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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3182762bfb
Original Articles

Prospective Assessment of Continuation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Pemetrexed

Yoshimura, Naruo MD, PhD*; Okishio, Kyoichi MD, PhD; Mitsuoka, Shigeki MD, PhD*; Kimura, Tatsuo MD, PhD*; Kawaguchi, Tomoya MD, PhD; Kobayashi, Masaji MD, PhD; Hirashima, Tomonori MD, PhD; Daga, Haruko MD, PhD§; Takeda, Koji MD, PhD§; Hirata, Kazuto MD, PhD*; Kudoh, Shinzoh MD, PhD*

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Author Information

*Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, Japan; National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Osaka, Japan; Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Osaka, Japan; and §Department of Clinical Oncology, Osaka City General Hospital, Miyakojima-ku, Osaka, Japan.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Naruo Yoshimura, MD, PhD, Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545–8585, Japan. E-mail:

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Introduction: Patients with epidermal growth factor receptor (EGFR) mutation positive non–small-cell lung cancer exhibited marked response to gefitinib or erlotinib. In most cases, however, the patients showed disease progression after EGFR-tyrosine kinase inhibitor (TKI) treatment. We evaluated the efficacy and safety of pemetrexed in combination with EGFR-TKI in patients with disease progression.

Methods: Patients with EGFR-mutant stage IIIB or IV non–small-cell lung cancer that progressed during gefitinib or erlotinib therapy were administered pemetrexed with the continuation of EGFR-TKI treatment. Pemetrexed was administered on day 1 at a dose of 500 mg/m2, and EGFR-TKI was sequentially administered on days 2 to 16. This treatment was repeated every 3 weeks until disease progression. The primary endpoint was disease control rate.

Results: Twenty-seven patients were enrolled in this study. The median number of treatment cycles was six. Overall response rate was 25.9% (95% confidence interval, 9.4%–42.4%) and disease control rate was 77.8% (95% confidence interval, 62.1%–93.5%). Grade 3/4 hematological toxicities were neutropenia (22.2%), leukopenia (14.8%), and anemia (7.4%). Grade 4 nonhematological toxicities were not observed. Major grade 3 nonhematological toxicities were anorexia (14.8%), infection (14.8%), and fatigue (11.1%). The median progression-free survival was 7.0 months, and median survival time was 11.4 months. No treatment-related deaths occurred.

Conclusions: Pemetrexed in combination with erlotinib or gefitinib after disease progression shows favorable response and acceptable toxicity.

Erlotinib and gefitinib are oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). These inhibitors have been found to induce marked radiographic and clinical improvement in patients with EGFR mutations. Two randomized phase III studies involving patients with untreated EGFR-mutant tumors compared gefitinib treatment with cytotoxic chemotherapy as the first-line treatment; the results indicated that the progression-free survival (PFS) was significantly longer in patients who received gefitinib than in those who underwent cytotoxic chemotherapy.1,2 Erlotinib has been similarly shown to be highly effective in patients with EGFR-mutant tumors.3,4

Despite the benefits of EGFR-TKIs in the treatment of patients with non–small-cell lung cancer (NSCLC) having EGFR mutation, most patients ultimately develop resistance to these drugs after a median of 9 to 13 months.5,6 In half of these patients, acquired resistance is associated with a secondary mutation, T790M, in EGFR.7,8 However, tumor cells bearing EGFR with T790M represent a minority of cells, and as such, some proportion of the tumor may remain responsive to erlotinib or gefitinib.9,10 Furthermore, in patients, who develop acquired resistance, inhibition of EGFR-TKI results in rapid symptomatic progression and increase in tumor size. The symptoms improve after restarting erlotinib or gefitinib, suggesting that some tumor cells remain sensitive to EGFR-TKI.11

Gefitinib is known to suppress the expression of thymidylate synthase (TS) in NSCLC cell lines.12 Low TS expression is a predictive factor for the treatment efficacy of pemetrexed in NSCLC patients.13 In patients with acquired resistance to gefitinib or erlotinib, continued treatment may be effective, and the addition of pemetrexed to gefitinib or erlotinib would increase the efficacy of the treatment.

Tianhong Li et al.14 reported the schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human NSCLC. They showed that the combination of pemetrexed and erlotinib was synergistic in NSCLC in vitro if exposure to erlotinib was avoided before administering pemetrexed, particularly in tumors that are sensitive to erlotinib. They explained that antagonism was associated with erlotinib-induced G1-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity and that pemetrexed induced an EGFR-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway, which was inhibited by erlotinib. The phase I of dose- and schedule-finding studies of combined erlotinib–pemetrexed treatment was performed in patients with refractory advanced NSCLC and solid tumors.15,16 The authors concluded that the combination of erlotinib and pemetrexed was well tolerated, and that the administration of pemetrexed on day 1 and erlotinib on days 2 to 16 is feasible.

Some preclinical studies and clinical data have indicated the potential benefit of EGFR-TKI in patients with disease progression. We designed a phase II trial to evaluate the efficacy and safety of pemetrexed combined with gefitinib or erlotinib after disease progression to these EGFR-TKI treatments in patients with advanced NSCLC having an active EGFR mutation.

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The primary endpoint of the study was to determine the disease control rate (DCR). Secondary endpoints included determination of the overall response rate (ORR), PFS, overall survival (OS), toxicity, and safety.

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Patient Eligibility

Eligibility criteria included histologically or cytologically proven NSCLC with an active EGFR mutation after disease progression to gefitinib or erlotinib, measurable lesions, stage IIIB (including only patients with no indications for curative radiotherapy) or IV, Eastern Cooperative Oncology Group Scale of performance status of 0 to 2, an estimated life expectancy of at least 12 weeks, and adequate major organ function (leukocyte count ≥3000/μl; platelet count ≥100,000/μl; hemoglobin concentration ≥9.0 g/dl; total serum bilirubin level <1.5 mg/dl; aspartate aminotransferase and alanine aminotransferase levels <100 IU/l; serum creatinine level <1.2 mg/dl; PaO2, ≥60 torr; and normal findings on electrocardiography). Pretreatment such as platinum-containing chemotherapy was required, except for patients aged 75 years or more. EGFR mutation was examined by PNA-LNA polymerase chain reaction clamp method.

Patients were excluded for any of the following reasons: myocardial infarction in the previous 3 months; uncontrolled angina pectoris or arrhythmia; symptomatic brain metastasis; uncontrolled hypertension or diabetes; active infection, pulmonary fibrosis, pleural effusion or ascites requiring drainage; or cerebrovascular disease. Written informed consent was obtained from all the patients, and the protocol was approved by the ethics committee.

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Patient Evaluation

The pretreatment evaluation consisted of a complete blood cell count, routine chemistry measurements, chest radiography, chest and abdominal computed tomography, brain magnetic resonance imaging or computed tomography, and radionuclide bone imaging. Laboratory tests were performed once a week during chemotherapy, and follow-up evaluations were repeated every 4 to 6 weeks to evaluate tumor response.

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Treatment Plan

Pemetrexed was administered at a dose of 500 mg/m2 over 10 minutes by intravenous infusion on day 1. Gefitinib or erlotinib was sequentially administered on days 2 to 16. This combination treatment was repeated every 3 weeks until the disease progressed. All patients received prophylactic dexamethasone dose (4 mg orally twice per day) on days 1 to 3. All patients received oral folic acid (500 μg) daily and a vitamin B12 injection (1000 μg) every 9 weeks, beginning 1 to 2 weeks before the first dose and continuing until 3 weeks after the last dose of study treatment.

Patients requiring dose reduction of pemetrexed, gefitinib, or erlotinib received the reduced dose for the remainder of the study. Patients who had two dose reductions and who experienced toxicity, thus requiring a third dose reduction, were excluded from the study. Cycle delays of up to 42 days were permitted for recovery from adverse events. The use of granulocyte colony-stimulating factor was allowed according to the American Society of Clinical Oncology guidelines.17 Chemotherapy was only administered if the patient had a leukocyte count of 3000/μl or more and a platelet count of 100,000/μl or more. If the leukocyte count or platelet count had not returned to these levels on day 1 of the next cycle of chemotherapy, both drugs were withheld until complete recovery. Pemetrexed dose was reduced by 100 mg/m2 in the first step and 200 mg/m2 in the second step for any of the following reasons: grade 4 neutropenia, leukopenia, thrombocytopenia, or grade 3/4 nonhematological toxicities, excluding nausea, vomiting, or anorexia. Gefitinib dose was reduced to 250 mg once every 2 days in the first step and once every 3 days in the second step for any of the following reasons: grade 2 to 4 diarrhea, grade 2 to 4 increase in aspartate aminotransferase/alanine aminotransferase levels, grade 3/4 other nonhematological toxicities, or grade 3/4 hematological toxicities. Erlotinib was reduced to 100 mg/day in the first step and 75 mg/day in the second step for the same reasons as of gefitinib.

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Response and Toxicity Evaluation

Revised Response Evaluation Criteria in Solid Tumors guidelines version 1.1 were used to evaluate antitumor activity.18 The assessments were performed by each physician in charge. Toxicity was graded according to the National Cancer Institute of Common Toxicity Criteria, version 4.0. The highest toxicity grade for each patient in all cycles of chemotherapy was used for the toxicity analysis.

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Statistical Analysis

To determine the sample size, a Southwest Oncology Group (SWOG) One Arm Binomial (the method of Fleming) design was selected.19 The null hypothesis for DCR was 30%, with an alternative hypothesis of 60% at a significance level of 0.05 and a statistical power of 80%. This trial required 23 patients. OS was calculated from the enrolment to the date of the last follow-up or death from any cause. PFS was calculated from the enrolment to the date of disease progression, recurrence, or death from any cause. Survival curves were estimated using the Kaplan–Meier method.

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Patient Characteristics

Between February 2010 and April 2011, 27 patients were enrolled in this study. All patients were treated and assessed for response, survival, and safety. The median age of the patients was 67 years (range, 48–83 years). Baseline characteristics are shown in Table 1. EGFR mutations were detected in all patients, 14 of whom had a deletion in or near E746-A750 in exon 19. Moreover, 11 patients had L858R point mutation in exon 21 and two patients had a previously unreported type of mutation. We knew the two patients had either of the active EGFR mutations, however, we could not get the information about the type of EGFR mutation. Further, 19 patients had undergone prior chemotherapy and 17 patients had undergone platinum-doublet treatment. Six partial responses (PRs) and 11 stable diseases (SDs) were recorded, with an ORR of 31.6% and DCR of 89.4% in the 19 patients who received prior treatment with cyotoxic drugs. Sixteen patients had undergone prior gefitinib treatment, seven had prior erlotinib treatment, and four had undergone both the treatments. Nineteen PRs and eight SDs were recorded, with an ORR of 70.4% and a DCR of 100% in the 27 patients who received prior treatment with EGFR-TKIs.

Table 1
Table 1
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Treatment Delivery

The total number of treatment cycles delivered was 231, and the median was 6 (range, 1– 32+). The frequency of dose reduction of pemetrexed was 22.2% (6 of 27) and EGFR-TKIs were 7.4% (2 of 27). Two patients received only one cycle because of grade 3 pneumonitis and worsening of PS. Two patients are now continuing treatment. Four (4.0%) of the treatment cycles were delayed by more than 6 days because of toxicity.

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Table 2 lists the incidence of hematological and nonhematological toxicities. Grade 3/4 neutropenia was the most common adverse event and occurred in 22.2% (6 of 27) of the patients, though febrile neutropenia did not occur. Other grade 3/4 hematological toxicities were leukopenia (14.8%, 4 of 27) and anemia (7.4%, 2 of 27). Grade 4 nonhematological toxicities were not observed. Grade 3 nonhematological toxicities were anorexia (14.8%, 4 of 27), infection (14.8%, 4 of 27), fatigue (11.1%, 3 of 27), nausea (7.4%, 2 of 27), vomiting (7.4%, 2 of 27), rash (7.4%, 2 of 27), pneumonitis (3.7%, 1 of 27), and escalation of total bilirubin levels (3.7%, 1 of 27). No treatment-related deaths occurred.

Table 2
Table 2
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The treatment response of all the patients was evaluated. Seven PRs and 14 SDs were recorded, with an ORR of 25.9% (95% confidence interval [CI], 9.4%–42.4%) and a DCR of 77.8% (95% CI, 62.1%–93.5%) (Table 3). With a median follow-up period of 11.4 months, the median PFS was 7.0 months (95% CI, 6.2–7.8 months) and the median survival time was 11.4 months (95% CI, 9.4–13.5 months). The 6-month and 1-year progression-free rates were 56.6% and 19.4%, respectively. The 6-month and 1-year OS rates were 75.5% and 50.0%, respectively (Fig. 1).

Table 3
Table 3
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Figure 1
Figure 1
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The most frequent site of metastasis was the lung (37.7%). Other sites of progression were the primary site (21.4%), liver (21.4%), brain (14.3%), and pleura (7.1%). Thirteen patients (48.1%) received systemic therapy after completing this study. Seven patients (53.8%) were treated with EGFR-TKI, three patients (23.1%) with docetaxel, two patients (15.4%) with a combination of carboplatin and gemcitabine, and one (7.7%) with vinorelbine.

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This is the first phase II trial for evaluating the efficacy and safety of pemetrexed in combination with gefitinib or erlotinib after the relapse to gefitinib or erlotinib treatments in patients with advanced NSCLC having an active EGFR mutation. The DCR and ORR were 77.8% and 25.9%, respectively. The median PFS and median survival time were 7.0 and 11.4 months, respectively. Grade 3/4 hematological toxicities were neutropenia, 22.2%; leukopenia, 14.8%; and anemia, 7.4%. Though this was the single-arm phase II study, we showed that this treatment modality was effective and well tolerated by the patients.

The most frequent cause of acquired resistance to gefitinib and erlotinib is the secondary T790M mutation in EGFR, and it has been reported in approximately 50% patients who develop resistance to these drugs.7,8 Investigators performed reconstitution experiments in vitro to estimate whether acquired resistance to EGFR inhibitors is related to the proportion of T790M-containing cells. The results showed that populations with small percentages of resistant cells (1%–10%) exhibited similar sensitivity to erlotinib as parental cells (0%) did, whereas the sensitivity reduced when T790M clones constituted more than 25% of the population.20 However, frequent monitoring of disease progression in patients with the T790M mutation is difficult because biopsy is an invasive procedure. Noninvasive monitoring techniques using circulating tumor cells are being investigated, but their clinical application is currently difficult.21 Several other mechanisms, including MET amplification and overexpression of hepatocyte growth factor, were reported to induce acquired resistance.22,23 Many new kinase inhibitors and antibodies targeted for these resistances have been developed; however, few new drugs are available at present.

Faehling et al.24 reported a retrospective analysis of NSCLC patients treated with erlotinib, who progressed on SD for at least 6 months. They showed that treatment beyond progression leads to prolonged OS compared with treatment with TKI-free chemotherapy or radiotherapy. Chaft J E et al.25 systematically evaluated an observed phenomenon of rapid and symptomatic disease progression that occurs in patients with EGFR-mutant lung cancer who acquired clinical resistance to gefitinib and/or erlotinib shortly after discontinuation of the EGFR-TKI. They found that 23% of the patients experienced a symptomatic disease flare. The data suggested that treatment with EGFR-TKIs beyond progression could inhibit disease flare. Tumors resistant to EGFR-TKIs may be composed of a heterogeneous mix of TKI-sensitive and TKI-resistant cells and stopping TKI therapy may permit the expansion of fast-growing TKI-sensitive cells.

Most patients of our study received platinum-doublets in the first-line treatment and, after relapse of the treatment EGFR-TKI was administered. The chemotherapy of pemetrexed or docetaxel was a standard care after the failure to platinum doublets followed by EGFR-TKI. At that time EGFR-TKI was replaced with docetaxel or pemetrexed. However, the efficacies of these agents were unsatisfactory. The median PFS of pemetrexed and docetaxel was 3.9 months and 4.1 months, respectively.26,27 The efficacy of our study was superior to these treatments.

Gefitinib induced down-regulation of TS in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR.12 A combination of 5-fluorouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, but not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification. The inhibition of EGFR phosphorylation and down-regulation of TS by gefitinib were associated with the synergistic interaction between gefitinib and S-1. The other side, TS expression may be an important predictive factor for treatment efficacy of pemetrexed in NSCLC patients, especially for patients with lung adenocarcinoma.13 Thus, the efficacy reinforcement of pemetrexed by down-regulation of TS might become one of the reasons of our favorable results.

In conclusion, we showed that combined pemetrexed and erlotinib or gefitinib therapy after the relapse to these EGRF-TKIs was effective and tolerated in patients with advanced NSCLC having an active EGFR mutation. These data suggest that EGFR-TKI treatment beyond progression might be promising strategy. The development of treatments for patients with acquired resistance to EGFR-TKIs is an urgent issue, and further assessment in prospective phase III study comparing pemetrexed alone versus pemetrexed with continuation of EGFR-TKI beyond progression is warranted.

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We thank Maki Nakai for data management and secretarial assistance.

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9. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA. 2005;102:7665–7670

10. Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695–2706

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13. Chen CY, Chang YL, Shih JY, et al. Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 2011;74:132–138

14. Li T, Ling YH, Goldman ID, Perez-Soler R. Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res. 2007;13:3413–3422

15. Ranson M, Reck M, Anthoney A, et al. Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study. Ann Oncol. 2010;21:2233–2239

16. Davies AM, Ho C, Beckett L, et al. Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation. J Thorac Oncol. 2009;4:862–868

17. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187–3205

18. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247

19. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982;38:143–151

20. Chmielecki J, Foo J, Oxnard GR, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3:90ra59

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22. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–1043

23. Yano S, Wang W, Li Q, et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 2008;68:9479–9487

24. Faehling M, Eckert R, Kuom S, et al. Treatment with TKI beyond progression in long-term responders to erlotinib improves survival in advanced non-small cell lung cancer. J Thoracic Oncol. 2011;6:S663–664

25. 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;17:6298–6303

26. Wu SG, Yang CH, Yu CJ, et al. Good response to pemetrexed in patients of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Lung Cancer. 2011;72:333–339

27. Douillard JY, Shepherd FA, Hirsh 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

Non–small-cell lung cancer; Erlotinib; Gefitinib; Pemetrexed; Epidermal growth factor receptor mutation; Acquired resistance.

© 2013International Association for the Study of Lung Cancer


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