EGFR-mutant NSCLC patients receiving adjuvant erlotinib.
31. Mooney MM, Welch J, Abrams JS. Clinical trial design and master protocols in NCI clinical treatment trials. [abstract]. In: Proceedings of the AACR–IASLC Joint conference on molecular origins of lung cancer; 6–9 January 2014; San Diego, CA/Philadelphia, PA: AACR. Clin Cancer Res 2014; 20 (2 Suppl.); abstract IA08. 32. Tada H, Takeda K, Nakagawa K, et al. Vinorelbine plus cisplatin vs gefitinib in resectable nonsmall cell lung cancer harbouring activating EGFR mutation (WTOG6410L). J Clin Oncol 2012; 30:abstract TPS7110. 33. Gefitinib versus vinorelbine/platinum as adjuvant treatment in stage II–IIIA (N1– N2) NSCLC with EGFR mutation (ADJUVANT). [clinicaltrial.gov identifier: NCT01405079. Available at https://clinicaltrials.gov/ct2/show/NCT0140 5079?term=NCT01405079&rank=1 [Accessed 30 September 2014]. 34. Kim YT, Seong YW, Jung YL, et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcomes after surgical resection of nonsmall cell lung cancer. J Thorac Oncol 2013; 8:171–178. 35. Lim KH, Huang MJ, Liu HC, et al. Lack of prognostic value of EGFR mutations in primary resected nonsmall cell lung cancer. Med Oncol 2007; 24:388– 393. 36. Douillard J, Rosell R, Delena M, et al. ANITA: phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (obs) in completely resected (stage I-III) nonsmall cell lung cancer (NSCLC) patients (pts): final results after 70-month median follow-up. Proceedings of the 2005 ASCO Annual Meeting. J Clin Oncol 2004; 23:abstract 7013. 37. Janne PA, Ramalingam SS, Yang JCH, et al. Clinical activity of the mutantselective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitorresistant nonsmall cell lung cancer (NSCLC). J Clin Oncol 2014; 32 (5S): abstract 8009. 38. Sequist LV, Soria JC, Gadgeel SM, et al. First-in-human evaluation of CO1686, and irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol 2014; 32 (5s); suppl.; abstract 8010. 39. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage nonsmall cell lung cancer (FASTACT-2): a randomized, double-blind trial. Lancet Oncol 2013; 14:777–786. 40. Schuler MH, Yang C-H, Park K, et al. Continuation of afatinib beyond progression: results of a randomized, open-label, phase III trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy in patients with metastatic nonsmall cell lung cancer progressed on erlotinib/gefitinib and afatinib – LUX-Lung 5. J Clin Oncol 2014; 32 (5s); suppl.; abstract 8109. 41. Pisters KM, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: a novel approach: Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 2000; 119:429–439. 42. Stinchcombe TE, Socinski MA. The role of induction therapy for resectable nonsmall cell lung cancer. Drugs 2007; 67:321–323. 43. Naidoo R, Windsor MN, Goldstraw P. Surgery in 2013 and beyond. J Thorac Dis 2013; 5:S593–S606. 44. Salva F, Felip E. Neoadjuvant chemotherapy in early-stage nonsmall cell lung cancer. Transl Lung Cancer Res 2013; 2:398–402. 45. Haura EB, Sommers E, Song L, et al. A pilot study of preoperative gefitinib for early stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance. J Thorac Oncol 2010; 5:1806–1814. 46. Andre F, Grunenwald. Pignon JP, et al. Survival of patients with resected N2 nonsmall cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18:2981–2989. 47. Soria JC, Barlesi F, Besse B, et al. Results of the prospective, randomized, and customised NSCLC adjuvant phase II trial (IFCT-0801, TASTE trial) from the French Collaborative Intergroup. J Clin Oncol 2013; 31 (Suppl.); abstract 7505. 48. Grossi F, Rijavec E, Barletta G, et al. A multicenter phase II randomized study of customized neoadjuvant therapy versus standard chemotherapy (CT) in nonsmall cell lung cancer (NSCLC) patients with resectable IIIA (N2) disease (CONTEST Trial). J Clin Oncol 2013; 13:abstract TPS7606. 49. Spaans JN, Goss GD. Trials to overcome drug resistance to EGFR and ALK targeted therapies – past, present and future. Front Oncol 2014; 4:233.
