In short Read article


State of affairs after 12 years of experience

Erlotinib (Tarceva®) was the first EGFR tyrokinase inhibitor to be authorized for the treatment of non-small-cell lung carcinoma (NSCLC). It enabled outpatient treatment, and has a more favourable adverse effects profile than the existing chemotherapy. The authorisation of erlotinib has meanwhile been specified to patients with NSCLC who have a mutation in the gene for epidermal growth factor receptor (EGFR). 

New developments regarding the treatment of NSCLC include the second- and third-generation EGFR tyrosine kinase inhibitors. Of these, osimertinib in particular appears to offer a better prognosis for progression-free survival. Dual blockage of EGFR and vascular EGFR using a combination of ramucirumab and erlotinib appears to extend the progression-free survival period further than erlotinib as monotherapy. A second extension of the indication for erlotinib concerns the treatment of pancreatic carcinoma, but adding erlotinib to gemcitabine on average adds only one month to the total survival of these patients, and has more adverse effects. 

  • Compared to chemotherapy, erlotinib extends the progression-free survival of patients with non-small-cell lung carcinoma who have an EGFR-activating mutation (which occurs in 10% of the Dutch population), but not the total survival. 
  • For patients with non-small-cell lung carcinoma stage IIIb of IV who have an EGFR-activating mutation, combining osimertinib or possibly ramucirumab with erlotinib is to be preferred over erlotinib as monotherapy. 
  • In the treatment of pancreatic cancer, adding erlotinib to gemcitabine offers no added value, and hence has no place in the therapy.
  • Adverse effects of erlotinib are generally not serious, the most common being skin rashes. The latter may also predict a response.

