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Review

Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance

by
Wen-Shuo Wu
and
Yuh-Min Chen
*
Department of Chest Medicine, Taipei Veteran General Hospital, Yang-Min National University, No. 21, Sec. 2, Shi-Pai Rd., Taipei 11217, Taiwan
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2014, 4(3), 297-310; https://doi.org/10.3390/jpm4030297
Submission received: 27 March 2014 / Revised: 15 April 2014 / Accepted: 4 June 2014 / Published: 25 June 2014
(This article belongs to the Special Issue Personalized Cancer Therapy)
Versions Notes

Abstract

:
In the era of personalized medicine, epidermal growth factor receptor (EGFR) inhibition with tyrosine kinase inhibitor (TKI) has been a mainstay of treatment for non-small cell lung cancer (NSCLC) patients with an EGFR mutation. Acquired resistance, especially substitution of methionine for threonine at position 790 (T790M), which has accounted for more than half of the cases, developed inevitably in patients who were previously treated with EGFR-TKI. At present, there is no standard treatment for patients who have developed a resistance to EGFR-TKI. Several strategies have been developed or suggested to treat such patients. This article aimsto review the EGFR-TKI re-treatment strategy and the efficacy of different generations of EGFR-TKIs in patients with acquired resistance to prior EGFR-TKI.

1. Introduction

Lung cancer is the leading cause of global cancer death. Patients are diagnosed mostly with non-small cell lung cancer (NSCLC) and usually have a poor prognosis [1,2]. The Iressa-Pan-Asia study, which is the first study to demonstrate that patients with special characteristics, female, non-smoker and adenocarcinoma, have a better response to gefitinib than conventional platinum-based doublet chemotherapy [3,4,5], in terms of response rate (RR), progression-free survival (PFS) and quality-of-life. The discovery of a mutation on the epidermal growth factor receptor (EGFR) gene made a huge difference in the treatment strategy for NSCLC, especially adenocarcinoma. The EGFR exon 19 deletion, or exon 21 L858R point mutation, is predictive of a treatment advantage with EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy [6,7]. The presence of an activating EGFR mutation in the tumor varies among different races [8]. About 10% to 15% of patients harboring an activating EGFR mutation are from Western societies [9], and about 50% are Asian [10,11]. The findings of the high efficacy of EGFR-TKI treatment in patients with activating EGFR mutations have had a great influence on the paradigm of NSCLC treatment. Since two Asian studies demonstrated a more than 70% RR in the activating EGFR mutation subgroup [5,12], several randomized prospective trials have confirmed that first-line EGFR-TKI in patients with activating EGFR mutations significantly improved the RR and PFS compared with standard platinum-based chemotherapy [13,14,15]. However, about 60% of patients with disease progression after the initial response to EGFR-TKI are associated with acquired resistance to EGFR-TKI, the substitution of methionine for threonine at position 790 (T790M) point mutation [16,17,18]. There is currently no standard treatment for patients resistant to EGFR-TKI. In this article, we want to review re-treatment with EGFR-TKI in NSCLC patients with activating EGFR mutation.

2. Acquired Resistance to EGFR-TKIs

Patients with an activating EGFR mutation developed resistance eventually, with a median PFS of approximately 8–11 months, when treated with gefitinib or erlotinib [5,12,15,19,20]. Jackman and colleagues [21] suggested a basic definition for acquired resistance to previous use of EGFR-TKI in order to provide a more uniform approach to investigation in further studies. Various mechanisms were later identified, and it is crucial to understand them so as to develop a strategy to overcome resistance. The EGFR exon 20 T790M point mutation is the first and most frequently reported mechanism [17,22,23,24]. It was initially proposed based on the crystallographic structure of the EGFR tyrosine kinase domain. The bulkier methionine residue T790M changes the ATP-binding pocket of the tyrosine kinase domain, leading to the blockade of gefitinib or erlotinib [22]. However, it was demonstrated recently that T790M increased the affinity of ATP to the EGFR tyrosine kinase domain; thus, it decreased the binding of gefitinib and erlotinib, because they are ATP-competitive agents [25]. Other acquired resistance mechanisms, such as small cell transformation, MET amplification, epithelial-mesenchymal transition and PIK3CA mutation, were found in small series of patients [17,24,26,27]. A small study in Korea demonstrated a similar result to the Western population [24]. The presence of T790M defines a clinical subgroup with a more favorable prognosis and more indolent progression among patients with acquired resistance [28,29]. Still, one-third of the mechanisms of acquired resistance are not yet understood [30].
In clinical practice, we usually define patients who develop resistance to EGFR-TKI treatment into three groups: those with oligo-site progression, systemic and multiple progression and isolated central nervous progression [31]. For those patients with oligo-site progression or isolated CNS progression, local treatment to the progression site and continuation of the present EGFR-TKI treatment is suggested [32,33,34]. For patients with a slowly progressing lesion(s) and with lesions smaller than pre-treatment and progression, as documented by Response Evaluation Criteria In Solid Tumor (RECIST), and without the worsening of systemic symptoms and/or signs, the continuation of the present EGFR-TKI is also suggested [20,35]. Thus, the present review of EGFR-TKI retreatment is focused mainly on those patients who need new systemic treatment and excludes those with slowly progressing tumor, oligometastases or isolated CNS metastases. In addition, only those modalities that involve re-treating with EGFR-TKI are discussed.