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
107
Epidermal growth factor receptor tyrosine kinase inhibitors in early-stage nonsmall cell lung cancer Johanna N. Spaans a and Glenwood D. Goss a,b,c
Purpose of review Targeted molecular therapy is playing an increasingly important role in the treatment of nonsmall cell lung cancer (NSCLC). Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the advanced disease setting. Preliminary findings suggest that EGFR-TKIs may also be beneficial as adjuvant therapy following complete resection in patients with EGFR-mutation-positive early-stage I–III NSCLC; however, many questions remain unanswered. Recent findings Single-arm trials of adjuvant EGFR-TKI therapy in patients with tumors harboring activating EGFR mutations show impressive 2-year disease-free survival (DFS). Phase III randomized trial data do not support adjuvant EGFR-TKI therapy in unselected completely resected stage I–III NSCLC, but show improved DFS in patients with completely resected EGFR-mutated NSCLC. Adverse events leading to treatment withdrawal and dose reductions are frequent with adjuvant EGFR-TKI therapy, and relapse following treatment withdrawal is common. Adjuvant EGFR-TKIs have not yet been shown to improve the overall survival (OS) in patients with tumors harboring activating EGFR mutations. Summary There are no data to support the use of adjuvant EGFR-TKIs in unselected early-stage NSCLC. Although EGFR-TKIs hold promise as adjuvant therapy in patients whose tumors harbor EGFR mutations, in the absence of definitive data confirming an OS benefit eligible patients should continue to receive adjuvant chemotherapy following complete resection. Keywords adjuvant, EGFR mutation, EGFR-TKI, toxicity
INTRODUCTION
disease setting and are currently being evaluated as adjuvant therapy in early-stage NSCLC [9 ,10 , 11,12]. Herein, we review the emerging data of the efficacy and safety of adjuvant EGFR-targeted therapy in stage IB–IIIA completely resected NSCLC and discuss the role of these agents in the management of early-stage disease. Unanswered questions regarding dose and treatment duration are discussed in the context of the toxicity of prolonged therapy. &
Surgical resection remains the primary modality of treatment in the management of early-stage I–III nonsmall cell lung cancer (NSCLC). Disease recurrence is common, with only 25–70% of stage I–III patients surviving 5 years [1,2]. As most recurrences occur distally [3], adjuvant chemotherapy in stage II and III disease has become the standard of care, with improvements in 5-year survival of 5–15% [4–6]. Improved survival in patients with stage IB disease with tumors greater than 4 cm has also been reported [7], albeit less consistently. Given the poor survival of patients with stage IB, II and III NSCLC and their low levels of compliance with adjuvant chemotherapy [8], alternate adjuvant therapies are required. Despite this need, the management of early-stage NSCLC has remained virtually unchanged for almost a decade. Molecular therapies targeting the epidermal growth factor receptor (EGFR) have demonstrated efficacy in the advanced www.co-oncology.com
&
a
Ottawa Hospital Research Institute, bOttawa Hospital Cancer Centre and cDepartment of Medicine, University of Ottawa, Ottawa, Ontario, Canada Correspondence to Dr Glenwood D. Goss, MD, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. E-mail: [email protected] Curr Opin Oncol 2015, 27:102–107 DOI:10.1097/CCO.0000000000000163 Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss
The optimal dose and duration of adjuvant EGFR-TKI therapy in EGFR-mutation-positive stage I–III NSCLC have not yet been defined.
patients with stage I–III NSCLC (n ¼ 183) found EGFR overexpression in more than 60% of surgical specimens [13]. Another retrospective study that included surgical specimens from more than 1000 patients with stage I–III adenocarcinoma NSCLC found an EGFR mutation prevalence of 20% [21], similar to those reported in the advanced disease setting [17]. The high proportion of stage IA patients whose tumors were found to harbor EGFR mutations in this, and other studies [22], also suggests that EGFR mutations in NSCLC are not stage dependent and supports the relevance of the EGFR pathway across all stages of NSCLC.
HISTORY OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN ADVANCED NONSMALL CELL LUNG CANCER
RETROSPECTIVE STUDIES OF ADJUVANT EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN EPIDERMAL GROWTH FACTOR RECEPTOR-MUTANT NONSMALL CELL LUNG CANCER
KEY POINTS Unselected patients with early-stage NSCLC should not receive adjuvant EGFR-TKI following surgical resection. Preliminary results of adjuvant EGFR-TKI therapy in patients whose tumors harbor EGFR mutations are encouraging; however, until overall survival data are available, adjuvant chemotherapy should not be replaced by EGFR-TKI therapy in EGFR-mutation-positive disease.
