- Email: [email protected]
Epidermal growth factor receptor (EGFR) inhibitors and derived treatments
symposium article
Annals of Oncology 23 (Supplement 10): x193–x196, 2012 doi:10.1093/annonc/mds351
Epidermal growth factor receptor (EGFR) inhibitors and derived treatments R. Dziadziuszko & J. Jassem Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland
Understanding the importance of EGFR signaling pathway in cancer has led to the development of several anti-EGFR therapeutics in the late 1990s, including reversible firstgeneration tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, as well as monoclonal antibodies such as cetuximab and panitumumab. These agents were subsequently tested in several tumor types in phase I–III clinical trials in pretreated patient populations. Results of the trials performed in non-small-cell lung cancer (NSCLC) indicated intriguingly high activity of TKIs given as monotherapy in a proportion of NSCLC patients and lack of their efficacy in combination with cytotoxic therapies. Contrary to the above, monoclonal antibodies appeared to enhance the efficacy of chemotherapy and had very modest single-agent activity. The associations of benefit from EGFR TKIs and molecular tumor characteristics became apparent after discovery of somatic activating EGFR gene mutations [1, 2]. These mutations occur in approximately 10%–20% of Western NSCLC patient populations, typically in those diagnosed with adenocarcinoma and with never/light smoking history, and indicate less aggressive course of the disease. Subset analyses of two important phase III trials evaluating the efficacy of single-agent gefitinib or erlotinib versus best supportive care in second- or third-line treatment of advanced NSCLC indicated the benefit for patients with tumors showing high EGFR gene copy number determined by in situ hybridization techniques (approximately 20%–40% of advanced NSCLC) [3, 4]. Based on the positive results of BR.21 trial, erlotinib was the first EGFR TKI registered in Europe for
*Correspondence to: Dr R. Dziadziuszko, Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland. Tel: +48-58-349-2979; Fax: +48-58-349-2210; E-mail: [email protected]
the treatment of advanced NSCLC patients whose treatment failed at least one line of chemotherapy irrespective of histology [5]. Gefitinib was registered in several Asian countries based on phase II and III data indicating its particularly high activity in the Far-East patient populations. Next generation of clinical trials compared EGFR TKIs with chemotherapy in the second-line setting in unselected NSCLC patients [6] or in the first-line setting in molecularly defined subsets [7–10]. Phase III data indicated that in chemonaïve patients with tumors harboring EGFR mutations, the response rate to EGFR TKIs is in the range of 60%–70% and progression-free survival is in the range of 9–13 months, both figures substantially superior to those achieved with chemotherapy [7–11]. Important improvements in the quality of life were also observed. Patients with tumors showing wildtype EGFR derive greater benefit from chemotherapy than from EGFR TKIs in the front-line setting [11]. At the same time, it was noted that EGFR gene copy gain was no longer a reliable predictor for the differential benefit from EGFR TKI versus chemotherapy [11, 12], suggesting that this molecular feature may be of importance only in heavily pretreated patients in clinical trials using placebo in a comparator arm. Based on the above data, both gefitinib and erlotinib are now registered in Europe for front-line treatment of advanced NSCLC patients with tumors harboring EGFR-activating mutations. The reversible EGFR inhibitors erlotinib [13] and gefitinib [14] have also been investigated as a ‘switch maintenance’ after first-line chemotherapy. SATURN trial with erlotinib demonstrated statistically significant but clinically modest survival improvement in all patients. The benefit from erlotinib was particularly pronounced in patients with tumors having EGFR-activating mutations [15]. Results from a clinical trial testing the addition of cetuximab to cisplatin—vinorelbine in patients with EGFR
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on July 16, 2015
Epidermal growth factor receptor inhibitors are used to treat advanced lung cancer patients for almost a decade. Current knowledge on their role in the first or subsequent lines of therapy serves as a model for other targeted therapies in development. Several molecular predictors of outcomes were successfully identified in preclinical and clinical studies. Evaluation of EGFR-activating mutations is currently used to define biologically distinct patient subsets with important consequences for prognosis and therapy. Ongoing translational and clinical research exploring EGFR inhibition in lung cancer focuses on better understanding of biology of EGFR-driven disease, efficacy of novel irreversible EGFR inhibitors and monoclonal antibodies, efficacy of combination strategies, and attempts to move EGFR inhibitors into therapy portfolio for early-stage disease. Key words: afatinib, cetuximab, dacomitinib, erlotinib, gefitinib, neratinib
