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International Journal of Clinical Oncology

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20-06-2022 | NSCLC | Original Article

Survival benefit of using pemetrexed for EGFR mutation-positive advanced non-small-cell lung cancer in a randomized phase III study comparing gefitinib to cisplatin plus docetaxel (WJTOG3405)

Authors: Naoki Haratake, Mototsugu Shimokawa, Takashi Seto, Hiroshige Yoshioka, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Tetsuya Mitsudomi

Published in: International Journal of Clinical Oncology | Issue 9/2022

Abstract

Background

Pemetrexed is common cytotoxic chemotherapy among non-squamous non-small cell lung cancer (non-Sq-NSCLC) patients; however, among epidermal growth factor receptor (EGFR)-positive lung cancer, there is no clear evidence to support the efficacy of sequential treatment with pemetrexed.

Material and methods

We performed a post-hoc analysis of subsequent chemotherapies among 144 patients who received the post-protocol treatment in the phase III trial WJTOG 3405 comparing gefitinib to cisplatin plus docetaxel, and analyzed the effect of pemetrexed on overall survival (OS).

Results

Patients with treatment including pemetrexed exhibited significantly longer OS in comparison to those without pemetrexed; the median OS in the pemetrexed + and pemetrexed– patients were 40.7 months and 28.0 months, respectively (0.55 of HR [95% CI: 0.38–0.80, p = 0.0020]). On the other hand, other treatments, including docetaxel, TS-1 and paclitaxel showed no significant impact on OS. The multivariate analysis with a time-dependent Cox proportional hazards model showed that treatment including pemetrexed, as well as PS 0 and post-operative recurrence, were independent predictors of a good prognosis. Moreover, among patients who received at least four lines of prior treatment, pemetrexed + treatment also significantly prolonged OS in comparison to pemetrexed– treatment (median OS pemetrexed + vs. pemetrexed–: 44.4 months vs. 32.6 months; HR: 0.55 [95% CI: 0.31–0.94, p = 0.0290]).

Conclusions

Sequential treatment including pemetrexed against EGFR-mutated NSCLC might be associated with a better outcome. It was considered that pemetrexed should be administered without fail as a sequential treatment to improve the prognosis of EGFR-mutated NSCLC as well as like EGFR-tyrosine kinase inhibitors.

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Mitsudomi T, Morita S, Yatabe Y et al (2010) 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 3 trial. Lancet Oncol 11(2):121–128. https://doi.org/10.1016/s1470-2045(09)70364-xCrossRefPubMed

Kris MG, Johnson BE, Berry LD et al (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311(19):1998–2006. https://doi.org/10.1001/jama.2014.3741CrossRefPubMedPubMedCentral

Recondo G, Facchinetti F, Olaussen KA et al (2018) Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol 15(11):694–708. https://doi.org/10.1038/s41571-018-0081-4CrossRefPubMed

Soria JC, Ohe Y, Vansteenkiste J et al (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2):113–125. https://doi.org/10.1056/NEJMoa1713137CrossRefPubMed

Ramalingam SS, Vansteenkiste J, Planchard D et al (2020) overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382(1):41–50. https://doi.org/10.1056/NEJMoa1913662CrossRefPubMed

Yoshioka H, Shimokawa M, Seto T et al (2019) Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. Ann Oncol 30(12):1978–1984. https://doi.org/10.1093/annonc/mdz399CrossRefPubMed

Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551. https://doi.org/10.1200/JCO.2007.15.0375CrossRefPubMed

Scagliotti G, Brodowicz T, Shepherd FA et al (2011) Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 6(1):64–70. https://doi.org/10.1097/JTO.0b013e3181f7c6d4CrossRefPubMed

Scagliotti GV, Gridelli C, de Marinis F et al (2014) Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: a cross-trial comparison of two phase III trials. Lung Cancer 85(3):408–414. https://doi.org/10.1016/j.lungcan.2014.07.005CrossRefPubMed

10.

Paz-Ares L, de Marinis F, Dediu M et al (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13(3):247–255. https://doi.org/10.1016/S1470-2045(12)70063-3CrossRefPubMed

11.

Zhou C, Wu YL, Chen G et al (2015) 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). Ann Oncol 26(9):1877–1883. https://doi.org/10.1093/annonc/mdv276CrossRefPubMed

12.

Inoue A, Kobayashi K, Maemondo M et al (2013) Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 24(1):54–59. https://doi.org/10.1093/annonc/mds214CrossRefPubMed

13.

Yang JC, Kang JH, Mok T et al (2014) First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer 50(13):2219–2230. https://doi.org/10.1016/j.ejca.2014.05.011CrossRefPubMed

14.

Yang JC, Srimuninnimit V, Ahn MJ et al (2016) First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol 11(3):370–379. https://doi.org/10.1016/j.jtho.2015.11.008CrossRefPubMed

15.

Sun JM, Ahn JS, Jung SH et al (2015) Pemetrexed plus cisplatin versus gemcitabine plus cisplatin according to thymidylate synthase expression in nonsquamous non-small-cell lung cancer: a biomarker-stratified randomized phase II trial. J Clin Oncol 33(22):2450–2456. https://doi.org/10.1200/JCO.2014.59.9324CrossRefPubMed

16.

Christoph DC, Asuncion BR, Hassan B et al (2013) Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed. J Thorac Oncol 8(1):19–30. https://doi.org/10.1097/JTO.0b013e31827628ffCrossRefPubMedPubMedCentral

17.

Wang L, Wang R, Pan Y et al (2014) The pemetrexed-containing treatments in the non-small cell lung cancer is -/low thymidylate synthase expression better than +/high thymidylate synthase expression: a meta-analysis. BMC Cancer 14:205. https://doi.org/10.1186/1471-2407-14-205CrossRefPubMedPubMedCentral

18.

Yoon JY, Park CK, Choi YD et al (2019) Predictive factors for long-term responders of pemetrexed maintenance treatment in non-small cell lung cancer. Thorac Cancer 10(4):942–949. https://doi.org/10.1111/1759-7714.13033CrossRefPubMedPubMedCentral

19.

Yang JC, Mok T, Han B et al (2018) A review of regimens combining pemetrexed with an epidermal growth factor receptor tyrosine kinase inhibitor in the treatment of advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer 19(1):27–34. https://doi.org/10.1016/j.cllc.2017.06.013CrossRefPubMed

20.

Ren S, Chen X, Kuang P et al (2012) Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. Cancer 118(22):5588–5594. https://doi.org/10.1002/cncr.27603CrossRefPubMed

21.

Okabe T, Okamoto I, Tsukioka S et al (2008) Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase. Mol Cancer Ther 7(3):599–606. https://doi.org/10.1158/1535-7163.MCT-07-0567CrossRefPubMed

22.

Yang JC, Cheng Y, Murakami H et al (2020) A randomized phase 2 study of gefitinib with or without pemetrexed as first-line treatment in nonsquamous NSCLC with EGFR mutation: final overall survival and biomarker analysis. J Thorac Oncol 15(1):91–100. https://doi.org/10.1016/j.jtho.2019.09.008CrossRefPubMed

23.

Schilsky JB, Ni A, Ahn L et al (2017) Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas. Lung Cancer 108:205–211. https://doi.org/10.1016/j.lungcan.2017.03.015CrossRefPubMed

24.

Sheffield BS, Bosdet IE, Ali RH et al (2014) Relationship of thyroid transcription factor 1 to EGFR status in non-small-cell lung cancer. Curr Oncol 21(6):305–308. https://doi.org/10.3747/co.21.2148CrossRefPubMedPubMedCentral

25.

Shanzhi W, Yiping H, Ling H et al (2014) The relationship between TTF-1 expression and EGFR mutations in lung adenocarcinomas. PLoS ONE 9(4):e95479. https://doi.org/10.1371/journal.pone.0095479CrossRefPubMedPubMedCentral

26.

Kenmotsu H, Yamamoto N, Yamanaka T et al (2020) Randomized phase III study of pemetrexed plus cisplatin versus vinorelbine plus cisplatin for completely resected stage II to IIIA nonsquamous non–small-cell lung cancer. J Clin Oncol 38(19):2187–2196. https://doi.org/10.1200/JCO.19.02674CrossRefPubMed

27.

Nokihara H, Lu S, Mok TSK et al (2017) Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 trial in lung cancer). Ann Oncol 28(11):2698–2706. https://doi.org/10.1093/annonc/mdx419CrossRefPubMedPubMedCentral

28.

Hosomi Y, Morita S, Sugawara S et al (2020) Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol 38(2):115–123. https://doi.org/10.1200/JCO.19.01488CrossRefPubMed

Title: Survival benefit of using pemetrexed for EGFR mutation-positive advanced non-small-cell lung cancer in a randomized phase III study comparing gefitinib to cisplatin plus docetaxel (WJTOG3405)
Authors: Naoki Haratake
Mototsugu Shimokawa
Takashi Seto
Hiroshige Yoshioka
Nobuyuki Yamamoto
Kazuhiko Nakagawa
Tetsuya Mitsudomi
Publication date: 20-06-2022
Publisher: Springer Nature Singapore
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
Lung Cancer
Gefitinib
Published in: International Journal of Clinical Oncology / Issue 9/2022
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-022-02193-x

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