  1. Wetenschappelijke discussie en IB-tekst erlotinib (Tarceva®). Available from: Accessed 15-11-2020.
  2. Croockewit AJ. Erlotinib (Tarceva®), tweedelijnsbehandeling van niet-kleincellig longcarcinoom. Gebu. 2008;42(3):27-28.
  3. Grimsky A, Shah KS, McKibbin T. Chapter 17: Monoclonal antibodies in cancer. P. 349-352. In: Crommelin DJA, Sindelar RD, Meibohm B. Pharmaceutical Biotechnology. Fundamentals and Applications. 4th ed. New York: Springer Science & Business Media, 2013.
  4. 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 meta-analysis. Oncotarget. 2016 Nov 29;7(48):78985-78993. doi: 10.18632/oncotarget.12587.
  5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. doi: 10.1056/NEJMoa050753.
  6. Zhong WZ, Chen KN, Chen C, Gu CD, Wang J, Yang XN, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol. 2019 Sep 1;37(25):2235-2245. doi: 10.1200/JCO.19.00075.
  7. Schaake EE, Kappers I, Codrington HE, Valdés Olmos RA, Teertstra HJ, van Pel R, et al. Tumor response and toxicity of neoadjuvant erlotinib in patients with early-stage non-small-cell lung cancer. J Clin Oncol. 2012 Aug 1;30(22):2731-8. doi: 10.1200/JCO.2011.39.4882.
  8. Dahabreh IJ, Linardou H, Kosmidis P, Bafaloukos D, Murray S. EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol. 2011 Mar;22(3):545-552. doi: 10.1093/annonc/mdq432. Erratum in: Ann Oncol. 2011 Jul;22(7):1693. Erratum in: Ann Oncol. 2011 Sep;22(9):2155.
  9. Greenhalgh J, Dwan K, Boland A, Bates V, Vecchio F, Dundar Y, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 2016 May 25;(5):CD010383. doi: 10.1002/14651858.CD010383.pub2.
  10. Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, et al. TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. doi: 10.1016/S1470-2045(13)70310-3.
  11. Pan Q, Pao W, Ladanyi M. Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J Mol Diagn. 2005 Aug;7(3):396-403. doi: 10.1016/S1525-1578(10)60569-7.
  12. Murray S, Dahabreh IJ, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P. Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol. 2008 Aug;3(8):832-9. doi: 10.1097/JTO.0b013e31818071f3.
  13. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. doi: 10.1016/S1470-2045(11)70184-X.
  14. Hochmair M. Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease. Target Oncol. 2018 Jun;13(3):269-285. doi: 10.1007/s11523-018-0566-1. Erratum in: Target Oncol. 2018 Oct;13(5):667.
  15. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. doi: 10.1016/S1470-2045(11)70393-X.
  16. Zhao Y, Liu J, Cai X, Pan Z, Liu J, Yin W, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ. 2019 Oct 7;367:l5460. doi: 10.1136/bmj.l5460.
  17. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137.
  18. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. doi: 10.1056/NEJMoa1913662.
  19. Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, et al. RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5.
  20. Chen F, Chen N, Yu Y, Cui J. Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR) Inhibitors Plus Antiangiogenic Agents as First-Line Treatments for Patients With Advanced EGFR-Mutated Non-small Cell Lung Cancer: A Meta-Analysis. Front Oncol. 2020 Jun 25;10:904. doi: 10.3389/fonc.2020.00904.
  21. Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2006 Aug 20;24(24):3831-7. doi: 10.1200/JCO.2006.05.8073. Erratum in: J Clin Oncol. 2007 Jan 1;25(1):167.
  22. Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol. 2013 Jun;24(6):1615-22. doi: 10.1093/annonc/mdt012.
  23. Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, et al. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advanced non-small-cell lung cancer. J Thorac Oncol. 2012 Dec;7(12):1830-1844. doi: 10.1097/JTO.0b013e318275b327.
  24. Leight NB, Karaseva N, Nakagawa K, et al. Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFRmutated advanced non-small-cell lung cancer. European Journal of Cancer 2020; 125: 49e57
  25. Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NALT). Richtlijn Niet-kleincellig longcarcinoom. Januari 2020. Available from: Accessed 15-11-2020
  26. NVMO-commissie ter Beoordeling van Oncologische Middelen (BOM). Ramucirumab en erlotinib bij niet-kleincellig longcarcinoom met een EGFR-mutatie. Med Oncol 2020;23(2):29-32.
  27. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966. doi:10.1200/JCO.2006.07.9525.
  28. Nederlandse Vereniging voor Heelkunde. Richtlijn Pancreascarcinoom. Juni 2019. Available from: Accessed 15-11-2020
  29. Salazar R, Capellà G, Tabernero J. Paracrine network: another step in the complexity of resistance to EGFR blockade? Clin Cancer Res. 2014 Dec 15;20(24):6227-9. doi: 10.1158/1078-0432.CCR-14-1615.