symposium article
understanding the biology of EGFRdriven tumors Tumors harboring EGFR-activating mutations constitute a unique subset of biologically distinct diseases, in which EGFR activation is a driving molecular event, fulfilling ‘oncogene addiction’ criteria. Other EGFR abnormalities (gene copy gain, high EGFR protein expression) constitute mechanisms of tumor progression, and are probably insufficient to indicate long-term benefit from the target inhibition. High-level EGFR gene amplification, occurring in wild-type tumors, may be an exception to this rule, although it is extremely rare. In patients with EGFR-mutated tumors showing acquired resistance to EGFR TKIs, mechanisms of progression are partially understood and include exon 20 T790M mutations (arising through a clonal selection during continuous exposure to EGFR TKIs), MET amplification (gene coding a receptor for hepatocyte growth factor), emergence of other mutations such as those located in PIK3CA and histological transformation to small-cell lung cancer through unknown molecular mechanisms [20]. Multiple mechanisms of resistance were described in the same patient. It was also observed that resistance events may occasionally be reversed after subsequent cytotoxic treatment, providing rationale for repeated testing and re-challenge with EGFR inhibitors in selected cases [20].
include neratinib (HKI-272), afatinib (BIBW2992) and dacomitinib (PF00299804). These agents share a 4anilinoquinazoline structure with the ability to form covalent bonds with Cys979 residue located directly at the ATP-binding cleft of EGFR protein, and thus potentially preventing T790M mutation-related resistance. While neratinib phase II data were disappointing [21], other two agents are currently evaluated in a number of phase II and III trials with hopes for a better efficacy in patients with EGFR mutation positive or negative tumors [22]. Interestingly, the neratinib phase II trial showed high activity of the drug in a rare subset of patients with tumors having exon 18 G719X mutations, which could be predicted based on low inhibiting concentrations of the drug in the cells harboring this aberration [21]. Some (but not all) clinical data with reversible EGFR inhibitors (erlotinib and gefitinib) indicate their better efficacy in patients with tumors harboring common exon 19 deletions when compared with exon 21 point mutations (L858R) [23, 24]. This association should be closely investigated in clinical trials with novel irreversible EGFR TKIs, expected to be more potent against L858R mutations than reversible agents. Contrary to structural and in vitro models, there are reports on limited activity of irreversible inhibitors in association with acquired resistance through EGFR T790M mutations [25, 26]. This may be due to relatively low achievable steady-state drug concentrations, insufficient for effective EGFR T790M inhibition, particularly when T790M allele is selectively amplified [27]. Development of mutant-selective EGFR inhibitors, currently at the preclinical stage, appears to be a promising strategy to improve therapeutic ratio with these agents [28]. EGFR inhibitors have also been combined with other targeted therapies directed at the same pathway. Phase Ib/II data of afatinib combined with cetuximab in patients with acquired resistance to reversible EGFR inhibitors showed promising 36% response rate with an acceptable toxicity profile [29]. Preclinical models demonstrate encouraging activity of combined EGFR and mTOR inhibition [30], a strategy that is currently explored in phase I trials. Based on promising phase II data, erlotinib is being evaluated with anti-MET agents (tivantinib and METMab) in two large phase III studies, results of which should be available in the near future. The combination of MET inhibitors with irreversible EGFR inhibitors has not reached the clinical phase. Taken together, the role of irreversible EGFR inhibitors in clinical practice is yet undefined and should be better understood after the reports from key clinical trials are available (some are expected in 2012). Ongoing clinical trials should mandate tissue collection at the time of initial biopsy and strongly encourage tissue and circulating tumor cell acquisition at the study entry.
anti-EGFR monoclonal antibodies irreversible EGFR inhibitors Several novel, irreversible pan-HER TKIs were developed with hopes to overcome some of the above-mentioned resistance mechanisms, particularly the most common T790M mutations. Three most extensively studied compounds in advanced NSCLC, both in patients with mutated and wild-type EGFR,
x | Dziadziuszko and Jassem
The role of anti-EGFR monoclonal antibodies in addition to front-line chemotherapy remains unproven. Although the survival benefit from cetuximab in patients with tumors showing high EGFR protein expression was impressive in the FLEX trial, the difference was found in a post-hoc analysis with exploratory cut-off point that needs a prospective validation. A
Volume 23 | Supplement 10 | September 2012
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on July 16, 2015
immunohistochemistry-positive tumors (First-line Erbitux Trial, FLEX)—indicated a modest survival benefit in favor of the experimental arm (difference in median survival of 1.2 months, corresponding to a hazard ratio [HR] of 0.87; P = 0.044) [16]. In an extensive biomarker study program based on immunohistochemical and genomic analyses of tumor tissue samples [17, 18], highly positive EGFR immunostaining (hybrid score ≥200 on a scale 0–300) was associated with a 2.4-month survival improvement [HR = 0.73], whereas there was no survival benefit for patients with low EGFR immunostaining [HR = 0.99; interaction test P = 0.044]. Another phase III trial with paclitaxel (Taxol, Bristol-Myers Squibb) and carboplatin with or without cetuximab (BMS099), performed in unselected advanced NSCLC patients, did not show the survival advantage in overall or biomarker-defined study groups [19]. Building on more than a decade of experience in basic, translational and clinical experience with EGFR inhibitors in lung cancer, how should we move forward with this important therapeutic strategy? The progress, briefly discussed in this review, includes better understanding of biology of EGFRdriven tumors, novel irreversible EGFR TKIs, novel anti-EGFR monoclonal antibodies and research strategies testing EGFR inhibitors in early-stage NSCLC.
Annals of Oncology
Annals of Oncology
novel fully human IgG1 anti-EGFR monoclonal antibody, necitumumab, is evaluated in two large phase III randomized trials: INSPIRE—in combination with cisplatin/pemetrexed for non-squamous histologies—stopped prematurely due to safety concerns, and SQUIRE—in combination with cisplatin– gemcitabine for squamous histologies—closed to patient accrual. EGFR protein expression will hopefully be analyzed in tumor samples from participants of these trials and should provide additional information on this promising strategy.
use of EGFR inhibitors in early-stage NSCLC
Volume 23 | Supplement 10 | September 2012
radiation [35], clinical reports supporting this observation are scarce [36]. The addition of EGFR TKI either as an induction treatment and/or concurrently with radiochemotherapy needs to be explored in the future studies. A possible cell cycle antagonistic mechanism of G1 arrest caused by EGFR TKI needs to be taken into account if concurrent treatment is planned.
disclosure RD and JJ have received honoraria for consultancy from Behringer-Ingelheim, Astra-Zeneca and Roche and research funding from Roche.
references 1. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139. 2. Paez JG, Jänne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500. 3. Hirsch FR, Varella-Garcia M, Bunn BA, Jr et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006; 24: 4170–4176. 4. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular predictors of outcome. N Engl J Med 2005; 353: 133–144. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132. 6. Kim ES, Hirsh V, Mok T et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase II trial. Lancet Oncol 2008; 372: 1809–1818. 7. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJ-TOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121–128. 8. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for nonsmall-cell cancer with mutated EGFR. N Engl J Med 2010; 362: 2380–2388. 9. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–246. 10. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicenter, open-label, randomized, phase 3 study. Lancet Oncol 2011; 12: 735–742. 11. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957. 12. Douillard JY, Shepherd FA, Hirsch V et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28: 744–752. 13. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 2010; 11: 521–529. 14. Gaafar RM, Surmont VF, Scagliotti GV et al. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer 2011; 47: 2331–2340. 15. Brugger W, Triller N, Blasinska-Morawiec M et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 4113–41120. 16. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet Oncol 2009; 373: 1525–1531.
