Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802)

Zhou, C.; Wu, Yi‐Long; Chen, G.; Feng, J.; Liu, Xiangyu; Wang, C.; Zhang, S.; Wang, J.; Zhou, Shunhua; Ren, Shengxiang; Lü, Shun; Zhang, L.; Hu, Chengping; Luo, Yi; Chen, L.; Ye, M.; Huang, Juanjuan; Zhi, Xiao; Zhang, Y.; Xiu, Qingyu; Ma, Jun; Zhang, L.; You, Changxuan

doi:10.1093/annonc/mdv276

Cited by 409 publications

(296 citation statements)

References 18 publications

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“…Thus, the sequence of treatment and consideration of the molecular status of the tumor is of key importance. In the Phase III trials of first-generation EGFR TKIs, rates of subsequent therapy were generally high (around 60-70%) [17,18,20]. With regard to the second-generation EGFR TKIs, detailed analysis of the LUX-Lung 3, 6 and 7 trials showed that 71% of patients received a further line of treatment following discontinuation of afatinib, with 28% of patients receiving four lines of subsequent treatment [43].…”

Section: Factors Influencing First-line Treatment Choice: Mechanisms mentioning

confidence: 99%

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Girard

2018

Future Oncology

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Despite the efficacy of standard-of-care EGFR tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib and afatinib, in EGFR mutation-positive non-small-cell lung cancer, resistance develops, most commonly due to the T790M mutation. Osimertinib showed clinical activity in the treatment of T790M-positive disease following progression on a first-line TKI, and is approved in this setting. Recently, osimertinib improved efficacy versus first-generation TKIs (erlotinib and gefitinib) in the first-line setting. Multiple factors can influence first-line treatment decisions, including subsequent therapy options, presence of brain metastases and tolerability, all of which should be considered in the long-term treatment plan. Further research into treatment sequencing is also needed, to optimize outcomes in EGFR mutation-positive non-small-cell lung cancer.

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Section: Factors Influencing First-line Treatment Choice: Mechanisms mentioning

confidence: 99%

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Girard

2018

Future Oncology

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“…The anticancer platinum drugs are necessary to improve survival even for those lung cancer patients treated with molecularly-targeted therapy (19). It may be noteworthy to determine whether the expression of OCT6 in lung cancer tissues, and potentially hematopoietic cells where OCT6 is also expressed (20), is an important predictor of efficacy and chemotoxicity after anticancer platinum drug chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Organic cation transporter 6 directly confers resistance to anticancer platinum drugs

et al. 2016

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Abstract. Organic cation transporters (OCTs) of the solute carrier family 22 have a critical role in the cellular uptake of anticancer platinum drugs. Recently, we found that a decreased OCT6 expression is associated with a reduced intracellular uptake of cisplatin (CDDP), and concomitant resistance to CDDP. In the present study, we examined whether OCTs directly confer resistance to another platinum drug, oxaliplatin (L-OHP). To address this, we used parental lung cancer cell lines, PC-14 and SBC3; L-OHP-resistant sublines, PC-14/L-OHP and SBC3/L-OHP; and one CDDP-resistant subline PC-14/CDDP, to examine the relationships between the expression of OCTs and intracellular platinum drug concentration or platinum drug resistance. The two L-OHP-resistant sublines showed cross resistance to CDDP and L-OHP, and a decreased expression of OCT6. The intracellular accumulation of L-OHP in PC-14/L-OHP cells was reduced compared with the parental cells. The findings suggested that a reduced OCT6 expression confers platinum drug resistance in the sublines by decreasing the uptake of platinum drugs. Using the PC-14/CDDP cell line engineered to overexpress OCT6, we confirmed that the intracellular L-OHP concentration was increased concomitantly with OCT6 overexpression compared with the parental cell line. Additionally, OCT6 was expressed in a screening panel of lung and colon cancer tissues and matched normal control tissues. Taken together with the previous results, the present findings indicate that OCT6 is directly involved in platinum drug resistance by mediating platinum drug uptake in cancer cells.

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“…Recently there has been a change in the management strategies of NSCLC, possibly due to implications from a number of large-scale clinical trials indicating that platinum-based chemotherapy has reached a therapeutic plateau (2,3). Due to improving detection methods, NSCLC may be sub-classified by oncogenic mutations (4) and thus novel gene-targeting therapies may improve the prognosis of patients with NSCLC (5).…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Wan

Yuan

Pan

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). However, their clinical efficacy is limited by acquired resistance. Drug resistance may be mediated by EGFR transduction, and a number of clinical trials have demonstrated that high-dose pulsatile TKIs may be effective at treating patients with acquired resistance, though their underlying mechanisms of action remain unknown. The aim of the present study was to investigate the antitumor activity of high-dose pulsatile gefitinib in NSCLC model cell lines, namely the EGFR-TKI-sensitive cell line PC9, as a control group, and the EGFR-TKI-resistant cell lines H1975 and H1650. The cell lines were administered with different doses of gefitinib and cell viability was measured using an MTT assay. Cell apoptosis and cycling were also determined by flow cytometry and the expression of phospho (p)-EGFR, EGFR, p-AKT and AKT were measured by western blot analysis. It was observed that the apoptotic rate of H1975 cells treated with high-dose pulsatile gefitinib significantly increased, while levels of p-EGFR and p-AKT were decreased. However, there was no significant difference in the apoptotic rate or level of p-AKT in gefitinib-treated H1650 cells, while p-EGFR levels decreased. By contrast, the EGFR-TKI-sensitive cell line PC9 exhibited sensitivity to gefitinib. It was demonstrated that the apoptosis rates were markedly increased when treated with high dose pulsatile gefitinib in PC9 cell line, while a decrease was noted in p-EGFR and p-AKT. These data suggest that high-dose pulsatile gefitinib treatment may overcome acquired resistance in NSCLC, though its efficacy is dependent on the type of drug resistance mutation(s) present. Furthermore, high-dose pulsatile gefitinib may inhibit tumor growth and induce cell apoptosis by blocking the EGFR signaling pathway. Therefore, if the signaling pathways involved in drug resistance are not activated by the EGFR gene, high-dose pulsatile gefitinib may have little efficacy in the treatment of NSCLC.

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Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802)

Abstract: NCT00874419.

Cited by 409 publications

References 18 publications

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Organic cation transporter 6 directly confers resistance to anticancer platinum drugs

Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors

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