3. Continue or Re-Treat with First-Generation EGFR-TKIs

Several first-generation EGFR-TKI treatment strategies have been developed for patients with an activating EGFR mutation after disease progression. Second-line chemotherapy is a reasonable choice, despite the lack of prospective evidence for this subset of patients. The subgroup analysis of the TORCH trial [35,36] demonstrated a 15% RR and a four-month median PFS in patients with an EGFR mutation who received chemotherapy after erlotinib. Discontinuation of EGFR-TKI may lead to rapid tumor regrowth [37,38] and many patients developed asymptomatic or slowly progressing disease. Thus, some oncologists chose to continue TKI and delayed further salvage chemotherapy [28]. Some retrospective studies supported the continuation of gefitinib in those who initially responded to gefitinib [39,40]. ASPIRATION (NCT01310026) is a large, prospective, multi-center, single-arm trial to evaluate the efficacy of first-line erlotinib in NSCLC patients harboring an EGFR mutation beyond disease progression [41]. The trial is ongoing and may give us more information about the continuation of EGFR-TKI in patients beyond progression.
The addition of chemotherapy and the continuation of EGFR-TKI have also been considered. A retrospective study [42] was performed with 16 NSCLC patients who had partial or complete response to prior gefitinib. They received continued gefitinib plus paclitaxel after disease progression. The study showed a 13% objective RR, a median PFS of 4.3 months and an overall survival (OS) of 8.1 months. Another retrospective study [43] reported a similar result. Seventy-eight advanced NSCLC patients with an EGFR mutation and acquired resistance received subsequent chemotherapy plus erlotinib or chemotherapy alone. The objective RR of 57 evaluable patients was 41% for those who received chemotherapy plus erlotinib and 18% for those who received chemotherapy alone (HR = 0.31, 95% CI = 0.09–1.04; p = 0.08). The median PFS of patients that received chemotherapy plus erlotinib was 4.4 months and for those that received chemotherapy alone, 4.2 months (p = 0.34). Worthy of noting is that 94% of patients in the chemotherapy plus erlotinib group had erlotinib as the initial TKI. There was no difference in OS between these two groups. In addition, a small prospective study was performed to evaluate patients with the EGFR mutation who were under treatment with gefitinib or erlotinib. It showed a 25.9% of overall RR and 77.8% disease control rate in those who were treated with gefitinib or erlotinib in addition to pemetrexed after disease progression [44]. There is an ongoing clinical trial (IMPRESS, NCT01544179) comparing the continuation of gefitinib with the addition of cisplatin plus pemetrexed versus cisplatin plus pemetrexed in NSCLC patients who have progressed on first-line gefitinib.
The other strategy is to re-treat with EGFR-TKI after progression with second-line salvage chemotherapy. A pre-clinical model revealed the re-gaining of sensitivity to TKI in NSCLC cell lines [45]. Several small retrospective studies found that patients can still be sensitive to EGFR-TKI after stopping treatment [46,47]. Another retrospective study reported a small group (14 patients) of patients that was heavily treated and then re-treated with erlotinib after a median interval from the discontinuation of EGFR-TKI to the second episode of 9.5 months (3–36 months) [48]. The RR was 36% (n = 5), and the disease control rate was 85.7% (n = 12). Before beginning the re-treatment, T790M was detected in 36% of patients (five of 14). Two of the five patients had a partial response; one had stable disease, and the other two had progressive disease [48]. In the American Society Clinical Oncology (ASCO) 2012 meeting, a small series of patients with EGFR mutation was re-treated with EGFR-TKI, which had a beneficial effect after a drug-free interval (median time: 11 months without TKI). The heavily-treated patients in this group had 4.4 months of PFS [49].
Furthermore, a phase I/II clinical trial with combined cetuximab, EGFR monoclonal antibody and erlotinib was conducted based on the hypothesis of overcoming acquired resistance by a combined EGFR pathway blockade [50]. However, the adenocarcinoma patients with an EGFR mutation who developed acquired resistance to erlotinib failed to show an objective response.
In patients with an EGFR mutation or that responded to prior EGFR-TKI either continued TKI combined with chemotherapy or re-treatment with EGFR-TKI after a drug-free interval could be considered as a further treatment strategy.

