Cancer Res Treat.  2019 Apr;51(2):718-726. 10.4143/crt.2018.324.

A Randomized, Open-Label, Phase II Study Comparing Pemetrexed Plus Cisplatin Followed by Maintenance Pemetrexed versus Pemetrexed Alone in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer after Failure of First-Line EGFR Tyrosine Kinase Inhibitor: KCSG-LU12-13

Affiliations
  • 1Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. silkahn@skku.edu
  • 2Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
  • 3Division of Hematology-Oncology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.
  • 4Division of Medical Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
  • 5Department of Hematology/Oncology, Keimyung Unversity Dongsan Hospital, Daegu, Korea.
  • 6Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.
  • 7Division of Hematology and Oncology, Department of Internal Medicine, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea.
  • 8Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
  • 9Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang Institute of Health Sciences, Gyeongsang National University College of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Korea.
  • 10Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.
  • 11Division of Hematology and Oncology, Department of Internal Medicine, National Medical Center, Seoul, Korea.
  • 12Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
  • 13Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
  • 14Division of Medical Oncology and Hematology, Department of Internal Medicine, Kyunghee University Hospital, Seoul, Korea.
  • 15Division of Hematology and Oncology, Department of Internal Medicine, Inje University Paik Hospital, Busan, Korea.
  • 16Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.

Abstract

PURPOSE
The optimal cytotoxic regimens have not been established for patients with non-small cell lung cancer (NSCLC) who develop disease progression on first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).
MATERIALS AND METHODS
We conducted a multi-center randomized phase II trial to compare the clinical outcomes between pemetrexed plus cisplatin combination therapy followed by maintenance pemetrexed (PC) and pemetrexed monotherapy (P) after failure of first-line EGFR-TKI. The primary objective was progression-free survival (PFS), and secondary objectives included overall response rate (ORR), overall survival (OS), health-related quality of life (HRQOL), and safety and toxicity profiles.
RESULTS
A total of 96 patientswere randomized, and 91 patientswere treated at 14 centers in Korea. The ORR was 34.8% (16/46) for the PC arm and 17.8% (8/45) for the P arm (p=0.066). With 23.4 months of follow-up, the median PFS was 5.4 months in the PC arm and 6.4 months in the P arm (p=0.114). The median OS was 17.9 months and 15.7 months in PC and P arms, respectively (p=0.787). Adverse events ≥ grade 3 were reported in 12 patients (26.1%) in the PC arm and nine patients (20.0%) in the P arm (p=0.491). The overall time trends of HRQOL were not significantly different between the two arms.
CONCLUSION
The outcomes of pemetrexed therapy in NSCLC patients with disease progression after firstline EGFR-TKI might not be improved by adding cisplatin.

Keyword

Non-small cell lung carcinoma; Epidermal growth factor receptor; Mutation; Pemetrexed; Cisplatin; Quality of life

MeSH Terms

Arm
Carcinoma, Non-Small-Cell Lung
Cisplatin*
Disease Progression
Disease-Free Survival
Epidermal Growth Factor*
Follow-Up Studies
Humans
Korea
Lung Neoplasms*
Lung*
Pemetrexed*
Protein-Tyrosine Kinases*
Quality of Life
Receptor, Epidermal Growth Factor*
Tyrosine*
Cisplatin
Epidermal Growth Factor
Pemetrexed
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Tyrosine

Figure

  • Fig. 1. Patient flow of this study. PC, pemetrexed plus cisplatin combination followed by maintenance pemetrexed; P, pemetrexed only; HRQOL, health-related quality of life.

  • Fig. 2. Kaplan-Meier survival curves of progression-free survival (PFS) (A) and overall survival (OS) (B). PC, pemetrexed plus cisplatin combination followed by maintenance pemetrexed; P, pemetrexed only; CI, confidence interval.

  • Fig. 3. Health-related quality of life (HRQOL) assessed by EORTC QLQ-C30. PC, pemetrexed plus cisplatin combination followed by maintenance pemetrexed; P, pemetrexed only; CI, confidence interval.


Reference

References

1. Zhou W, Christiani DC. East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians. Chin J Cancer. 2011; 30:287–92.
Article
2. Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and metaanalysis. Oncotarget. 2016; 7:78985–93.
Article
3. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–57.
Article
4. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12:735–42.
Article
5. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31:3327–34.
Article
6. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. 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.
Article
7. Onitsuka T, Uramoto H, Nose N, Takenoyama M, Hanagiri T, Sugio K, et al. Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Lung Cancer. 2010; 68:198–203.
Article
8. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013; 31:3987–96.
Article
9. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015; 16:990–8.
Article
10. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017; 376:629–40.
Article
11. D'Addario G, Rauch D, Stupp R, Pless M, Stahel R, Mach N, et al. Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03. Ann Oncol. 2008; 19:739–45.
12. Wu JY, Shih JY, Yang CH, Chen KY, Ho CC, Yu CJ, et al. Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer. Int J Cancer. 2010; 126:247–55.
Article
13. Lee SJ, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. Pemetrexed plus platinum versus pemetrexed alone in non-small cell lung cancer patients who have progressed after first-line EGFR TKIs. Lung Cancer. 2015; 90:261–6.
Article
14. Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013; 31:2895–902.
Article
15. Sun JM, Ahn JS, Jung SH, Sun J, Ha SY, Han J, et al. 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. 2015; 33:2450–6.
Article
16. Park S, Keam B, Kim SH, Kim KH, Kim YJ, Kim JS, et al. Pemetrexed singlet versus nonpemetrexed-based platinum doublet as second-line chemotherapy after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor failure in nonsmall cell lung cancer patients with EGFR mutations. Cancer Res Treat. 2015; 47:630–7.
17. Tseng YH, Hung HY, Sung YC, Tseng YC, Lee YC, Whang-Peng J, et al. Efficacy of chemotherapy in epidermal growth factor receptor (EGFR) mutated metastatic pulmonary adenocarcinoma patients who had acquired resistance to first-line EGFR tyrosine kinase inhibitor (TKI). J Chemother. 2016; 28:50–8.
Article
18. Yang CJ, Tsai MJ, Hung JY, Liu TC, Chou SH, Lee JY, et al. Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment. Onco Targets Ther. 2016; 9:1579–87.
Article
19. Sun JM, Han J, Ahn JS, Park K, Ahn MJ. Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol. 2011; 6:1392–9.
Article
20. Nicolson MC, Fennell DA, Ferry D, O'Byrne K, Shah R, Potter V, et al. Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial. J Thorac Oncol. 2013; 8:930–9.
Article
21. Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. 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; 17:1616–22.
Article
22. Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptortyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013; 119:4325–32.
23. Li W, Ren S, Li J, Li A, Fan L, Li X, et al. T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 2014; 84:295–300.
Article
24. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, non-small cell lung cancer (version 3.2017) [Internet]. Plymouth Meeting, PA: National Comprehensive Cancer Network;c2016. [cited 2016 Nov 16]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
25. Khozin S, Weinstock C, Blumenthal GM, Cheng J, He K, Zhuang L, et al. Osimertinib for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer. Clin Cancer Res. 2017; 23:2131–5.
Article
26. Kim ES. Olmutinib: first global approval. Drugs. 2016; 76:1153–7.
Article
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