The high prevalence of EGFR protein expression in NSCLC and its association with aggressive biology [13] provided the initial impetus to evaluate therapies targeting the EGF receptor in advanced disease, including small molecule EGFR tyrosine kinase inhibitors (EGFR-TKIs) and EGFR monoclonal antibodies. Although early reports did suggest higher response rates among patients overexpressing EGFR protein [14], activating mutations of exons 19 and 21 of the EGFR kinase domain have now been established as the most salient biomarkers predictive of EGFR-TKI efficacy [15–17]. Since the identification of these biomarkers, three EGFR-TKIs (erlotinib, gefitinib, and afatinib) have been approved in the first-line treatment of patients with EGFRmutant tumors, with response rates of approximately 60% [18–20]. Owing to the results of BR 21, a randomized trial showing improved progression-free survival (PFS) and overall survival (OS) in unselected patients with advanced NSCLC [14], erlotinib is also approved in advanced NSCLC following chemotherapy failure, regardless of EGFR mutation status.
EPIDERMAL GROWTH FACTOR RECEPTOR OVEREXPRESSION IN EARLY-STAGE NONSMALL CELL LUNG CANCER Activation of the EGFR pathway in early-stage NSCLC is supported by a number of studies showing EGFR protein overexpression and EGFR mutation rates in surgically resected tumors, comparable to those observed in patients with advanced NSCLC [13,21,22]. Specifically, a retrospective study of EGFR expression and copy number limited to
Early signals of the predictive significance of EGFR mutations in the adjuvant setting came from retrospective series that considered the impact of adjuvant EGFR-TKI therapy following surgery on relapse-free survival and OS among patients with activating EGFR mutations [23]. The first of these reports from the Memorial Sloan Kettering Cancer Center (MSKCC) included a cohort of 167 EGFR-mutant NSCLC patients treated between 2002 and 2008, a third of whom had received EGFR-TKIs [23]. In this study, among patients who received adjuvant EGFR-TKIs there was a trend toward improved 2-year diseasefree survival (DFS: 89 vs. 72%; P ¼ 0.06) [23]. It should be noted, however, that less than one-third of patients included in this study (28%) had received perioperative chemotherapy [23], which has now become the standard of care. In a subsequent 2012 publication of an expansion of this cohort (n ¼ 286), adjuvant treatment with erlotinib or gefitinib was found to improve the DFS (hazard ratio: 0.43, 95% CI: 0.26–0.72; P ¼ 0.001), with a trend toward improved OS (hazard ratio 0.50, 95% CI: 0.23–1.08; P ¼ 0.076) [21]. The better DFS in patients receiving adjuvant EGFR-TKIs in the expanded cohort, despite their higher disease stage (48 vs. 16% stage II/III), was intriguing enough to prompt further prospective investigations of EGFR-TKIs in the adjuvant setting.