4. Change to Second-Generation EGFR-TKIs

The resistance to first-generation EGFR-TKIs developed inevitably during treatment. The second-generation of EGFR-TKIs were then developed with some theoretical advantages. Compared to the reversible EGFR-TKIs, the irreversible second-generation TKIs have a higher affinity to tyrosine kinase, which may result in a longer blockade of signaling [51]. Besides, the second-generation EGFR-TKIs are pan-HER inhibitors and may block the EGFR signaling pathway more completely. They also have in vitro activity against the T790M mutation. Of the second generation EGFR-TKIs, neratinib, dacomitinib and afatinib have been getting more attention recently (Table 1).
Neratinib (HKI-272) is an oral, irreversible inhibitor of EGFR and HER2 [52]. In pre-clinical studies, neratinib inhibited the growth of NCI-H1975 bronchoalveolar cancer cells harboring both substitution of arginine for leucine at position 858 (L858R) and T790M and cell lines harboring the HER2 mutation [51]. A phase I study of the advanced stage of solid tumors showed that the maximum tolerated dose (MTD) of neratinib was 320 mg once daily [53]. An open-label, single-agent, phase II study revealed only a 3% RR in patients with an EGFR mutation who had been treated with gefitinib or erlotinib for more than 12 weeks. The median PFS was 15.3 weeks in this subset of patients [54]. Of note, three of four patients (75%) with a substitution of amino aicd for glycine at position 719 (G719X) mutation in EGFR achieved a partial response. The median PFS was 52.7 weeks for these four patients. Since the diarrhea (46% in grade 3/4) and other adverse events (58% in grade 3/4) were unacceptably high, the dosage in this study was decreased to 240 mg daily, which may not achieve a therapeutic level [54]. Neratinib is not being developed for NSCLC currently, due to the disappointing result.
Dacomitinib (PF-00299804) is an irreversible pan-HER inhibitor that binds to each of the three tyrosine kinase active members of the HER family. In preclinical models, dacomitinib was highly potent in inhibiting the HER domain and anti-cancer activity in gefitinib-resistant cell lines and xenograft with HER2 and T790M mutation NSCLC models [55,56]. A phase I study was conducted with patients with advanced malignant solid tumors and revealed the MTD of a dacomitinib dose to be 45 mg once daily [57]. In a phase II trial [58], NSCLC patients with one or two prior chemoregimens were included. Dacomitinib was compared with erlotinib as a second or third-line treatment. The median PFS in this study was 2.86 months with dacomitinib and 1.91 months with erlotinib (hazard ratio (HR) = 0.66; 95% CI, 0.47 to 0.91; two-sided p = 0.012). The subgroup analysis was more in favor of dacomitinib in the EGFR mutation group (hazard ration (HR) = 0.46; 95% CI, 0.18 to 1.18). In another phase II study [59] with 66 patients previously treated with one or two chemotherapy regimens and erlotinib, dacomitinib demonstrated a 5% objective RR in patients with adenocarcinoma. Median PFS was 12 weeks overall and 18 weeks in patients with an EGFR mutation. Gastrointestinal and dermatological adverse events, predominantly grade 1 to 2, were more common in the dacomitinib group than with erlotinib [58,59]. Based on the above data, a randomized, double-blinded, phase 3 study (ARCHER 1009; NCT01360554) comparing dacomitinib to erlotinib, was conducted with advanced NSCLC patients with at least one prior treatment. However, it failed to meet its objective of demonstrating statistically significant improvement in PFS when compared to erlotinib. The BR.26 trial, a double-blind, placebo-controlled, randomized study, comparing dacomitinib and placebo in patients with advanced NSCLC after standard therapy with both chemotherapy and an EGFR-TKI, also had failed to meet its objective of prolonging OS versus placebo. Another clinical trial (ARCHER 1050; NCT01774721) comparing dacomitinib to gefitinib in advanced NSCLC with EGFR mutation in a first-line setting is also ongoing.
Table
Table 1. The second generation EGFR-TKIs.
Table 1. The second generation EGFR-TKIs.
AgentPhaseNPatient PopulationORR (%)DCR (%)PFS (mon)OS (mon)Ref.
Neratinib291EGFR mutation, prior treatment with EGFR-TKI3.453.43.8N/A[50]
248EGFR wild type, prior treatment with EGFR-TKI0644.0N/A[50]
Dacomitinib223EGFR mutation, prior treatment with chemotherapy and/or EGFR-TKI9304.514.8[55]
294NSCLC, prior treatment with one or two chemoregimens, EGFR-TKI naive17N/A2.869.53[54]
219EGFR mutation, prior treatment with one or two chemoregimens, EGFR-TKI naïveN/AN/A7.44N/A[54]
Afatinib261Adenocarcinoma, prior treatment with EGFR-TKIs and chemotherapy for ≥12 weeks8.265.64.419.0[59]
2/3390Adenocarcinoma, prior treatment with chemotherapy and EGFR-TKIs, EGFR status not reported7583.310.8[60]
ORR: objective response rate; DCR: disease control rate; PFS: progression-free survival; OS: overall survival.
Afatinib (BIBW 2992) is a highly selective, irreversible inhibitor of EGFR and a pan-HER inhibitor [60]. In both in vitro and in vivo preclinical models, afatinib demonstrated increased affinity to common EGFR mutations, as well as the T790M mutation [60]. After several phase I studies [61,62], MTD at 50 mg orally daily was established, and the LUX-Lung series of trials has shown promising results.
First, the single-arm phase II trial (LUX-Lung 4), involving Japanese patients with pulmonary adenocarcinoma that progressed after ≥12 weeks of prior gefitinib and/or erlotinib, has shown a modest effect in a third- or fourth-line setting [63]. The majority of the patients (72.6%) were EGFR mutation-positive, and 95.2% of all patients had EGFR-TKI for at least 24 weeks. The median time interval between discontinuation of the previous EGFR-TKI and the start of afatinib was three weeks (ranging from two to 13 weeks); 83.9% of the patients (52 of 62 patients) had an interval of less than four weeks. Fifty-two patients had one chemotherapy regimen and 10 patients had two before starting afatinib. The objective RR was 8.2% (five of 61 evaluable patients, 95% CI, 2.7% to 18.1%), and the disease control rate was 65.6% (40 of 61 evaluable patients, 95% CI, 52.3% to 77.3%). The median PFS was 4.4 months (95% CI, 2.8 to 4.6 months). The predominant adverse events were diarrhea (100%) and rash/acne (91.9%) in all grades.
Second, the phase IIb/III randomized trial (LUX-lung 1) examined the use of afatinib plus best supportive care (BSC) versus placebo plus BSC in 585 NSCLC patients who had disease progression with one or two prior chemotherapy regimens and gefitinib/erlotinib [64]. The objective response was 7% (29 of 585 patients) in the afatinib group. The median PFS was 3.3 months (95% CI, 2.79–4.40) in the afatinib group and 1.1 months in the placebo group (95% CI, 0.95–1.68), with an HR of 0.38 (95% CI, 0.31–0.48; p < 0.0001). The subgroup analysis was more in favor of afatinib use in EGFR mutation-positive patients, with an HR of 0.51 (95% CI, 0.31–0.85). However, the study did not meet its primary endpoint, as the median OS was 10.8 months versus 12.0 months (HR = 1.08; 95% CI: 0.86–1.35) for afatinib and the placebo, respectively. Diarrhea (87%) and rash/acne (78%) were the most frequently reported adverse events. Afatinib was further evaluated combined with chemotherapy, like gefitinib, in a multicenter, phase III, randomized study (LUX-lung 5). LUX-lung 5 (NCT01085136) is going to compare afatinib plus paclitaxel versus chemotherapy of the investigator’s choice alone following afatinib monotherapy in NSCLC patients failing previous gefitinib or erlotinib treatment. Preliminary results will be reported in the ASCO 2014 annual meeting. Afatinib was also compared with standard chemotherapy in the first-line setting [65,66].
Third, there have been recent advances in the combination of afatinib and cetuximab. In the xenograft model of mice, the combination of cetuximab and afatinib can lead to a significant reduction of erlotinib-resistant tumor harboring T790M, compared to gefitinib plus cetuximab [67]. A phase II study supported by the above preclinical data was then conducted using the combination of cetuximab and afatinib in NSCLC patients who developed acquired resistance to first-generation EGFR-TKIs by clinical definition [68,69]. There were confirmed partial responses reported in eight of 22 patients (36%, 95% CI: 0.17–0.59), including 4/13 patients (29%) with a positive T790M mutation. The median PFS was 4.7 months.

