Lung Cancer 83 (2014) 408–410
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Overcoming resistance to first generation EGFR TKIs with cetuximab in combination with chemotherapy in an EGFR mutated advanced stage NSCLC patient A. Pircher a,∗ , C. Manzl b , M. Fiegl a , H. Popper b , R. Pirker c , W. Hilbe a a
Department of Hematology and Oncology, Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria Department of Pathology, Innsbruck Medical University, Innsbruck, Austria c Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 13 December 2013 Accepted 16 December 2013 Keywords: Cetuximab Acquired resistance Non-small cell lung cancer (NSCLC) EGFR mutation
a b s t r a c t We report the case of a female never-smoking patient with an epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) who received multiple lines of treatment. When she evolved clinical resistance to first generation EGFR tyrosine kinase inhibitors (TKI), she was treated with a fifth-line combination therapy with cetuximab and vinorelbine. This combination was highly active with a treatment response lasting for 9 months supporting the hypothesis that EGFR monoclonal antibodies in combination with chemotherapy may play a role in reversing EGFR-TKI resistance in EGFR mutation-positive NSCLC. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients with EGFR mutation positive non-small cell lung cancer (NSCLC) have a favorable prognosis and are preferentially treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) [1,2]. Here we present an extraordinary clinical course of a female never-smoker with an EGFR mutated NSCLC, who showed a dramatic response to a combination of cetuximab plus chemotherapy after clinical resistance to first generation EGFR TKIs (erlotinib and gefitinib) had evolved. 2. Case report A 68 years old woman was diagnosed with stage IIIA NSCLC (cT3N2M0, adenocarcinoma) in 2008. She underwent complete tumor resection (including mediastinal lymph node dissection) and due to pathologically proven N2 involvement adjuvant radiotherapy (50.4 Gy). Two months after end of treatment the patient developed pleural carcinosis and received first-line palliative chemotherapy with cisplatin plus pemetrexed which resulted in disease stabilization. Three months after end of chemotherapy,
∗ Corresponding author at: Department of Hematology and Oncology, Internal Medicine V, Medical University of Innsbruck, Anichstr.35, A-6020 Innsbruck, Austria. Tel.: +43 0 512 504 82430; fax: +43 0 512 504 25615. E-mail address: [email protected] (A. Pircher). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.12.007
progression of the disease led to second-line treatment with erlotinib (150 mg/day) without knowledge of the EGFR mutational status. Erlotinib therapy resulted in a partial response (PR). After 9 months the patient wished to interrupt treatment due to irritating skin rash. Shortly thereafter, the tumor progressed and thirdline treatment with pemetrexed plus bevacizumab was given. EGFR mutational analysis (TheraScreen® by DxS: EGFR29 Mutation Kit and EGFR Sanger Sequencing) of the archived primary tumor revealed activating EGFR mutation (exon 19 E746-A750 deletion, see Fig. 1A). Thus, chemotherapy was switched to gefitinib as fourth-line therapy (250 mg/day), which led to a PR. After approximately one year, however, the patient developed clinical resistance and fifth-line treatment with afatinib (named patient program, 50 mg/day) was initiated but had to be stopped due to diarrhea. Two months later, the patient had to be admitted to the hospital due to severe dyspnea and clinical signs of respiratory failure. CT scan showed massive intrapulmonal tumor progression with multiple nodes in both lungs (Fig. 2A). Due to the limited respiratory reserve, a re-biopsy of the tumor for molecular analysis was considered to be too risky and was not performed. With the exception of the tumor-associated dsypnea, the patient was still in a reasonably good condition. After discussing different treatment options including best supportive care alone, the patient opted for additional systemic anti-tumor treatment. Thus it was decided to administer vinorelbine (plus carboplatin in the first cycle) in combination with cetuximab (400 mg/m2 d1, then 250 mg/m2 weekly). This combined treatment resulted in rapid relief of tumor-related
A. Pircher et al. / Lung Cancer 83 (2014) 408–410
409
Fig. 1. (A) EGFR exon 19 deletion: pE746-A750del (c.2236 2249del) analyzed by Sanger Sequencing is depicted with chromatogram for sense primer sequencing (upper panel) and anti-sense primer sequencing (lower panel). (B) Representative images of H&E staining (left panel) and immunohistochemistry monitoring EGFR expression (right panel) are shown.
dyspnea and in a near complete remission after 3 months (Fig. 2 B) which allowed the patient to perform normal daily activities. Therapy was well tolerated and continued for 9 months (22 applications of vinorelbine, 24 applications of cetuximab, 1 application of carboplatin, and the latter was refused by the patient subsequently). Retrospective EGFR immunohistochemical expression analysis revealed an H-score of 180 (Fig. 1B). Then the patient relapsed and 3 months after stop of vinorelbine/cetuximab the patient developed a pathological humerus fracture, which was operated. Retrospective analysis of the metastatic lesion proved a T790M EGFR mutation. Finally, however, the patient died in 2012. 3. Discussion Many patients with EGFR mutant NSCLC initially respond to EGFR inhibitors, as observed here with second-line erlotinib and fourth-line gefitinib therapy, but they eventually develop resistance to TKI treatment with 70% of them progressing within one year of therapy [3–6]. In about 50% of the patients resistance is due to a T790M point mutation in exon 21 of the EGFR gene, but multiple other mechanisms of acquired resistance like activation of other receptor tyrosine kinases (30–40% e.g. ERBB2 amplification, ERK amplification, epithelial–mesenchymal transition (EMT)), mutation of PIK3CA (5%), small cell lung cancer (SCLC) transformation (5%), BRAF mutations (1%) or amplifications of MET (5–10%) have been described [7–9]. Therefore, strategies to overcome TKI resistance are urgently needed [5,6]. Cytotoxic therapies may be a reasonable treatment option [10] and second generation EGFR TKIs as well as other strategies are evaluated within clinical trials [4].
Preclinical data suggest that EGFR kinase inhibitors combined with EGFR monoclonal antibodies may also overcome resistance [11,12]. In a phase I/II trial, the addition of cetuximab to erlotinib was insufficient to overcome resistance [13], but the combination of afatinib and cetuximab resulted in responses in 36% of EGFR-TKI resistant patients and disease stabilization in the remaining patients [14]. Because our patient clearly benefitted from EGFR TKIs, we decided for additional anti-EGFR treatment, at the time of clinical resistance to TKIs. Based on the results of the FLEX trial, which demonstrated improved survival for advanced NSCLC patients treated with cetuximab combined with cisplatin and vinorelbine [15], we treated our patient with cetuximab in combination with vinorelbine (plus carboplatin in cycle one). Furthermore, the IHC score of 180 (see Fig. 1B) was above the score at which benefit from the addition of cetuximab to chemotherapy started to develop within the FLEX trial [16]. Treatment resulted in complete resolvement of tumor-related symptoms (dyspnea) within a few days and a near complete remission of the tumor for 9 months (Fig. 2). Although diagnosed afterwards it is strongly suggestive that EGFR resistance was induced by a T790M mutation. To our knowledge this is the first report on reversal of TKI resistance by chemotherapy plus cetuximab. In a recent study, 12 patients with EGFR mutations after progression on EGFR inhibitors received combination therapy with EGFR inhibition (combinational regimens with the following drugs were performed: dasatinib, bevacizumab, sirolimus combined with erlotinib or cetuximab or both EGFR inhibitors) [4]. Five patients achieved stable disease and one patient a partial remission but benefits from these treatments were short-lasting.
Fig. 2. Computer tomography scans showing intrapulmonal lesions before start of sixth line combination therapy (A) with vinorelbine and cetuximab and 3 months later during therapy (B).
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A. Pircher et al. / Lung Cancer 83 (2014) 408–410
Despite a short progression-free interval after first-line platinum combination probably due to platin resistance, our patient achieved a long-lasting response to subsequent EGFR TKI therapy. This observation is consistent with the results of the TITAN study which showed that platinum-refractory patients with EGFR wildtype tumors may also benefit from EGFR TKI therapy [17]. The massive intrapulmonal disease flare after EGFR discontinuation in our patient is consistent with other reports. Disease flare occurs in about 23% of patients during the EGFR wash-out period and was more frequently observed in patients with shorter progression-free intervals during TKI therapy [18]. In summary, our case shows that cetuximab in combination with vinorelbine was highly active at the time of acquired resistance to first generation EGFR TKI and suggests that EGFR monoclonal antibodies may play a role in reversing TKI resistance in patients with advanced EGFR mutation-positive NSCLC. Conflicts of interest statement AP, CM and MF have no conflicts of interest to declare. HP has received speaker’s fee and honoraria for advisory boards and consulting and also unrestricted grants for scientific investigations Astra Zeneca, Roche, Pfizer, Boehringer Ingelheim and Novartis. RP has received speaker’s fee and honoraria for advisory boards and consulting from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Merck KGaA, Pfizer and Synta. WH has received speaker’s fee and honoraria for advisory boards and consulting and also unrestricted grants for scientific investigations from Astra Zeneca, Roche, Pfizer, Boehringer Ingelheim, Ratiopharm and Eli Lilly. Acknowledgement The case report was supported by the “Verein für Tumorforschung”. References [1] Pircher A, Ploner F, Popper H, Hilbe W. Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients. Lung Cancer 2010;69:265–71. [2] Pircher A, Ulsperger E, Hack R, Jamnig H, Pall G, Zelger B, et al. Basic clinical parameters predict gefitinib efficacy in non-small cell lung cancer. Anticancer Res 2011;31:2949–55.