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Despite high activity of EGFR TKIs in advanced NSCLC with EGFR mutations, the strategy of moving these drugs to earlystage disease has been unsuccessful so far. Two randomized clinical trials with adjuvant gefitinib in unselected patients, National Cancer Institute of Canada BR.19 trial and a Japanese trial, were closed prematurely due to lack of efficacy of gefitinib in the phase III ISEL study and toxicity concerns (interstitial lung disease), respectively. Data from BR.19 trial were subsequently analyzed according to the EGFR mutation status in primary tumor and showed trends toward inferior survival in overall and mutation-positive study populations [31]. Maintenance gefitinib after definitive radiochemiotherapy and docetaxel consolidation was significantly detrimental in a phase III SWOG S0023 trial (unselected patients) [32]. The results of RADIANT, an adjuvant erlotinib phase III trial in patients with tumors positive for EGFR protein or with high EGFR gene copy number, should be available in the near future. Concurrent administration of EGFR TKIs or cetuximab with definitive radiotherapy has been assessed in locally advanced unresectable NSCLC. Data from head and neck cancer and from in vivo models indicate a possible synergistic activity, particularly for the latter combination. Two phase II trials conducted in the United States (RTOG 0324, weekly cetuximab, carboplatin and paclitaxel concurrent with radiotherapy followed by two cycles of chemotherapy consolidation with cetuximab [33] and CALGB 30407, carboplatin plus pemetrexed with or without cetuximab concurrent with radiotherapy followed by single-agent pemetrexed [34]) showed acceptable toxicity profiles and survival comparable with that seen in modern chemoradiotherapy series. RTOG 0617 phase III trial compared two doses of radiotherapy (74Gy versus 60Gy) in combination with carboplatin and paclitaxel with or without cetuximab followed by two cycles of chemotherapy consolidation with or without cetuximab (factorial design). The study was closed to patient accrual, with early termination of the high-dose radiotherapy arms due to futility analysis. Mature results with regard to cetuximab comparison should define the role of this agent in unresectable NSCLC. Currently, the management of patients with locally advanced lung adenocarcinoma harboring activating EGFR mutations remains the same as that for patients with wild-type tumors. Although in vitro data support higher sensitivity of EGFR mutant cells through defective DNA damage repair after
symposium article
symposium article
x | Dziadziuszko and Jassem
27. Ercan D, Zejnullahu K, Yonesaka K et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010; 29: 2346–2356. 28. Zhou W, Ercan D, Chen L et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009; 462: 1070–1074. 29. Gandhi L, Bahleda R, Cleary JM et al. Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors. J Clin Oncol 2011; 29 (suppl): 3027. 30. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702–4711. 31. Goss GD, Lorimer I, Tsao MS et al. A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. J Clin Oncol 2010; 28 (LBA 7005). 32. 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: 2450–2456. 33. Blumenschein GR, Jr, Paulus R, Curran WJ et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 2011; 29: 2312–2318. 34. Govindan R, Bogart J, Stinchcombe T et al. Randomized phase II study of pemetrexed, carboplatin and thoracic irradiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B Trial 30407. J Clin Oncol 2011; 29: 3120–3125. 35. Das AK, Sato M, Story MD et al. Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 2006; 66: 9601–9608. 36. Mak RH, Doran E, Muzikansky A et al. Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. Oncologist 2011; 16: 886–895.
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17. O’Byrne KJ, Gatzemeier U, Bondarenko I et al. Molecular biomarkers in nonsmall-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011; 12: 795–805. 18. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-smallcell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012: 13; 33–42. 19. Lynch TJ, Patel T, Dreisbach L et al. Cetuximab and first-line taxane /carboplatin chemotherapy in advanced non-small lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010; 28: 911–917. 20. Sequist LV, Waltman B, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26. 21. Sequist LV, Beese B, Lynch TJ et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28: 3076–3083. 22. Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist 2011; 16: 1498–1507. 23. Jackman DM, Yeap BY, Sequist LV et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in nonsmall cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006; 12: 3908–3914. 24. Hirsch FR, Varella-Garcia M, Capuzzo F et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol 2007; 18: 752–760. 25. Sequist LV, Besse B, Lynch TJ et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28: 3076–3083. 26. Sos ML, Rode HB, Heynck S et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010; 70: 868–874.
Annals of Oncology
Annals of Oncology 23 (Supplement 10): x193–x196, 2012 doi:10.1093/annonc/mds351
Epidermal growth factor receptor (EGFR) inhibitors and derived treatments R. Dziadziuszko & J. Jassem Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland
Understanding the importance of EGFR signaling pathway in cancer has led to the development of several anti-EGFR therapeutics in the late 1990s, including reversible firstgeneration tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, as well as monoclonal antibodies such as cetuximab and panitumumab. These agents were subsequently tested in several tumor types in phase I–III clinical trials in pretreated patient populations. Results of the trials performed in non-small-cell lung cancer (NSCLC) indicated intriguingly high activity of TKIs given as monotherapy in a proportion of NSCLC patients and lack of their efficacy in combination with cytotoxic therapies. Contrary to the above, monoclonal antibodies appeared to enhance the efficacy of chemotherapy and had very modest single-agent activity. The associations of benefit from EGFR TKIs and molecular tumor characteristics became apparent after discovery of somatic activating EGFR gene mutations [1, 2]. These mutations occur in approximately 10%–20% of Western NSCLC patient populations, typically in those diagnosed with adenocarcinoma and with never/light smoking history, and indicate less aggressive course of the disease. Subset analyses of two important phase III trials evaluating the efficacy of single-agent gefitinib or erlotinib versus best supportive care in second- or third-line treatment of advanced NSCLC indicated the benefit for patients with tumors showing high EGFR gene copy number determined by in situ hybridization techniques (approximately 20%–40% of advanced NSCLC) [3, 4]. Based on the positive results of BR.21 trial, erlotinib was the first EGFR TKI registered in Europe for
*Correspondence to: Dr R. Dziadziuszko, Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland. Tel: +48-58-349-2979; Fax: +48-58-349-2210; E-mail: [email protected]
the treatment of advanced NSCLC patients whose treatment failed at least one line of chemotherapy irrespective of histology [5]. Gefitinib was registered in several Asian countries based on phase II and III data indicating its particularly high activity in the Far-East patient populations. Next generation of clinical trials compared EGFR TKIs with chemotherapy in the second-line setting in unselected NSCLC patients [6] or in the first-line setting in molecularly defined subsets [7–10]. Phase III data indicated that in chemonaïve patients with tumors harboring EGFR mutations, the response rate to EGFR TKIs is in the range of 60%–70% and progression-free survival is in the range of 9–13 months, both figures substantially superior to those achieved with chemotherapy [7–11]. Important improvements in the quality of life were also observed. Patients with tumors showing wildtype EGFR derive greater benefit from chemotherapy than from EGFR TKIs in the front-line setting [11]. At the same time, it was noted that EGFR gene copy gain was no longer a reliable predictor for the differential benefit from EGFR TKI versus chemotherapy [11, 12], suggesting that this molecular feature may be of importance only in heavily pretreated patients in clinical trials using placebo in a comparator arm. Based on the above data, both gefitinib and erlotinib are now registered in Europe for front-line treatment of advanced NSCLC patients with tumors harboring EGFR-activating mutations. The reversible EGFR inhibitors erlotinib [13] and gefitinib [14] have also been investigated as a ‘switch maintenance’ after first-line chemotherapy. SATURN trial with erlotinib demonstrated statistically significant but clinically modest survival improvement in all patients. The benefit from erlotinib was particularly pronounced in patients with tumors having EGFR-activating mutations [15]. Results from a clinical trial testing the addition of cetuximab to cisplatin—vinorelbine in patients with EGFR
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on July 16, 2015
Epidermal growth factor receptor inhibitors are used to treat advanced lung cancer patients for almost a decade. Current knowledge on their role in the first or subsequent lines of therapy serves as a model for other targeted therapies in development. Several molecular predictors of outcomes were successfully identified in preclinical and clinical studies. Evaluation of EGFR-activating mutations is currently used to define biologically distinct patient subsets with important consequences for prognosis and therapy. Ongoing translational and clinical research exploring EGFR inhibition in lung cancer focuses on better understanding of biology of EGFR-driven disease, efficacy of novel irreversible EGFR inhibitors and monoclonal antibodies, efficacy of combination strategies, and attempts to move EGFR inhibitors into therapy portfolio for early-stage disease. Key words: afatinib, cetuximab, dacomitinib, erlotinib, gefitinib, neratinib
symposium article
understanding the biology of EGFRdriven tumors Tumors harboring EGFR-activating mutations constitute a unique subset of biologically distinct diseases, in which EGFR activation is a driving molecular event, fulfilling ‘oncogene addiction’ criteria. Other EGFR abnormalities (gene copy gain, high EGFR protein expression) constitute mechanisms of tumor progression, and are probably insufficient to indicate long-term benefit from the target inhibition. High-level EGFR gene amplification, occurring in wild-type tumors, may be an exception to this rule, although it is extremely rare. In patients with EGFR-mutated tumors showing acquired resistance to EGFR TKIs, mechanisms of progression are partially understood and include exon 20 T790M mutations (arising through a clonal selection during continuous exposure to EGFR TKIs), MET amplification (gene coding a receptor for hepatocyte growth factor), emergence of other mutations such as those located in PIK3CA and histological transformation to small-cell lung cancer through unknown molecular mechanisms [20]. Multiple mechanisms of resistance were described in the same patient. It was also observed that resistance events may occasionally be reversed after subsequent cytotoxic treatment, providing rationale for repeated testing and re-challenge with EGFR inhibitors in selected cases [20].
include neratinib (HKI-272), afatinib (BIBW2992) and dacomitinib (PF00299804). These agents share a 4anilinoquinazoline structure with the ability to form covalent bonds with Cys979 residue located directly at the ATP-binding cleft of EGFR protein, and thus potentially preventing T790M mutation-related resistance. While neratinib phase II data were disappointing [21], other two agents are currently evaluated in a number of phase II and III trials with hopes for a better efficacy in patients with EGFR mutation positive or negative tumors [22]. Interestingly, the neratinib phase II trial showed high activity of the drug in a rare subset of patients with tumors having exon 18 G719X mutations, which could be predicted based on low inhibiting concentrations of the drug in the cells harboring this aberration [21]. Some (but not all) clinical data with reversible EGFR inhibitors (erlotinib and gefitinib) indicate their better efficacy in patients with tumors harboring common exon 19 deletions when compared with exon 21 point mutations (L858R) [23, 24]. This association should be closely investigated in clinical trials with novel irreversible EGFR TKIs, expected to be more potent against L858R mutations than reversible agents. Contrary to structural and in vitro models, there are reports on limited activity of irreversible inhibitors in association with acquired resistance through EGFR T790M mutations [25, 26]. This may be due to relatively low achievable steady-state drug concentrations, insufficient for effective EGFR T790M inhibition, particularly when T790M allele is selectively amplified [27]. Development of mutant-selective EGFR inhibitors, currently at the preclinical stage, appears to be a promising strategy to improve therapeutic ratio with these agents [28]. EGFR inhibitors have also been combined with other targeted therapies directed at the same pathway. Phase Ib/II data of afatinib combined with cetuximab in patients with acquired resistance to reversible EGFR inhibitors showed promising 36% response rate with an acceptable toxicity profile [29]. Preclinical models demonstrate encouraging activity of combined EGFR and mTOR inhibition [30], a strategy that is currently explored in phase I trials. Based on promising phase II data, erlotinib is being evaluated with anti-MET agents (tivantinib and METMab) in two large phase III studies, results of which should be available in the near future. The combination of MET inhibitors with irreversible EGFR inhibitors has not reached the clinical phase. Taken together, the role of irreversible EGFR inhibitors in clinical practice is yet undefined and should be better understood after the reports from key clinical trials are available (some are expected in 2012). Ongoing clinical trials should mandate tissue collection at the time of initial biopsy and strongly encourage tissue and circulating tumor cell acquisition at the study entry.