PROSPECTIVE TRIALS OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN EARLY-STAGE NONSMALL CELL LUNG CANCER Following the positive results of the EGFR-TKI erlotinib in the advanced disease setting (BR 21) [14], a
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
103
Lung and mediastinum
large phase III trial in unselected patients with stage IB–IIIA completely resected NSCLC was initiated to evaluate the role of another EGFR-TKI, gefitinib, in the adjuvant setting (BR 19) [24]. Despite its ambitious target accrual of 1242, only 503 patients were randomized prior to its early closure, based on the negative findings of the Iressa Survival Evaluation in Lung cancer (ISEL) trial of gefitinib in advanced disease [25]. In the final analysis of BR 19, treatment with gefitinib following surgery did not improve DFS or OS and, in fact, was potentially harmful (hazard ratio: DFS: 1.22, OS: 1.24; P ¼ ns) [26]. The limited time on gefitinib (median 4.8 months), the low EGFR mutation rate (4%) and the study’s early closure, however, limit the interpretation of these study results [26]. Given its established role in the advanced disease setting, erlotinib was subsequently evaluated in the adjuvant setting in patients with stage IB–IIIA disease in a randomized, placebo-controlled trial. The RADIANT trial selectively enrolled patients with EGFR overexpression to erlotinib or placebo (2 : 1), with planned EGFR mutation testing and subgroup analysis of the primary endpoint of DFS, the preliminary results of which were recently presented at the American Society of Clinical Oncology (ASCO) 2014 meeting [9 ,10 ,27]. Among the 973 patients randomized, adjuvant erlotinib vs. placebo did not improve DFS (median DFS: 50.5 vs. 48.2 months; P ¼ 0.32) [9 ]. Notably, for the full study set, the median treatment duration for adjuvant erlotinib (12 months) was half of the planned regimen (2 years), with adverse events leading to treatment termination in approximately one-third of patients [27]. In subgroup analysis, limited to patients whose tumors harbored EGFR mutations (n ¼ 161), longer DFS was noted in patients on erlotinib compared with placebo (46.4 vs. 28.5 months); however, these results were not statistically significant because of the hierarchical testing employed [10 ]. Of note, among study patients randomized to the control arm in the RADIANT trial (n ¼ 350), DFS in EGFR-mutant NSCLC patients has since been reported to be considerably shorter than their wildtype counterparts. Specifically, in exploratory analyses evaluating the prognostic significance of EGFR-mutant disease in RADIANT presented at the European Society for Medical Oncology (ESMO) 2014 meeting, the DFS in patients with activating EGFR mutations in the control arm was approximately half that of the wildtype population (28.5 vs. 55.1 months; P ¼ 0.23) [28 ]. Interpretation of these results and their impact on the efficacy analysis in the EGFR-mutant population in RADIANT is, however, limited by the small number of patients with EGFR-mutant NSCLC receiving placebo (n ¼ 59). &
&
&
&
&
104
www.co-oncology.com
Importantly, despite similar adverse-event-driven treatment withdrawals in the EGFR-mutant subgroup in the RADIANT trial, the median treatment duration (21 months) approached the prescribed regimen, highlighting the role of patient motivation in the adjuvant context [10 ]. Finally, as approximately half of the patients with EGFR-mutant NSCLC have received prior adjuvant chemotherapy (49%) [10 ], the results of the RADIANT trial provide some indication that adjuvant EGFR-TKI therapy may be beneficial in patients with activation EGFR mutations who receive adjuvant chemotherapy. The subgroup results in the EGFR-mutant population of the RADIANT trial are consistent with the emerging data from single-arm prospective trials in this population, which have reported impressive long-term DFS with the use of adjuvant EGFR-TKIs following surgical resection in stage I–III NSCLC [29,30 ]. For example, a trial in Surgically resected EGFR mutant Lung cancer with adjuvant Erlotinib Cancer Treatment (SELECT) which prospectively enrolled patients with EGFR-mutation-positive NSCLC to 2 years of adjuvant erlotinib following any prescribed chemotherapy or radiation, reported 2-year DFS of 90% in 100 EGFR-mutation-positive patients, over half of whom had stage II or III disease [30 ]. Notably, although two-thirds of patients in this study completed at least 22 months of therapy, treatment toxicity continued to be a problem, with 40 and 16% of patients requiring dose reductions to 100 and 50 mg, respectively [30 ]. Despite the encouraging DFS results in both EGFR-mutation-positive NSCLC single-arm trials and subgroup analyses in randomized studies in early-stage disease, adjuvant EGFR-TKIs have not yet been shown to improve OS. RADIANT was only powered to detect an improvement in DFS and the limited follow-up in this trial precludes an evaluation of adjuvant EGFR-TKI therapy on OS. The recently initiated Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) study [31] (clinicaltrials.gov identifier: NCT02193282) is a large randomized trial of adjuvant erlotinib or placebo in patients with activating EGFR mutations powered to detect an improvement in OS (HR¼0.67), the results of which are not expected until 2017. It should be noted that a number of other adjuvant studies in Asia limited to EGFR-mutant NSCLC are also underway, evaluating the efficacy of immediate EGFR-TKI therapy in head-to-head comparisons with four cycles of standard cisplatin-based chemotherapy [32,33]. The results of these studies may further define the role of EGFR-TKIs in the adjuvant setting. &