5. Third-Generation EGFR-TKIs

The second-generation EGFR-TKIs, such as dacomitinib and afatinib, have shown promising effects in pre-clinical models, but limited activity in clinical trials for patients with acquired resistance to previous EGFR-TKIs, due to their toxicity. A new class of TKIs is under development to target T790M. Among these, CO-1686 and AZD9291 are third-generation EGFR-TKIs currently in an early clinical development status, but with some clinical data available (Table 2).
Table
Table 2. Third-generation EGFR-TKIs.
Table 2. Third-generation EGFR-TKIs.
AgentsNumber of PatientsNumber of Patients with Acquired Resistance and T790MObjective Response RateRef.
CO-16869n/a67%[70]
AZD9291351843%[71]
CO-1686, a 2,4-disubstituted pyrimidine compound, is a novel, oral EGFR inhibitor for NSCLC. It can inhibit mutant EGFR in vivo and in vitro, both irreversibly and selectively, particularly in the T790M mutation [70]. In pre-clinical models, it demonstrated anti-tumor activity in human EGFRL858R- and EGFRL858R/T79°M-expressing transgenic mice. The activity was spared in vivo in EGFR wild-type receptor signaling [70]. In the 2014 ELCC meeting [72], the result of the phase I part of the phase I/II study of CO-1686 in EGFR mutation patients who had disease progression after prior EGFR-TKI was reported. A total of 62 patients were enrolled with doses ranging from 150 mg QD to 900 mg BID in free base formulation and 500 mg QD to 1,000 mg QD in hydrobromide (HBr) salt formulation. About seventy-five percent of them came directly off of TKI with progressive TKI resistance. CO-1686 is well tolerated, and there has only been one patient discontinued due to an adverse event. Treatment-related adverse events were noticed in more than 20% of patients. Grade 3 (19%) hyperglycemia was reported, but it was typically asymptomatic. QTc prolongation grade 3 was observed in 5% of cases and resolved mostly after the dose reduction. Other adverse effects, such as nausea, diarrhea, decreased appetite and fatigue, were noticed in >10% of patients, but mainly in grade 1. Dose-related wild-type-driven diarrhea and skin rashes have not been seen. Based on the promising results, several clinical trials are planned this year to evaluate the efficacy of CO-1686 in different clinical settings.
AZD9291 is a potent, irreversible and effective inhibitor, both in sensitizing EGFR mutations and resistant mutations in cell lines in vitro, while sparing EGFR wild-type [71]. The drug demonstrated anti-tumor activity in EGFR-mutant xenografts at a low dose level [71]. A phase I open-label, multi-center trial has been performed with both Asian and Western patients with advanced NSCLC who had disease progression with prior EGFR-TKI therapy. AZD9291 was well tolerated in the trial with no dose-limiting toxicities at doses of 20, 40, 80 or 160 mg/day. The preliminary data [73] showed that 15 of 35 patients had a confirmed and unconfirmed partial response (43%), including nine of 18 patients with positive T790M. One of them, with negative T790M, also had a partial response.
The successful results with CO-1686 and AZD9291 may have a great influence on the treatment of advanced lung cancer with EGFR mutations. They both showed activity in sensitizing EGFR mutations, as well as resistant mutations. Further clinical trials with third-generation EGFR-TKIs will demonstrate the anti-tumor activities.

6. Conclusions

The standard treatment for patients with acquired resistance to EGFR-TKIs has not yet been defined. Chemotherapy is still an acceptable choice for these patients. Re-treatment with first-generation TKIs after a drug-free interval or the combination with chemotherapy in patients beyond progression may have a modest effect. Second-generation EGFR-TKIs seem to have the same activity as first-generation TKIs in heavily-treated patients, although there were very good responses in a first-line setting compared to chemotherapy [65,66]. Furthermore, afatinib in combination with cetuximab had good activity in patients who developed resistance to erlotinib or gefitinib. However, the adverse effects of second-generation EGFR-TKIs are more severe than those of gefitinib or erlotinib. The third-generation EGFR-TKIs, CO-1686 and AZD9291, demonstrated anti-tumor activity in both sensitizing and resistant EGFR mutation tumors in preclinical models. The phase I trials of these two drugs showed promising effects in TKI-resistant patients, with a low rate of adverse effects in preliminary reports. Further trials are ongoing currently.

Acknowledgments

The authors declare that we did not receive any financial support.

Author Contributions

Wen-Shuo Wu is responsible for constructing the basic concept and drafting the manuscript. Yuh-Min Chen is responsible for revising the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. Cancer J. Clin. 2012, 62, 10–29. [Google Scholar] [CrossRef]
  2. Ettinger, D.S. Ten years of progress in non-small cell lung cancer. J. Natl. Compr. Cancer Netw. 2012, 10, 292–295. [Google Scholar]
  3. Schiller, J.H.; Harrington, D.; Belani, C.P.; Langer, C.; Sandler, A.; Krook, J.; Zhu, J.; Johnson, D.H. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 2002, 346, 92–98. [Google Scholar] [CrossRef]
  4. Ohe, Y.; Ohashi, Y.; Kubota, K.; Tamura, T.; Nakagawa, K.; Negoro, S.; Nishiwaki, Y.; Saijo, N.; Ariyoshi, Y.; Fukuoka, M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann. Oncol. 2007, 18, 317–323. [Google Scholar]
  5. Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009, 361, 947–957. [Google Scholar] [CrossRef]
  6. Miller, V.A.; Riely, G.J.; Zakowski, M.F.; Li, A.R.; Patel, J.D.; Heelan, R.T.; Kris, M.G.; Sandler, A.B.; Carbone, D.P.; Tsao, A.; et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J. Clin. Oncol. 2008, 26, 1472–1478. [Google Scholar] [CrossRef]
  7. Sequist, L.V.; Martins, R.G.; Spigel, D.; Grunberg, S.M.; Spira, A.; Janne, P.A.; Joshi, V.A.; McCollum, D.; Evans, T.L.; Muzikansky, A.; et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J. Clin. Oncol. 2008, 26, 2442–2449. [Google Scholar] [CrossRef]
  8. Gazdar, A.F. EGFR mutations in lung cancer: Different frequencies for different folks. J. Thorac. Oncol. 2014, 9, 139–140. [Google Scholar]
  9. Rosell, R.; Moran, T.; Queralt, C.; Porta, R.; Cardenal, F.; Camps, C.; Majem, M.; Lopez-Vivanco, G.; Isla, D.; Provencio, M.; et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 2009, 361, 958–967. [Google Scholar] [CrossRef]
  10. Shi, Y.; Au, J.S.; Thongprasert, S.; Srinivasan, S.; Tsai, C.M.; Khoa, M.T.; Heeroma, K.; Itoh, Y.; Cornelio, G.; Yang, P.C. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J. Thorac. Oncol. 2014, 9, 154–162. [Google Scholar] [CrossRef]
  11. Hirsch, F.R.; Bunn, P.A., Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009, 10, 432–433. [Google Scholar] [CrossRef]
  12. Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010, 362, 2380–2388. [Google Scholar] [CrossRef]
  13. Zhou, C.; Wu, Y.L.; Chen, G.; Feng, J.; Liu, X.Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; 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 multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011, 12, 735–742. [Google Scholar] [CrossRef]
  14. Rosell, R.; Carcereny, E.; Gervais, R.; Vergnenegre, A.; Massuti, B.; Felip, E.; Palmero, R.; Garcia-Gomez, R.; Pallares, C.; Sanchez, J.M.; 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. [Google Scholar] [CrossRef]
  15. Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase III trial. Lancet Oncol. 2010, 11, 121–128. [Google Scholar] [CrossRef]
  16. Pao, W.; Miller, V.A.; Politi, K.A.; Riely, G.J.; Somwar, R.; Zakowski, M.F.; Kris, M.G.; Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005, 2, e73. [Google Scholar] [CrossRef] [Green Version]
  17. Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 2011, 3, 75ra26. [Google Scholar]
  18. Yu, H.A.; Arcila, M.E.; Rekhtman, N.; Sima, C.S.; Zakowski, M.F.; Pao, W.; Kris, M.G.; Miller, V.A.; Ladanyi, M.; Riely, G.J. 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, 2240–2247. [Google Scholar] [CrossRef]
  19. Wu, W.S.; Chen, Y.M.; Tsai, C.M.; Shih, J.F.; Chiu, C.H.; Chou, K.T.; Lai, S.L.; Wu, C.H.; Luo, Y.H.; Huang, C.Y.; et al. Erlotinib has better efficacy than gefitinib in adenocarcinoma patients without EGFR-activating mutations, but similar efficacy in patients with EGFR-activating mutations. Exp. Ther. Med. 2012, 3, 207–213. [Google Scholar]
  20. Shepherd, F.A.; Bunn, P.A.; Paz-Ares, L. Lung cancer in 2013. In American Society of Clinical Oncology Educational Book/ASCO; American Society of Clinical Oncology Meeting: Alexandria, VA, USA, 2013; pp. 339–346. [Google Scholar]
  21. Jackman, D.; Pao, W.; Riely, G.J.; Engelman, J.A.; Kris, M.G.; Janne, P.A.; Lynch, T.; Johnson, B.E.; Miller, V.A. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 2010, 28, 357–360. [Google Scholar] [CrossRef]
  22. Nguyen, K.S.; Kobayashi, S.; Costa, D.B. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin. Lung Cancer 2009, 10, 281–289. [Google Scholar] [CrossRef]
  23. Kobayashi, S.; Boggon, T.J.; Dayaram, T.; Janne, P.A.; Kocher, O.; Meyerson, M.; Johnson, B.E.; Eck, M.J.; Tenen, D.G.; Halmos, B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2005, 352, 786–792. [Google Scholar] [CrossRef]
  24. Ji, W.; Choi, C.M.; Rho, J.K.; Jang, S.J.; Park, Y.S.; Chun, S.M.; Kim, W.S.; Lee, J.S.; Kim, S.W.; Lee, D.H.; et al. Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer. BMC Cancer 2013, 13. [Google Scholar] [CrossRef]
  25. Yun, C.H.; Mengwasser, K.E.; Toms, A.V.; Woo, M.S.; Greulich, H.; Wong, K.K.; Meyerson, M.; Eck, M.J. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA 2008, 105, 2070–2075. [Google Scholar] [CrossRef]
  26. Engelman, J.A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland, C.; Park, J.O.; Lindeman, N.; Gale, C.M.; Zhao, X.; Christensen, J.; et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007, 316, 1039–1043. [Google Scholar]
  27. Zakowski, M.F.; Ladanyi, M.; Kris, M.G. EGFR mutations in small-cell lung cancers in patients who have never smoked. N. Engl. J. Med. 2006, 355, 213–215. [Google Scholar] [CrossRef]
  28. Oxnard, G.R.; Arcila, M.E.; Sima, C.S.; Riely, G.J.; Chmielecki, J.; Kris, M.G.; Pao, W.; Ladanyi, M.; Miller, V.A. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin. Cancer Res. 2011, 17, 1616–1622. [Google Scholar] [CrossRef]
  29. Fujita, Y.; Suda, K.; Kimura, H.; Matsumoto, K.; Arao, T.; Nagai, T.; Saijo, N.; Yatabe, Y.; Mitsudomi, T.; Nishio, K. Highly sensitive detection of egfr T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J. Thorac. Oncol. 2012, 7, 1640–1644. [Google Scholar] [CrossRef]
  30. Ohashi, K.; Maruvka, Y.E.; Michor, F.; Pao, W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J. Clin. Oncol. 2013, 31, 1070–1080. [Google Scholar] [CrossRef]
  31. Gandara, D.R.; Li, T.; Lara, P.N.; Kelly, K.; Riess, J.W.; Redman, M.W.; Mack, P.C. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: Approach to subtyping progressive disease and clinical implications. Clin. Lung Cancer 2013, 15, 1–6. [Google Scholar]
  32. Shukuya, T.; Takahashi, T.; Naito, T.; Kaira, R.; Ono, A.; Nakamura, Y.; Tsuya, A.; Kenmotsu, H.; Murakami, H.; Harada, H.; et al. Continuous EGFR-TKI administration following radiotherapy for non-small cell lung cancer patients with isolated CNS failure. Lung Cancer 2011, 74, 457–461. [Google Scholar] [CrossRef]
  33. Katayama, T.; Shimizu, J.; Suda, K.; Onozato, R.; Fukui, T.; Ito, S.; Hatooka, S.; Sueda, T.; Hida, T.; Yatabe, Y.; et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J. Thorac. Oncol. 2009, 4, 1415–1419. [Google Scholar] [CrossRef]
  34. Weickhardt, A.J.; Scheier, B.; Burke, J.M.; Gan, G.; Lu, X.; Bunn, P.A., Jr.; Aisner, D.L.; Gaspar, L.E.; Kavanagh, B.D.; Doebele, R.C.; et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J. Thorac. Oncol. 2012, 7, 1807–1814. [Google Scholar] [CrossRef]
  35. West, H.; Oxnard, G.R.; Doebele, R.C. Acquired resistance to targeted therapies in advanced non-small cell lung cancer. In American Society of Clinical Oncology Educational Book/ASCO; American Society of Clinical Oncology Meeting: Alexandria, VA, USA, 2013; pp. 272–278. [Google Scholar]
  36. Gridelli, C.; Ciardiello, F.; Gallo, C.; Feld, R.; Butts, C.; Gebbia, V.; Maione, P.; Morgillo, F.; Genestreti, G.; Favaretto, A.; et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: The TORCH randomized trial. J. Clin. Oncol. 2012, 30, 3002–3011. [Google Scholar] [CrossRef]
  37. Riely, G.J.; Kris, M.G.; Zhao, B.; Akhurst, T.; Milton, D.T.; Moore, E.; Tyson, L.; Pao, W.; Rizvi, N.A.; Schwartz, L.H.; et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin. Cancer Res. 2007, 13, 5150–5155. [Google Scholar] [CrossRef]
  38. Chaft, J.E.; Oxnard, G.R.; Sima, C.S.; Kris, M.G.; Miller, V.A.; Riely, G.J. 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, 6298–6303. [Google Scholar] [CrossRef]
  39. Maruyama, R.; Wataya, H.; Seto, T.; Ichinose, Y. Treatment after the failure of gefitinib in patients with advanced or recurrent non-small cell lung cancer. Anticancer Res. 2009, 29, 4217–4221. [Google Scholar]
  40. Asami, K.; Okuma, T.; Hirashima, T.; Kawahara, M.; Atagi, S.; Kawaguchi, T.; Okishio, K.; Omachi, N.; Takeuchi, N. Continued treatment with gefitinib beyond progressive disease benefits patients with activating EGFR mutations. Lung Cancer 2013, 79, 276–282. [Google Scholar] [CrossRef]
  41. Park, K.; Tsai, C.-M.; Ahn, M.-J.; Yu, C.-J.; Kim, S.-W.; Sriuranpong, V.; Kuo, H.P.; Lee, J.-S.; Kang, J.H.; Lin, M.-C.; et al. ASPIRATION: Phase II study of continued erlotinib beyond recist progression in asian patients (PTS) with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). ASCO Meet. Abstr. 2012, 30, TPS7614. [Google Scholar]
  42. Shukuya, T.; Takahashi, T.; Tamiya, A.; Ono, A.; Igawa, S.; Nakamura, Y.; Tsuya, A.; Murakami, H.; Naito, T.; Kaira, K.; et al. Gefitinib plus paclitaxel after failure of gefitinib in non-small cell lung cancer initially responding to gefitinib. Anticancer Res. 2009, 29, 2747–2751. [Google Scholar]
  43. Goldberg, S.B.; Oxnard, G.R.; Digumarthy, S.; Muzikansky, A.; Jackman, D.M.; Lennes, I.T.; Sequist, L.V. Chemotherapy with erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. Oncologist 2013, 18, 1214–1220. [Google Scholar] [CrossRef]
  44. Yoshimura, N.; Okishio, K.; Mitsuoka, S.; Kimura, T.; Kawaguchi, T.; Kobayashi, M.; Hirashima, T.; Daga, H.; Takeda, K.; Hirata, K.; et al. Prospective assessment of continuation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed. J. Thorac. Oncol. 2013, 8, 96–101. [Google Scholar] [CrossRef]
  45. Sharma, S.V.; Lee, D.Y.; Li, B.; Quinlan, M.P.; Takahashi, F.; Maheswaran, S.; McDermott, U.; Azizian, N.; Zou, L.; Fischbach, M.A.; et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010, 141, 69–80. [Google Scholar] [CrossRef]
  46. Watanabe, S.; Tanaka, J.; Ota, T.; Kondo, R.; Tanaka, H.; Kagamu, H.; Ichikawa, K.; Koshio, J.; Baba, J.; Miyabayashi, T.; et al. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: A retrospective analysis. BMC Cancer 2011, 11. [Google Scholar] [CrossRef]
  47. Yokouchi, H.; Yamazaki, K.; Kinoshita, I.; Konishi, J.; Asahina, H.; Sukoh, N.; Harada, M.; Akie, K.; Ogura, S.; Ishida, T.; et al. Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer. BMC Cancer 2007, 7. [Google Scholar] [CrossRef]
  48. Becker, A.; Crombag, L.; Heideman, D.A.; Thunnissen, F.B.; van Wijk, A.W.; Postmus, P.E.; Smit, E.F. Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur. J. Cancer 2011, 47, 2603–2606. [Google Scholar]
  49. Heon, S.; Nishino, M.; Goldberg, S.B.; Porter, J.; Sequist, L.V.; Jackman, D.M.; Johnson, B.E. Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance. ASCO Meet. Abstr. 2012, 30. Abstract No. 7525. [Google Scholar]
  50. Janjigian, Y.Y.; Azzoli, C.G.; Krug, L.M.; Pereira, L.K.; Rizvi, N.A.; Pietanza, M.C.; Kris, M.G.; Ginsberg, M.S.; Pao, W.; Miller, V.A.; 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, 2521–2527. [Google Scholar] [CrossRef]
  51. Kwak, E.L.; Sordella, R.; Bell, D.W.; Godin-Heymann, N.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Driscoll, D.R.; Fidias, P.; Lynch, T.J.; et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. USA 2005, 102, 7665–7670. [Google Scholar] [CrossRef]
  52. Rabindran, S.K.; Discafani, C.M.; Rosfjord, E.C.; Baxter, M.; Floyd, M.B.; Golas, J.; Hallett, W.A.; Johnson, B.D.; Nilakantan, R.; Overbeek, E.; et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004, 64, 3958–3965. [Google Scholar] [CrossRef]
  53. Wong, K.K.; Fracasso, P.M.; Bukowski, R.M.; Lynch, T.J.; Munster, P.N.; Shapiro, G.I.; Janne, P.A.; Eder, J.P.; Naughton, M.J.; Ellis, M.J.; et al. A phase I study with neratinib (HKI-272), an irreversible pan ERBB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 2009, 15, 2552–2558. [Google Scholar] [CrossRef]
  54. Sequist, L.V.; Besse, B.; Lynch, T.J.; Miller, V.A.; Wong, K.K.; Gitlitz, B.; Eaton, K.; Zacharchuk, C.; Freyman, A.; Powell, C.; et al. Neratinib, an irreversible pan-ERBB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 2010, 28, 3076–3083. [Google Scholar] [CrossRef]
  55. Engelman, J.A.; Zejnullahu, K.; Gale, C.M.; Lifshits, E.; Gonzales, A.J.; Shimamura, T.; Zhao, F.; Vincent, P.W.; Naumov, G.N.; Bradner, J.E.; et al. PF00299804, an irreversible pan-ERbb inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007, 67, 11924–11932. [Google Scholar] [CrossRef]
  56. Gonzales, A.J.; Hook, K.E.; Althaus, I.W.; Ellis, P.A.; Trachet, E.; Delaney, A.M.; Harvey, P.J.; Ellis, T.A.; Amato, D.M.; Nelson, J.M.; et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-ERBB receptor tyrosine kinase inhibitor. Mol. Cancer Ther. 2008, 7, 1880–1889. [Google Scholar] [CrossRef]
  57. Janne, P.A.; Boss, D.S.; Camidge, D.R.; Britten, C.D.; Engelman, J.A.; Garon, E.B.; Guo, F.; Wong, S.; Liang, J.; Letrent, S.; et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin. Cancer Res. 2011, 17, 1131–1139. [Google Scholar] [CrossRef]
  58. Ramalingam, S.S.; Blackhall, F.; Krzakowski, M.; Barrios, C.H.; Park, K.; Bover, I.; Seog Heo, D.; Rosell, R.; Talbot, D.C.; Frank, R.; et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 2012, 30, 3337–3344. [Google Scholar] [CrossRef]
