Sciendo Logo
  1. bookVolume 48 (2014): Issue 4 (December 2014)
Radiology and Oncology's Cover Image
Radiology and Oncology
Journal Details
License
Format
Journal
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
access type Open Access

Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations

Matjaz Zwitter
Karmen Stanic
Mirjana Rajer
Izidor Kern
Martina Vrankar
Natalija Edelbaher
Viljem Kovac
Published Online: 05 Nov 2014
Page range: 361 - 368
Received: 25 Aug 2014
Accepted: 08 Sep 2014
Journal Details
License
Format
Journal
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
Abstract

Background. Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC).

Patients and methods. Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance.

Results. Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2-3 (11 patients - 21%) and brain metastases (15 patients - 28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months.

Conclusions. While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations

Keywords

  • Non-small cell lung cancer
  • EGFR activating mutations
  • gemcitabine
  • cisplatin
  • erlotinib
  • intercalated therapy
  • metabolic response

1. 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: 947-57.10.1056/NEJMoa0810699Search in Google Scholar

2. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958-67.10.1056/NEJMoa0904554Search in Google Scholar

3. Sequist LV, Yang JC-H, 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: 3327-34.10.1200/JCO.2012.44.2806Search in Google Scholar

4. Ratti M, Tomasello G. Emerging combination therapies to overcome resistance in EGFR-driven tumors. Anti-Cancer Drugs 2014; 25: 127-39.10.1097/CAD.0000000000000035Search in Google Scholar

5. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced nonsmall- cell lung cancer: a phase III trial - INTACT 1. J Clin Oncol 2004; 22: 777-84.10.1200/JCO.2004.08.001Search in Google Scholar

6. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 2. J Clin Oncol 2004; 22: 785-94.10.1200/JCO.2004.07.215Search in Google Scholar

7. Herbst RS, Prager D, Herman R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 5892-9.10.1200/JCO.2005.02.840Search in Google Scholar

8. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 1545-52.10.1200/JCO.2005.05.1474Search in Google Scholar

9. Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out? J Clin Oncol 2005; 23: 5856-8.Search in Google Scholar

10. Reck M. Beyond the TRIBUTE trial: integrating HER1/EGFR tyrosine kinase inhibitors with chemotherapy in advanced NSCLC. Future Oncol 2006; 2: 47-51.10.2217/14796694.2.1.47Search in Google Scholar

11. Tsai CM, Chen JT, Chiu CH, Lai CL, Hsiao SY, Chang KT. Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib. Lung Cancer 2013; 82: 305-12.10.1016/j.lungcan.2013.08.028Search in Google Scholar

12. Mahaffey CM, Davies AM, Lara PN Jr, Pryde B, Holland W, Mack PC, et al. Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation. Clin Lung Cancer 2007; 8: 548-53.10.3816/CLC.2007.n.041Search in Google Scholar

13. Davies AM, Ho C, Lara PN Jr, Mack P, Gumerlock PH, Gandara DR. Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer 2006; 7: 385-8.10.3816/CLC.2006.n.021Search in Google Scholar

14. Zwitter M, Rajer M, Kovac V, Kern I, Vrankar M, Smrdel U. Intermittent chemotherapy and erlotinib for non-smokers or light smokers with advanced adenocarcinoma of the lung: A phase II clinical trial. J Biomed Biotechnol 2011; 2011: 185646.10.1155/2011/185646Search in Google Scholar

15. Ocvirk J, Heeger S, McCloud P, Hofheinz RD. A review of the treatment options for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis. Radiol Oncol 2013; 47: 166-75.10.2478/raon-2013-0014Search in Google Scholar

16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205-16.10.1093/jnci/92.3.205Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo