Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment

Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-Gu, Seoul, South Korea.
Annals of Oncology (Impact Factor: 7.04). 12/2008; 19(12):2039-42. DOI: 10.1093/annonc/mdn423
Source: PubMed


Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors, but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC).
Patients with advanced/metastatic NSCLC who had shown disease progression on gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity.
Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients, one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea.
Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular markers in tumors is important to understand and overcome acquired resistance to gefitinib.

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    • "Moreover, clinical study revealed that NSCLC patients with EGFR mutations have a significantly longer survival than those with wild-type EGFR when treated with EGFR TKIs [14]. Despite experiencing dramatic clinical responses, patients who initially respond to gefitinib eventually develop progressive disease or incomplete cross-resistance to the currently available EGFR-TKIs like erlotinib [15,16]. Therefore, how to improve gefitinib efficacy and let more NSCLC patietns gain benefit from TKI therapy is still the goal of physicians and researchers. "
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    ABSTRACT: Background Non-small cell lung cancer (NSCLC) expressed high levels of epidermal growth factor receptor (EGFR). Gefitinib (Iressa) has demonstrated clinical efficacy in NSCLC patients harboring EGFR mutations or refractory to chemotherapy. However, most of NSCLC patients are with wild type EGFR, and showed limited response to gefitinib. Therefore, to develop new effective therapeutic interventions for NSCLC is still required. Our previous study showed Marsdenia tenacissima extract (MTE) restored gefitinib efficacy in the resistant NSCLC cells, but whether MTE acts in the gefitinib-sensitive NSCLC cells is the same as it in the resistant one is unknown. Methods Dose response curves for gefitinib and MTE were generated for two sensitive NSCLC cell lines with mutant or wild type EGFR status. Three different sequential combinations of MTE and gefitinib on cell growth were evaluated using IC50 and Combination Index approaches. The flow cytometric method was used to detect cell apoptosis and cell cycle profile. The impact of MTE combined with gefitinib on cell molecular network response was studied by Western blotting. Results Unlike in the resistant NSCLC cells, our results revealed that low cytotoxic dose of MTE (8 mg/ml) combined gefitinib with three different schedules synergistically or additively enhanced the growth inhibition of gefitinib. Among which, MTE → MTE + gefitinib treatment was the most effective one. MTE markedly prompted cell cycle arrest and apoptosis caused by gefitinib both in EGFR mutant (HCC827) and wild type of NSCLC cells (H292). The Western blotting results showed that MTE → MTE + gefitinib treatment further enhanced the suppression of gefitinib on cell growth and apoptosis pathway such as ERK1/2 and PI3K/Akt/mTOR. This combination also blocked the activation of EGFR and c-Met which have cross-talk with each other. Unlike in gefitinib-resistant NSCLC cells, MTE alone also demonstrated certain unexpected modulation on EGFR related cell signal pathways in the sensitive cells. Conclusion Our results suggest that MTE is a promising herbal medicine to improve gefitinib efficacy in NSCLC regardless of EGFR status. However, why MTE acted differently between gefitinib-sensitive and -resistant NSCLC cells needs a further research.
    BMC Complementary and Alternative Medicine 05/2014; 14(1):165. DOI:10.1186/1472-6882-14-165 · 2.02 Impact Factor
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    • "Patients who benefited from the cytotoxic chemotherapy immediately after the failure of non-first line TKIs were identified. Though the retreatment of TKIs is the focus of studies on the treatment after failure of initial TKIs treatment for NSCLC [7, 8, 13, 24, 25], chemotherapy is the main treatment option once TKIs fails in clinical practice. In the current study, chemotherapy accounted for 70.8% (51/72) and retreatment of TKIs just accounted for 29.2% (21/72). "
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    ABSTRACT: The standard therapy after failure of the initial non-first line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in advanced non-small cell lung cancer (NSCLC) has not yet been established. The aim of the current study was to identify whether the 2(nd) TKI treatment or chemotherapy (paclitaxel-containing or non-paclitaxel regimen) is the appropriate treatment for patients with NSCLC based on the efficacy of the initial TKIs. Seventy-two advanced NSCLC patients who had accepted 2(nd) TKIs or chemotherapy immediately after failure of the initial TKIs in non-first line setting from May 1, 2004 to January 31, 2010 at the Sun Yat-sen University Cancer Center were enrolled. The primary endpoint [2(nd) progression-free survival (PFS)] and the second endpoint [overall survival (OS)] were compared among the 2(nd) TKI and chemotherapy groups as well as their subgroups. (1) Twenty-one patients were treated with 2(nd) TKIs, and 51 patients were administered chemotherapy after failure of the initial non-first line TKI treatment. There was nonsignificant difference in the responses (P=0.900) [2(nd) PFS (P=0.833) and OS (P=0.369)] between the 2(nd) TKI and chemotherapy groups. (2) In the 2(nd) TKI group, 9 patients exhibited PFS≥7 months. The initial TKI treatment group exhibited a longer 2(nd) PFS than the other 12 patients with an initial PFS<7 months (7 months vs. 2 months, P=0.019). However, these groups had nonsignificantly different OS (P=0.369). (3) In the chemotherapy group, patients with PFS<5 months exhibited longer 2(nd) PFS than those with PFS ≥ 5 months in the initial TKI treatment (3 months vs. 2 months, P=0.039). (4) In the chemotherapy group, patients treated with paclitaxel-containing regimen showed longer 2(nd) PFS than those treated with non-paclitaxel regimen (5 months vs. 2.3 months, P=0.043). Patients with PFS≥7 months or <5 months under the initial TKI treatment potentially benefit from the 2(nd) TKI treatment or chemotherapy immediately after failure of the non-first line TKIs. The paclitaxel-containing regimen may improve the 2(nd) PFS. However, more patient samples are urgently needed to validate these findings.
    Cancer Biology and Medicine 03/2012; 9(1):38-43. DOI:10.3969/j.issn.2095-3941.2012.01.007
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    • "Therefore, BCRP/ABCG2 does not seem to be the major determinant of the cross-resistance to erlotinib in the cell model used in this study, and other mechanisms remain to be clarified. Since BCRP/ABCG2-positive tumors were found in 46% of advanced NSCLC patients [33], the BCRP/ABCG2-dependent drug resistance to gefitinib but not erlotinib might explain why erlotinib provides a better clinical outcome than gefitinib [7], [8] and may serve as a salvage treatment for NSCLC patients after failure of gefitinib treatment [34], [35]. In addition to BCRP/ABCG2, gefitinib and other TKIs have also been reported to function as inhibitors, but not substrates, of MDR1/ABCB1 [19], [32], [36], [37], another important ABC transporter for chemotherapeutic agents, indicating that MDR1/ABCB1 may be a potential target of TKIs to overcome chemoresistance rather than contributing to the drug resistance to these EGFR TKIs. "
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    ABSTRACT: The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive. Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib. Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.
    PLoS ONE 06/2011; 6(6):e21428. DOI:10.1371/journal.pone.0021428 · 3.23 Impact Factor
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