anti-EGFR monoclonal antibodies irreversible EGFR inhibitors Several novel, irreversible pan-HER TKIs were developed with hopes to overcome some of the above-mentioned resistance mechanisms, particularly the most common T790M mutations. Three most extensively studied compounds in advanced NSCLC, both in patients with mutated and wild-type EGFR,
x | Dziadziuszko and Jassem
The role of anti-EGFR monoclonal antibodies in addition to front-line chemotherapy remains unproven. Although the survival benefit from cetuximab in patients with tumors showing high EGFR protein expression was impressive in the FLEX trial, the difference was found in a post-hoc analysis with exploratory cut-off point that needs a prospective validation. A
Volume 23 | Supplement 10 | September 2012
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on July 16, 2015
immunohistochemistry-positive tumors (First-line Erbitux Trial, FLEX)—indicated a modest survival benefit in favor of the experimental arm (difference in median survival of 1.2 months, corresponding to a hazard ratio [HR] of 0.87; P = 0.044) [16]. In an extensive biomarker study program based on immunohistochemical and genomic analyses of tumor tissue samples [17, 18], highly positive EGFR immunostaining (hybrid score ≥200 on a scale 0–300) was associated with a 2.4-month survival improvement [HR = 0.73], whereas there was no survival benefit for patients with low EGFR immunostaining [HR = 0.99; interaction test P = 0.044]. Another phase III trial with paclitaxel (Taxol, Bristol-Myers Squibb) and carboplatin with or without cetuximab (BMS099), performed in unselected advanced NSCLC patients, did not show the survival advantage in overall or biomarker-defined study groups [19]. Building on more than a decade of experience in basic, translational and clinical experience with EGFR inhibitors in lung cancer, how should we move forward with this important therapeutic strategy? The progress, briefly discussed in this review, includes better understanding of biology of EGFRdriven tumors, novel irreversible EGFR TKIs, novel anti-EGFR monoclonal antibodies and research strategies testing EGFR inhibitors in early-stage NSCLC.
Annals of Oncology
Annals of Oncology
novel fully human IgG1 anti-EGFR monoclonal antibody, necitumumab, is evaluated in two large phase III randomized trials: INSPIRE—in combination with cisplatin/pemetrexed for non-squamous histologies—stopped prematurely due to safety concerns, and SQUIRE—in combination with cisplatin– gemcitabine for squamous histologies—closed to patient accrual. EGFR protein expression will hopefully be analyzed in tumor samples from participants of these trials and should provide additional information on this promising strategy.
use of EGFR inhibitors in early-stage NSCLC
Volume 23 | Supplement 10 | September 2012
radiation [35], clinical reports supporting this observation are scarce [36]. The addition of EGFR TKI either as an induction treatment and/or concurrently with radiochemotherapy needs to be explored in the future studies. A possible cell cycle antagonistic mechanism of G1 arrest caused by EGFR TKI needs to be taken into account if concurrent treatment is planned.
disclosure RD and JJ have received honoraria for consultancy from Behringer-Ingelheim, Astra-Zeneca and Roche and research funding from Roche.
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Despite high activity of EGFR TKIs in advanced NSCLC with EGFR mutations, the strategy of moving these drugs to earlystage disease has been unsuccessful so far. Two randomized clinical trials with adjuvant gefitinib in unselected patients, National Cancer Institute of Canada BR.19 trial and a Japanese trial, were closed prematurely due to lack of efficacy of gefitinib in the phase III ISEL study and toxicity concerns (interstitial lung disease), respectively. Data from BR.19 trial were subsequently analyzed according to the EGFR mutation status in primary tumor and showed trends toward inferior survival in overall and mutation-positive study populations [31]. Maintenance gefitinib after definitive radiochemiotherapy and docetaxel consolidation was significantly detrimental in a phase III SWOG S0023 trial (unselected patients) [32]. The results of RADIANT, an adjuvant erlotinib phase III trial in patients with tumors positive for EGFR protein or with high EGFR gene copy number, should be available in the near future. Concurrent administration of EGFR TKIs or cetuximab with definitive radiotherapy has been assessed in locally advanced unresectable NSCLC. Data from head and neck cancer and from in vivo models indicate a possible synergistic activity, particularly for the latter combination. Two phase II trials conducted in the United States (RTOG 0324, weekly cetuximab, carboplatin and paclitaxel concurrent with radiotherapy followed by two cycles of chemotherapy consolidation with cetuximab [33] and CALGB 30407, carboplatin plus pemetrexed with or without cetuximab concurrent with radiotherapy followed by single-agent pemetrexed [34]) showed acceptable toxicity profiles and survival comparable with that seen in modern chemoradiotherapy series. RTOG 0617 phase III trial compared two doses of radiotherapy (74Gy versus 60Gy) in combination with carboplatin and paclitaxel with or without cetuximab followed by two cycles of chemotherapy consolidation with or without cetuximab (factorial design). The study was closed to patient accrual, with early termination of the high-dose radiotherapy arms due to futility analysis. Mature results with regard to cetuximab comparison should define the role of this agent in unresectable NSCLC. Currently, the management of patients with locally advanced lung adenocarcinoma harboring activating EGFR mutations remains the same as that for patients with wild-type tumors. Although in vitro data support higher sensitivity of EGFR mutant cells through defective DNA damage repair after
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27. Ercan D, Zejnullahu K, Yonesaka K et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010; 29: 2346–2356. 28. Zhou W, Ercan D, Chen L et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009; 462: 1070–1074. 29. Gandhi L, Bahleda R, Cleary JM et al. Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors. J Clin Oncol 2011; 29 (suppl): 3027. 30. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702–4711. 31. Goss GD, Lorimer I, Tsao MS et al. A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. J Clin Oncol 2010; 28 (LBA 7005). 32. 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: 2450–2456. 33. Blumenschein GR, Jr, Paulus R, Curran WJ et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 2011; 29: 2312–2318. 34. Govindan R, Bogart J, Stinchcombe T et al. Randomized phase II study of pemetrexed, carboplatin and thoracic irradiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B Trial 30407. J Clin Oncol 2011; 29: 3120–3125. 35. Das AK, Sato M, Story MD et al. Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 2006; 66: 9601–9608. 36. Mak RH, Doran E, Muzikansky A et al. Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. Oncologist 2011; 16: 886–895.
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17. O’Byrne KJ, Gatzemeier U, Bondarenko I et al. Molecular biomarkers in nonsmall-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011; 12: 795–805. 18. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-smallcell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012: 13; 33–42. 19. Lynch TJ, Patel T, Dreisbach L et al. Cetuximab and first-line taxane /carboplatin chemotherapy in advanced non-small lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010; 28: 911–917. 20. Sequist LV, Waltman B, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26. 21. Sequist LV, Beese B, Lynch TJ et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28: 3076–3083. 22. Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist 2011; 16: 1498–1507. 23. Jackman DM, Yeap BY, Sequist LV et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in nonsmall cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006; 12: 3908–3914. 24. Hirsch FR, Varella-Garcia M, Capuzzo F et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol 2007; 18: 752–760. 25. Sequist LV, Besse B, Lynch TJ et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2010; 28: 3076–3083. 26. Sos ML, Rode HB, Heynck S et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010; 70: 868–874.
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