  30. Kaveh S, Ebrahimi P, Rezapour A, Mozafari M, Sayehmiri K. Bevacizumab and erlotinib versus bevacizumab for colorectal cancer treatment: systematic review and meta-analysis. Int J Clin Pharm. 2019 Feb;41(1):30-41. doi: 10.1007/s11096-018-0754-1.
  31. Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mésange P, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1493-1505. doi: 10.1016/S1470-2045(15)00216-8. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589.
  32. Johnsson A, Hagman H, Frödin JE, Berglund A, Keldsen N, Fernebro E, et al. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013 Sep;24(9):2335-41. doi: 10.1093/annonc/mdt236.
  33. Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, et al. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016 Jan;27(1):140-7. doi: 10.1093/annonc/mdv490.
  34. Nederlandse Vereniging voor Heelkunde. Richtlijn Colorectaal carcinoom. Oktober 2019. Available from: Accessed 15-11-2020
  35. Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. doi: 10.1158/1078-0432.CCR-16-0399.
  36. von Pawel J, Wagner H, Duell T, Poellinger B. Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: two case reports. Onkologie. 2008;31(3):123-126. doi:10.1159/000113928
  37. Luu M, Lai SE, Patel J, Guitart J, Lacouture ME. Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed. 2007 Feb;23(1):42-5. doi: 10.1111/j.1600-0781.2007.00273.x.
  38. Tjin-A-ton ML, van Montfrans C, Koldenhof JJ, Sigurdsson V, Voest EE, Witteveen PO. Huidafwijkingen als bijwerking van remmers van epidermale-groeifactorreceptor [Skin eruptions as an adverse reaction to epidermal growth-factor receptor inhibitors]. Ned Tijdschr Geneeskd. 2007 Apr 28;151(17):945-52. 
  39. Kozuki T. Skin problems and EGFR-tyrosine kinase inhibitor. Jpn J Clin Oncol. 2016 Apr;46(4):291-8. doi: 10.1093/jjco/hyv207.
  40. ter Heine R, van den Bosch RT, Schaefer-Prokop CM, Lankheet NA, Beijnen JH, Staaks GH, et al. Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature. Lung Cancer. 2012 Mar;75(3):391-7. doi: 10.1016/j.lungcan.2011.10.008.
  41. Hotta K, Kiura K, Takigawa N, Yoshioka H, Harita S, Kuyama S, et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol. 2010 Feb;5(2):179-84. doi: 10.1097/JTO.0b013e3181ca12e0.
  42. Wnorowski AM, de Souza A, Chachoua A, Cohen DE. The management of EGFR inhibitor adverse events: a case series and treatment paradigm. Int J Dermatol. 2012 Feb;51(2):223-32. doi: 10.1111/j.1365-4632.2011.05082.x.
  43. Liu HB, Wu Y, Lv TF, Yao YW, Xiao YY, Yuan DM, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2013;8(1):e55128. doi: 10.1371/journal.pone.0055128.
  44. van Leeuwen RW, Peric R, Hussaarts KG, Kienhuis E, IJzerman NS, de Bruijn P, et al. Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Apr 20;34(12):1309-14. doi: 10.1200/JCO.2015.65.2560. Erratum in: J Clin Oncol. 2016 Aug 10;34(23):2806.
  45. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007 Sep 15;64(18):1917-21. doi: 10.2146/ajhp060414.
  46. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. doi: 10.1158/1078-0432.CCR-05-2235.
  47. Ren JH, He WS, Yan GL, Jin M, Yang KY, Wu G. EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. Environ Mol Mutagen. 2012 Jan;53(1):78-82. doi: 10.1002/em.20680.
  48. Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, et al. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2006 Aug;80(2):136-45. doi: 10.1016/j.clpt.2006.04.007.
  49. Smit EF, Wu YL, Gervais R, Zhou C, Felip E, Feng J, et al. A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS). Lung Cancer. 2016 Sep;99:94-101. doi: 10.1016/j.lungcan.2016.06.019.
  50. Ferketich AK, Niland JC, Mamet R, Zornosa C, D'Amico TA, Ettinger DS, et al. Smoking status and survival in the national comprehensive cancer network non-small cell lung cancer cohort. Cancer. 2013 Feb 15;119(4):847-53. doi: 10.1002/cncr.27824.
  51. Jotte RM, Spigel DR. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance. Cancer Med. 2015 Nov;4(11):1621-32. doi: 10.1002/cam4.506.
  52. Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014 Sep;23(133):356-66. doi: 10.1183/09059180.00004614.
  53. Morgillo F, Bareschino MA, Bianco R, Tortora G, Ciardiello F. Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy. Differentiation. 2007 Nov;75(9):788-99. doi: 10.1111/j.1432-0436.2007.00200.x.
  54. Dong JK, Lei HM, Liang Q, Tang YB, Zhou Y, Wang Y, et al. Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase. Theranostics. 2018 Feb 12;8(7):1808-1823. doi: 10.7150/thno.23177. Erratum in: Theranostics. 2021 Feb 9;11(8):3963.


  • Juul M. Cox
  • Lisanne L. Krens, dr, pharmacist