&
&
&
&
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss
DISCUSSION Given the results from BR 19, and more recently RADIANT, unselected early-stage NSCLC patients should not receive adjuvant EGFR-TKIs, particularly given the toxicity of long-term therapy. Among earlystage NSCLC patients whose tumors harbor activating EGFR mutations, preliminary data suggest that EGFR-TKIs may prolong the DFS. This is supported by the results of the single-arm SELECT trial and confirmed in the subgroup analysis of the RADIANT trial. The worse prognosis of the EGFR-mutant population on the placebo arm in RADIANT is, however, counterintuitive and contrary to our current understanding of EGFR-mutation-positive disease. Indeed, much controversy exists on the prognostic and predictive significance of EGFR mutation status in early-stage NSCLC [21,22,34,35]. The poor prognosis of the EGFR-mutant comparator in RADIANT may not be representative of the mutant population in earlystage NSCLC because of small numbers (n ¼ 59) and cannot be dismissed as a factor contributing to the positive results for treatment with EGFR-TKIs in the EGFR-mutant population. Consequently, efficacy of adjuvant EGFR-TKI therapy in patients with mutant-positive disease requires confirmation in ALCHEMIST. Among patients with EGFR-mutation positive NSCLC given 2 years of adjuvant EGFR-TKI therapy, there are few recurrences on treatment, with the majority of disease recurrence occurring within a year of treatment cessation [30 ]. These results compare favorably with the disease recurrence patterns observed in adjuvant chemotherapy trials, which all show a steady decline in DFS in the first 2 years [4,5,36]. Progressive worsening of DFS in the 2 years following surgery is also a pattern observed in patients with EGFR-mutant NSCLC with adjuvant chemotherapy [10 ]. Although extending the duration of adjuvant EGFR-TKI treatment in the EGFR-mutant NSCLC might be a tempting option to delay disease progression, the feasibility of this approach from a tolerability perspective is uncertain. In both the single-arm trials and the randomized RADIANT trial, dose reductions and early treatment termination were common, with only 34–69% of patients receiving 22 months of the planned 24 months of adjuvant EGFR-TKI therapy [9 ,30 ]. Given the above, the excellent tolerability and safety profile of the newer third-generation EGFRTKIs is particularly relevant in the adjuvant setting. Early results of both CO-1686 and AZD9291, selective inhibitors of activating EGFR mutations and T790M mutations, have shown rates of diarrhea, rash, and fatigue in the range of 20–30% [37,38], roughly half the rates observed with first-generation EGFR-TKIs. &
&
&
&
To date, dose-limiting toxicities for these novel agents are uncommon and dose reductions infrequent [37,38]. Given their improved safety profile, these new EGFR-TKIs may replace erlotinib and gefitinib in the adjuvant setting in patients with EGFRmutant NSCLC, assuming comparable efficacy, and may also afford prolonged administration of adjuvant therapy beyond the current 2-year regimen. Finally, the improved safety profile of the thirdgeneration EGFR-TKIs may also allow for combination regimens with chemotherapy, a therapeutic approach that has met with some success in advanced NSCLC [39,40]. The prevention of disease recurrence through preoperative induction therapy has a long history in early-stage NSCLC [41,42]. In the case of induction chemotherapy, the potential for down staging of the disease and increased rates of resection must be weighed against treatment toxicity that may preclude surgery [43,44], which is why it continues to remain controversial in early-stage NSCLC [42]. Given their better tolerability, adjuvant EGFR-TKIs may represent an attractive alternative in the induction setting. In support of this approach, induction EGFR-TKIs have demonstrated good tumor penetration in a recent study by Haura et al. [45], who found drug concentration in resected tumors to be 40-fold higher than in plasma [45]. Given their poor prognosis and resection rates [46], induction therapy with EGFR-TKIs maybe a particularly attractive therapeutic option in patients with stage III disease. There are currently a number of clinical trials underway evaluating EGFR-TKIs as induction therapy in EGFR-mutant stage II and III NSCLC (clinicaltrials.gov identifiers: NCT01843647, NCT01407822, and NCT01470716), which may further help tailor adjuvant treatment in this population. Importantly, the feasibility of tailoring adjuvant treatments based on the molecular characteristics of the tumor, including EGFR status, has recently been demonstrated in both the adjuvant setting [47] and the neoadjuvant setting [48], and may become the standard of care.
CAUTIONS The impact of previous exposure to EGFR-TKIs in early-stage disease on the future effectiveness of EGFR-TKIs is currently unknown. EGFR-TKIs have an established role in advanced NSCLC in patients whose tumors harbor activating EGFR mutations, with response rates of greater than 60% and improvements in PFS of 5–10 months over chemotherapy alone [49]. The third-generation EGFR-TKIs have been specifically engineered to target the most common resistance mutation (T790M), which may
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
105
Lung and mediastinum
further improve the long-term prognosis of advanced EGFR-mutant NSCLC. Although preliminary reports suggest that patients with EGFRmutant NSCLC who recur following adjuvant EGFR-TKI therapy do remain sensitive to EGFR-TKIs [29], the possibility that prior exposure could breed resistant clones and worsen long-term OS cannot be ignored. Further, the newer T790M-specific EGFRTKIs may also not be as efficacious in patients previously exposed in the adjuvant setting, given data showing a low frequency of T790M mutations among patients who recur after adjuvant EGFR-TKI therapy [30 ]. What implications these differing patterns of resistance will have on the overall effectiveness of EGFR-TKI therapy in NSCLC is unclear. In addition, enthusiasm for adjuvant EGFR-TKI therapy should be tempered by the fact that, to date, there is no evidence that treatment with EGFR-TKIs leads to disease cure in either the advanced disease setting or in early-stage NSCLC. As most lung cancers are multiclonal, targeted therapies which only inhibit a narrow set of oncogenic pathways are unlikely to ever successfully eliminate residual cancer, even in early-stage disease. &
CONCLUSION Currently, there are no data to support the use of adjuvant EGFR-TKIs in unselected early-stage NSCLC. Data showing improved DFS with adjuvant EGFR-TKIs in stage I–III NSCLC patients whose tumors harbor activating EGFR mutations, although encouraging, are not definitive. In the absence of data showing improved OS in early-stage mutantpositive NSCLC treated with adjuvant EGFR-TKIs, adjuvant chemotherapy must remain the gold standard for eligible populations. Whether EGFRTKIs after adjuvant chemotherapy will become the standard of care in the adjuvant setting in EGFRmutant-positive NSCLC will depend largely on the OS results of the EGFR-mutation-positive subgroup in RADIANT and the OS results of the ALCHEMIST trial. It is uncertain whether EGFR-TKIs will replace chemotherapy as adjuvant therapy following surgical resection. This will only be answered by the ongoing trials in Asia. Collectively, if these trials are able to establish a role for adjuvant EGFR-TKIs in early-stage EGFR-mutant NSCLC, then future studies should focus on optimizing EGFR-TKI dose and duration and tailoring therapeutic approaches, including the possible inclusion of neoadjuvant EGFR-TKIs in patients with poorer prognosis. Acknowledgements There are no acknowledgements.
106
www.co-oncology.com
Financial support and sponsorship The authors have no support or sponsorship to declare. Conflicts of interest Although G.D.G. has previously received honoraria from AstraZeneca, Roche, Pfizer, and Boehringer Ingelheim, with regard to this review there is no conflict of interest. J.N.S. has no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumors. J Thorac Oncol 2007; 2:706–714. 2. Ravdin PM, Davis G. Prognosis of patients with resected nonsmall cell lung cancer: Impact of clinical and pathologic variables. Lung Cancer 2006; 52:207–212. 3. Uramoto H, Tanaka F. Prediction of recurrence after complete resection in patients with NSCLC. Anticancer Res 2012; 32:3953–3960. 4. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall-cell lung cancer. N Engl J Med 2004; 350:351–360. 5. Winton T, Livingston R, Johnson D, et al., National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected nonsmall-cell lung cancer. N Engl J Med 2005; 352:2589– 2597. 6. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation (LACE): a pooled analysis of five randomized clinical trials including 4584 patients. J Clin Oncol 2006; 24 (18s):7008. [abstract] 7. Strauss GM, Herdone JE, Maddau S, et al. Adjuvant chemotherapy in stage IB nonsmall cell lung cancer (NSCLC): update on Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 2006; 24:. (no. 18 suppl): abstract 2007. 8. Uramoto H, Nakanishi R, Nagashima A, et al. A randomized phase III trial of adjuvant chemotherapy with bi-weekly carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with completely resected nonsmall cell lung cancer. Anticancer Res 2010; 30:4695–4699. 9. Kelly K, Altorki NK, Eberhardlt WEE, et al. A randomized, double-blind & phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with and without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) nonsmall cell lung cancer (NSCLC): RADIANT results. J Clin Oncol 2014; 32 (5s); suppl.; abstract 7501. The results of the RADIANT trial in the full study population provided definitive confirmation that EGFR-TKI therapy should not be used in unselected early-stage NSCLC. 10. Shepherd FA, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus & placebo (P) in nonsmall cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitive mutations from the RADIANT trial. J Clin Oncol 2014; 32 (5s); suppl.; abstract 7513. The subgroup analysis in the EGFR-mutation-positive NSCLC population has provided some of the most convincing evidence to date on the treatment effect of adjuvant EGFR-TKI therapy in patients with activating EGFR mutations. 11. Wang SY, Ou W, Li N, et al. Pemetrexed–carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA–N2 nonsmall cell lung cancer harbouring EGFR mutations: A randomized phase II study. J Clin Oncol 2013; 31:suppl.; abstract 7519. 12. Guangdong Association of Clinical Trials. Gefitinib versus vinorelbine/platinum as adjuvant treatment in stage II–IIIA (N1–N2) NSCLC with EGFR mutation (ADJUVANT). ClinicalTrials.gov Available at http://clinicaltrials. gov/ct2/show/NCT01405079?term=NCT01405079&rank=1. [Accessed 29 September 2014] 13. Hirsch FR, Varella-Garcia M, Bunn PA, et al. Epidermal growth factor receptor in nonsmall cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21:3798– 3807.
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
EGFR-TKIs in early-stage nonsmall cell lung cancer Spaans and Goss 14. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated nonsmall cell lung cancer. N Engl J Med 2005; 353:123–132. 15. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129–2139. 16. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefinitib therapy. Science 2004; 304:1497– 1500. 17. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 2005; 353:133– 144. 18. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive nonsmall-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735–742. 19. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for nonsmall cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–2388. 20. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327–3334. 21. D’Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFRmutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 2012; 7:1815– 1822. 22. Izar B, Sequist L, Lee M, et al. The impact of EGFR mutation status on outcomes in patients with resected stage I nonsmall cell lung cancer. Ann Thorac Surg 2013; 96:962–968. 23. Janjijian YY, Park BJ, Zakowski MF, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor epidermal growth factor (EGFR) mutations. J Thorac Oncol 2011; 6:569–575. 24. Goss SD, Tsao MS, O’Callaghan CJ, et al. A phase III randomized, doubleblind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB–IIIA nonsmall cell lung cancer (NSCLC): NCIC CTG BR 19. J Clin Oncol 2010; 28 (18s); suppl.; abstract LBA 7005. 25. Thatcher N, Chang A, Pariku P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall cell lung cancer: results from a randomized placebo-controlled multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005; 366:1527–1537. 26. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected nonsmall cell lung cancer: results of the NCIC CTG BR 19 study. J Clin Oncol 2013; 31:3320–3326. 27. O’Brien MER, Eberhardt WEE, Altorki NK, et al. Analysis of treatment duration and safety of adjuvant erlotinib versus placebo after surgery in patients (pts) with nonsmall cell lung cancer (NSCLC): RADIANT trial. J Clin Oncol 2014; 32 (5s); abstract 7535. 28. Altorki N, Kelly K, O’Brien M, et al. EGFR del19/L858R activating mutation & (Mþ) subgroup in RADIANT. Baseline characteristics, prognostic role, and disease-free survival (DFS) by stage. In: ESMO 2014 Congress, Madrid, Spain; 26–30 September; abstract 1177PD. The poor prognosis of EGFR-mutant NSCLC patients on placebo reported by Altorki at ESMO 2014 may provide an alternate explanation for the impressive results of RADIANT in the EGFR-mutant population. Validation studies will therefore be required to confirm the benefit of adjuvant EGFR-TKIs in EGFR-mutant NSCLC. 29. Neal JW, Pennell NA, Govindan R, et al. The SELECT study: a multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC). J Clin Oncol 2012; 30:suppl.; abstract 7010. 30. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of & adjuvant erlotinib in resected early-stage EGFR mutant-positive NSCLC. J Clin Oncol 2014; 32 (5s); abstract 7514. This large single-arm prospective trial has demonstrated impressive 2-year disease-free survival in stage I–III EGFR-mutant NSCLC patients receiving adjuvant erlotinib.