  59. Reckamp, K.L.; Giaccone, G.; Camidge, D.R.; Gadgeel, S.M.; Khuri, F.R.; Engelman, J.A.; Koczywas, M.; Rajan, A.; Campbell, A.K.; Gernhardt, D.; et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer 2014, 120, 1145–1154. [Google Scholar] [CrossRef]
  60. Li, D.; Ambrogio, L.; Shimamura, T.; Kubo, S.; Takahashi, M.; Chirieac, L.R.; Padera, R.F.; Shapiro, G.I.; Baum, A.; Himmelsbach, F.; et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008, 27, 4702–4711. [Google Scholar]
  61. Murakami, H.; Tamura, T.; Takahashi, T.; Nokihara, H.; Naito, T.; Nakamura, Y.; Nishio, K.; Seki, Y.; Sarashina, A.; Shahidi, M.; et al. Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother. Pharmacol. 2012, 69, 891–899. [Google Scholar] [CrossRef]
  62. Yap, T.A.; Vidal, L.; Adam, J.; Stephens, P.; Spicer, J.; Shaw, H.; Ang, J.; Temple, G.; Bell, S.; Shahidi, M.; et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J. Clin. Oncol. 2010, 28, 3965–3972. [Google Scholar] [CrossRef]
  63. Katakami, N.; Atagi, S.; Goto, K.; Hida, T.; Horai, T.; Inoue, A.; Ichinose, Y.; Koboyashi, K.; Takeda, K.; Kiura, K.; et al. Lux-Lung 4: A phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J. Clin. Oncol. 2013, 31, 3335–3341. [Google Scholar] [CrossRef]
  64. Miller, V.A.; Hirsh, V.; Cadranel, J.; Chen, Y.M.; Park, K.; Kim, S.W.; Zhou, C.; Su, W.C.; Wang, M.; Sun, Y.; et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol. 2012, 13, 528–538. [Google Scholar] [CrossRef]
  65. Wu, Y.L.; Zhou, C.; Hu, C.P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J.H.; Lee, K.Y.; et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15, 213–222. [Google Scholar] [CrossRef]
  66. Sequist, L.V.; Yang, J.C.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C.M.; Boyer, M.; 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. [Google Scholar]
  67. Regales, L.; Gong, Y.; Shen, R.; de Stanchina, E.; Vivanco, I.; Goel, A.; Koutcher, J.A.; Spassova, M.; Ouerfelli, O.; Mellinghoff, I.K.; et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J. Clin. Investig. 2009, 119, 3000–3010. [Google Scholar]
  68. Yamamoto, N.; Katakami, N.; Atagi, S.; Hida, T.; Goto, K.; Horai, T.; Inoue, A.; Ichinose, Y.; Kobayashi, K.; Takeda, K.; et al. A phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (e) or gefitinib (g). ASCO Meet. Abstr. 2011, 29. Abstract No. 7524. [Google Scholar]
  69. Janjigian, Y.Y.; Groen, H.J.; Horn, L.; Smit, E.F.; Fu, Y.; Wang, F.; Shahidi, M.; Denis, L.J.; Pao, W.; Miller, V.A. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in nsclc patients with acquired resistance to erlotinib or gefitinib. ASCO Meet. Abstr. 2011, 29. Abstract No. 7525. [Google Scholar]
  70. Walter, A.O.; Sjin, R.T.; Haringsma, H.J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z.; Wang, Z.; et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013, 3, 1404–1415. [Google Scholar] [CrossRef]
  71. Cross, D.; Ashton, S.; Nebhan, C.; Eberlein, C.; Finlay, M.R.V.; Hughes, G.; Jacobs, V.; Mellor, M.; Brewer, M.R.; Meador, C.; et al. AZD9291: An irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma. Mol. Cancer Ther. 2013, 12. Abstract No. A109. [Google Scholar]
  72. Wakelee, H.A.; Soria, J.C.; Sequist, L.V.; Gadgeel, S.; Goldman, J.W.; Verfa, A.; Fidias, P.; Wozniak, A.J.; Neal, J.W.; Doebele, R.C.; et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J. Thorac. Oncol. 2013. Abstract No. 2524. [Google Scholar]
  73. Ranson, M.; Pao, W.; Kim, D.W. AZD9291: An irreversible, potent, and selective tyrosine kinase inhibitor (TKI) of activating (EGFR+) and resistance mutation (T790M+) mutations in advanced NSCLC. J. Thorac. Oncol. 2013. Abstract No. P.1.11. [Google Scholar]

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Wu, W.-S.; Chen, Y.-M. Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance. J. Pers. Med. 2014, 4, 297-310. https://doi.org/10.3390/jpm4030297

AMA Style

Wu W-S, Chen Y-M. Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance. Journal of Personalized Medicine. 2014; 4(3):297-310. https://doi.org/10.3390/jpm4030297

Chicago/Turabian Style

Wu, Wen-Shuo, and Yuh-Min Chen. 2014. "Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance" Journal of Personalized Medicine 4, no. 3: 297-310. https://doi.org/10.3390/jpm4030297

APA Style

Wu, W. -S., & Chen, Y. -M. (2014). Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance. Journal of Personalized Medicine, 4(3), 297-310. https://doi.org/10.3390/jpm4030297

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