[3] Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007;25:587–95. [4] Wheler J, Falchook G, Tsimberidou AM, Hong D, Naing A, Piha-Paul S, et al. Revisiting clinical trials using egfr inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center Phase I Population. Oncotarget 2013;4:772–84. [5] Hammerman PS, Janne PA, Johnson BE. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2009;15:7502–9. [6] Mumenthaler SM, Foo J, Leder K, Choi NC, Agus DB, Pao W, et al. Evolutionary modeling of combination treatment strategies to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer. Mol Pharm 2011;8:2069–79. [7] Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013;31:1070–80. [8] Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [9] Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240–7. [10] Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Non-small cell lung cancer. J Natl Compr Canc Netw 2010;8:740–801. [11] Regales L, Gong Y, Shen R, de SE, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 2009;119:3000–10. [12] Wang M, Zhao J, Zhang LM, Li H, Yu JP, Ren XB, et al. Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. J Cancer Res Clin Oncol 2012;138:2069–77. [13] Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res 2011;17:2521–7. [14] Janjigian YY, Groen HJ, Horn L, Smit EF, Fu Y, Wang F, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 2011;29(Suppl) (abstr 7525). [15] Pirker R, Pereira JR, Szczesna A, von PJ, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525–31. [16] Pirker R, Pereira JR, von PJ, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33–42. [17] Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012;13:300–8. [18] Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 2011;17:6298–303.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Overcoming resistance to first generation EGFR TKIs with cetuximab in combination with chemotherapy in an EGFR mutated advanced stage NSCLC patient A. Pircher a,∗ , C. Manzl b , M. Fiegl a , H. Popper b , R. Pirker c , W. Hilbe a a
Department of Hematology and Oncology, Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria Department of Pathology, Innsbruck Medical University, Innsbruck, Austria c Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria b
a r t i c l e
i n f o
Article history: Received 30 September 2013 Received in revised form 13 December 2013 Accepted 16 December 2013 Keywords: Cetuximab Acquired resistance Non-small cell lung cancer (NSCLC) EGFR mutation
a b s t r a c t We report the case of a female never-smoking patient with an epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) who received multiple lines of treatment. When she evolved clinical resistance to first generation EGFR tyrosine kinase inhibitors (TKI), she was treated with a fifth-line combination therapy with cetuximab and vinorelbine. This combination was highly active with a treatment response lasting for 9 months supporting the hypothesis that EGFR monoclonal antibodies in combination with chemotherapy may play a role in reversing EGFR-TKI resistance in EGFR mutation-positive NSCLC. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients with EGFR mutation positive non-small cell lung cancer (NSCLC) have a favorable prognosis and are preferentially treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) [1,2]. Here we present an extraordinary clinical course of a female never-smoker with an EGFR mutated NSCLC, who showed a dramatic response to a combination of cetuximab plus chemotherapy after clinical resistance to first generation EGFR TKIs (erlotinib and gefitinib) had evolved. 2. Case report A 68 years old woman was diagnosed with stage IIIA NSCLC (cT3N2M0, adenocarcinoma) in 2008. She underwent complete tumor resection (including mediastinal lymph node dissection) and due to pathologically proven N2 involvement adjuvant radiotherapy (50.4 Gy). Two months after end of treatment the patient developed pleural carcinosis and received first-line palliative chemotherapy with cisplatin plus pemetrexed which resulted in disease stabilization. Three months after end of chemotherapy,
∗ Corresponding author at: Department of Hematology and Oncology, Internal Medicine V, Medical University of Innsbruck, Anichstr.35, A-6020 Innsbruck, Austria. Tel.: +43 0 512 504 82430; fax: +43 0 512 504 25615. E-mail address: [email protected] (A. Pircher). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.12.007
progression of the disease led to second-line treatment with erlotinib (150 mg/day) without knowledge of the EGFR mutational status. Erlotinib therapy resulted in a partial response (PR). After 9 months the patient wished to interrupt treatment due to irritating skin rash. Shortly thereafter, the tumor progressed and thirdline treatment with pemetrexed plus bevacizumab was given. EGFR mutational analysis (TheraScreen® by DxS: EGFR29 Mutation Kit and EGFR Sanger Sequencing) of the archived primary tumor revealed activating EGFR mutation (exon 19 E746-A750 deletion, see Fig. 1A). Thus, chemotherapy was switched to gefitinib as fourth-line therapy (250 mg/day), which led to a PR. After approximately one year, however, the patient developed clinical resistance and fifth-line treatment with afatinib (named patient program, 50 mg/day) was initiated but had to be stopped due to diarrhea. Two months later, the patient had to be admitted to the hospital due to severe dyspnea and clinical signs of respiratory failure. CT scan showed massive intrapulmonal tumor progression with multiple nodes in both lungs (Fig. 2A). Due to the limited respiratory reserve, a re-biopsy of the tumor for molecular analysis was considered to be too risky and was not performed. With the exception of the tumor-associated dsypnea, the patient was still in a reasonably good condition. After discussing different treatment options including best supportive care alone, the patient opted for additional systemic anti-tumor treatment. Thus it was decided to administer vinorelbine (plus carboplatin in the first cycle) in combination with cetuximab (400 mg/m2 d1, then 250 mg/m2 weekly). This combined treatment resulted in rapid relief of tumor-related
A. Pircher et al. / Lung Cancer 83 (2014) 408–410
409
Fig. 1. (A) EGFR exon 19 deletion: pE746-A750del (c.2236 2249del) analyzed by Sanger Sequencing is depicted with chromatogram for sense primer sequencing (upper panel) and anti-sense primer sequencing (lower panel). (B) Representative images of H&E staining (left panel) and immunohistochemistry monitoring EGFR expression (right panel) are shown.
dyspnea and in a near complete remission after 3 months (Fig. 2 B) which allowed the patient to perform normal daily activities. Therapy was well tolerated and continued for 9 months (22 applications of vinorelbine, 24 applications of cetuximab, 1 application of carboplatin, and the latter was refused by the patient subsequently). Retrospective EGFR immunohistochemical expression analysis revealed an H-score of 180 (Fig. 1B). Then the patient relapsed and 3 months after stop of vinorelbine/cetuximab the patient developed a pathological humerus fracture, which was operated. Retrospective analysis of the metastatic lesion proved a T790M EGFR mutation. Finally, however, the patient died in 2012. 3. Discussion Many patients with EGFR mutant NSCLC initially respond to EGFR inhibitors, as observed here with second-line erlotinib and fourth-line gefitinib therapy, but they eventually develop resistance to TKI treatment with 70% of them progressing within one year of therapy [3–6]. In about 50% of the patients resistance is due to a T790M point mutation in exon 21 of the EGFR gene, but multiple other mechanisms of acquired resistance like activation of other receptor tyrosine kinases (30–40% e.g. ERBB2 amplification, ERK amplification, epithelial–mesenchymal transition (EMT)), mutation of PIK3CA (5%), small cell lung cancer (SCLC) transformation (5%), BRAF mutations (1%) or amplifications of MET (5–10%) have been described [7–9]. Therefore, strategies to overcome TKI resistance are urgently needed [5,6]. Cytotoxic therapies may be a reasonable treatment option [10] and second generation EGFR TKIs as well as other strategies are evaluated within clinical trials [4].
Preclinical data suggest that EGFR kinase inhibitors combined with EGFR monoclonal antibodies may also overcome resistance [11,12]. In a phase I/II trial, the addition of cetuximab to erlotinib was insufficient to overcome resistance [13], but the combination of afatinib and cetuximab resulted in responses in 36% of EGFR-TKI resistant patients and disease stabilization in the remaining patients [14]. Because our patient clearly benefitted from EGFR TKIs, we decided for additional anti-EGFR treatment, at the time of clinical resistance to TKIs. Based on the results of the FLEX trial, which demonstrated improved survival for advanced NSCLC patients treated with cetuximab combined with cisplatin and vinorelbine [15], we treated our patient with cetuximab in combination with vinorelbine (plus carboplatin in cycle one). Furthermore, the IHC score of 180 (see Fig. 1B) was above the score at which benefit from the addition of cetuximab to chemotherapy started to develop within the FLEX trial [16]. Treatment resulted in complete resolvement of tumor-related symptoms (dyspnea) within a few days and a near complete remission of the tumor for 9 months (Fig. 2). Although diagnosed afterwards it is strongly suggestive that EGFR resistance was induced by a T790M mutation. To our knowledge this is the first report on reversal of TKI resistance by chemotherapy plus cetuximab. In a recent study, 12 patients with EGFR mutations after progression on EGFR inhibitors received combination therapy with EGFR inhibition (combinational regimens with the following drugs were performed: dasatinib, bevacizumab, sirolimus combined with erlotinib or cetuximab or both EGFR inhibitors) [4]. Five patients achieved stable disease and one patient a partial remission but benefits from these treatments were short-lasting.
Fig. 2. Computer tomography scans showing intrapulmonal lesions before start of sixth line combination therapy (A) with vinorelbine and cetuximab and 3 months later during therapy (B).
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A. Pircher et al. / Lung Cancer 83 (2014) 408–410
Despite a short progression-free interval after first-line platinum combination probably due to platin resistance, our patient achieved a long-lasting response to subsequent EGFR TKI therapy. This observation is consistent with the results of the TITAN study which showed that platinum-refractory patients with EGFR wildtype tumors may also benefit from EGFR TKI therapy [17]. The massive intrapulmonal disease flare after EGFR discontinuation in our patient is consistent with other reports. Disease flare occurs in about 23% of patients during the EGFR wash-out period and was more frequently observed in patients with shorter progression-free intervals during TKI therapy [18]. In summary, our case shows that cetuximab in combination with vinorelbine was highly active at the time of acquired resistance to first generation EGFR TKI and suggests that EGFR monoclonal antibodies may play a role in reversing TKI resistance in patients with advanced EGFR mutation-positive NSCLC. Conflicts of interest statement AP, CM and MF have no conflicts of interest to declare. HP has received speaker’s fee and honoraria for advisory boards and consulting and also unrestricted grants for scientific investigations Astra Zeneca, Roche, Pfizer, Boehringer Ingelheim and Novartis. RP has received speaker’s fee and honoraria for advisory boards and consulting from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Merck KGaA, Pfizer and Synta. WH has received speaker’s fee and honoraria for advisory boards and consulting and also unrestricted grants for scientific investigations from Astra Zeneca, Roche, Pfizer, Boehringer Ingelheim, Ratiopharm and Eli Lilly. Acknowledgement The case report was supported by the “Verein für Tumorforschung”. References [1] Pircher A, Ploner F, Popper H, Hilbe W. Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients. Lung Cancer 2010;69:265–71. [2] Pircher A, Ulsperger E, Hack R, Jamnig H, Pall G, Zelger B, et al. Basic clinical parameters predict gefitinib efficacy in non-small cell lung cancer. Anticancer Res 2011;31:2949–55.
[3] Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007;25:587–95. [4] Wheler J, Falchook G, Tsimberidou AM, Hong D, Naing A, Piha-Paul S, et al. Revisiting clinical trials using egfr inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center Phase I Population. Oncotarget 2013;4:772–84. [5] Hammerman PS, Janne PA, Johnson BE. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2009;15:7502–9. [6] Mumenthaler SM, Foo J, Leder K, Choi NC, Agus DB, Pao W, et al. Evolutionary modeling of combination treatment strategies to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer. Mol Pharm 2011;8:2069–79. [7] Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013;31:1070–80. [8] Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [9] Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240–7. [10] Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Non-small cell lung cancer. J Natl Compr Canc Netw 2010;8:740–801. [11] Regales L, Gong Y, Shen R, de SE, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 2009;119:3000–10. [12] Wang M, Zhao J, Zhang LM, Li H, Yu JP, Ren XB, et al. Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. J Cancer Res Clin Oncol 2012;138:2069–77. [13] Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res 2011;17:2521–7. [14] Janjigian YY, Groen HJ, Horn L, Smit EF, Fu Y, Wang F, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 2011;29(Suppl) (abstr 7525). [15] Pirker R, Pereira JR, Szczesna A, von PJ, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525–31. [16] Pirker R, Pereira JR, von PJ, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33–42. [17] Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012;13:300–8. [18] Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 2011;17:6298–303.