31. Mooney MM, Welch J, Abrams JS. Clinical trial design and master protocols in NCI clinical treatment trials. [abstract]. In: Proceedings of the AACR–IASLC Joint conference on molecular origins of lung cancer; 6–9 January 2014; San Diego, CA/Philadelphia, PA: AACR. Clin Cancer Res 2014; 20 (2 Suppl.); abstract IA08. 32. Tada H, Takeda K, Nakagawa K, et al. Vinorelbine plus cisplatin vs gefitinib in resectable nonsmall cell lung cancer harbouring activating EGFR mutation (WTOG6410L). J Clin Oncol 2012; 30:abstract TPS7110. 33. Gefitinib versus vinorelbine/platinum as adjuvant treatment in stage II–IIIA (N1– N2) NSCLC with EGFR mutation (ADJUVANT). [clinicaltrial.gov identifier: NCT01405079. Available at https://clinicaltrials.gov/ct2/show/NCT0140 5079?term=NCT01405079&rank=1 [Accessed 30 September 2014]. 34. Kim YT, Seong YW, Jung YL, et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcomes after surgical resection of nonsmall cell lung cancer. J Thorac Oncol 2013; 8:171–178. 35. Lim KH, Huang MJ, Liu HC, et al. Lack of prognostic value of EGFR mutations in primary resected nonsmall cell lung cancer. Med Oncol 2007; 24:388– 393. 36. Douillard J, Rosell R, Delena M, et al. ANITA: phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (obs) in completely resected (stage I-III) nonsmall cell lung cancer (NSCLC) patients (pts): final results after 70-month median follow-up. Proceedings of the 2005 ASCO Annual Meeting. J Clin Oncol 2004; 23:abstract 7013. 37. Janne PA, Ramalingam SS, Yang JCH, et al. Clinical activity of the mutantselective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitorresistant nonsmall cell lung cancer (NSCLC). J Clin Oncol 2014; 32 (5S): abstract 8009. 38. Sequist LV, Soria JC, Gadgeel SM, et al. First-in-human evaluation of CO1686, and irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol 2014; 32 (5s); suppl.; abstract 8010. 39. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage nonsmall cell lung cancer (FASTACT-2): a randomized, double-blind trial. Lancet Oncol 2013; 14:777–786. 40. Schuler MH, Yang C-H, Park K, et al. Continuation of afatinib beyond progression: results of a randomized, open-label, phase III trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy in patients with metastatic nonsmall cell lung cancer progressed on erlotinib/gefitinib and afatinib – LUX-Lung 5. J Clin Oncol 2014; 32 (5s); suppl.; abstract 8109. 41. Pisters KM, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: a novel approach: Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 2000; 119:429–439. 42. Stinchcombe TE, Socinski MA. The role of induction therapy for resectable nonsmall cell lung cancer. Drugs 2007; 67:321–323. 43. Naidoo R, Windsor MN, Goldstraw P. Surgery in 2013 and beyond. J Thorac Dis 2013; 5:S593–S606. 44. Salva F, Felip E. Neoadjuvant chemotherapy in early-stage nonsmall cell lung cancer. Transl Lung Cancer Res 2013; 2:398–402. 45. Haura EB, Sommers E, Song L, et al. A pilot study of preoperative gefitinib for early stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance. J Thorac Oncol 2010; 5:1806–1814. 46. Andre F, Grunenwald. Pignon JP, et al. Survival of patients with resected N2 nonsmall cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18:2981–2989. 47. Soria JC, Barlesi F, Besse B, et al. Results of the prospective, randomized, and customised NSCLC adjuvant phase II trial (IFCT-0801, TASTE trial) from the French Collaborative Intergroup. J Clin Oncol 2013; 31 (Suppl.); abstract 7505. 48. Grossi F, Rijavec E, Barletta G, et al. A multicenter phase II randomized study of customized neoadjuvant therapy versus standard chemotherapy (CT) in nonsmall cell lung cancer (NSCLC) patients with resectable IIIA (N2) disease (CONTEST Trial). J Clin Oncol 2013; 13:abstract TPS7606. 49. Spaans JN, Goss GD. Trials to overcome drug resistance to EGFR and ALK targeted therapies – past, present and future. Front Oncol 2014; 4:233.
1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-oncology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
107
