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Classification: C!

Drug products: Gefitinib Accord, Gefitinib Avansor, Gefitinib Glenmark, Gefitinib Orion, Gefitinib STADA, IRESSA

ATC code: L01EB01

Substances: gefitinib


Female sex is correlated with better response to gefitinib treatment of patients with advanced non-small cell lung cancer (NSCLC). Among NSCLC patients receive gefitinib treatment, women achieve more prolongation of progression free survival (PFS) and overall survival (OS) than men. Even in the maintenance setting of gefitinib therapy of NSCLC-patients prolongation of PFS is observed more significantly for women. In general, female sex and younger age are associated with a better prognosis for NSCLC.

Additional information

Women harbor EGFR mutations at a higher frequency than men, which has therapeutic implications [1].Generally, women mount stronger innate and adaptive immune responses than men [2]. Women with lung cancer have a more favorable survival compared to men [1]. The 5-year survival is 17 percent among men, and 24 percent among women, in Sweden [3].The incidence of lung cancer has decreased among men since from1980s but has increased significantly among women, which reflects women's changing smoking habits. Now the proportion of smoking women is greater than the proportion of smoking men. In Sweden lung cancer made up 6.1% of all yearly cases of cancer, year 2016. The incidence was higher among women (6.8%, n=2067), compared to men (5.4% , n=1824) [3].

Pharmacokinetics and dosing

Based on population pharmacokinetic data from cancer patients, there are no sex differences in trough concentration at steady state [4]. Women on average display higher expression and activity of CYP3A4. Sex-related differences in exposure could be of relevance for several substrates of the CYP3A family [1].


Clinical characteristics of never smoker, adenocarcinoma histology, and female sex have been shown to be independent predictors of positive EGFR mutation status in a multivariate analysis of 786 Caucasian patients from gefitinib studies [4].

A multicenter, randomized, double-blind, parallel-group phase II trial (IDEAL 1) evaluated the efficacy and safety of daily oral doses of 250 and 500 mg of gefitinib in patients (148 men,62 women ) with locally advanced or metastatic NSCLC who had previously received either one, or a maximum of two, chemotherapy regimens (≥one platinum-based regimen). The odds of responding (an Objective Response According to a Multivariate Analysis) was over 2.5 times higher for women than men [5].

INTEREST was a randomized phase III non-inferiority study of gefitinib versus docetaxel in previously treated (≥one platinum-based regimen) non-small-cell lung cancer (954 men, 512 women). Subgroup analysis of data showed longer OS for women compared to men with both gefitinib (11.2 vs 6.1 months) and docetaxel (10 vs 7 months). [6].

A placebo-controlled phase III study (IRESSA Survival Evaluation in Lung cancer [ISEL]) evaluated either gefitinib (250 mg/day) or placebo plus best supportive care in patients with advanced NSCLC who were refractory to or intolerant of their most recent chemotherapy regimen (1139 men, 553 women). The objective-response rate was higher in the gefitinib group than in the placebo group. Exploratory subgroup analyses showed a higher objective-response rate for gefitinib than for placebo in women than men (14.7 vs 5.1) [7].

A non-interventional study (REASON) analyzed data obtained from EGFR-positive NSCLC patients (n= 559; 285 first line therapy, 274 any line) treated either with chemotherapy or gefitinib. Analysis performed according to age, patient's sex, smoking history and histology. Female sex was an independent positive predictive factor for OS in patients treated with gefitinib (HR male: 1.74) [8].

Two parallel phase III, randomized, placebo-controlled, double-blind trials (INTACT 1&2) evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC (805 men,288 women; 619 men,418 women). A favorable gefitinib safety profile observed in INTACT 2, but gefitinib showed no added benefit in survival, time to progression or response rate compared with standard chemotherapy alone. No survival differences were seen between men and women for either treatments [9, 10]. 

A meta-analysis performed 2012 included five phase III randomized trials of maintenance therapy with gefitinib or erlotinib in patients with advanced NSCLC (n = 2436). The results showed that maintenance therapy with these agents produces a significant PFS and OS benefit compared with placebo or observation. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit [11]. Two of the studies (INFORM (175 men,125 women) and EORTC 08021/ILCP 01/03 (133 men, 40 women) used gefitinib (250 mg/qd). The analysis of PFS in subgroups indicated a HR of 0.34 for women, and 0.49 for men in the INFORM study [12]. The HR for women compared to men in EORTC 08021/ILCP 01/03 trial was 0.63and 0.75, respectively [13].

Adverse effects

The toxicity associated with gefitinib and other EGFR TKIs maintenance was generally low and well tolerated [11]. No sex difference in onset or severity of side effects has been reported.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Clinical characteristics of female sex, never smoker, and adenocarcinoma histology have been shown to be independent predictors of positive EGFR mutation status. The prevalence of EGFR mutation in women is 1.7 times higher than men [4].

Updated: 2021-01-02

Date of litterature search: 2020-06-04


  1. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
  2. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. PubMed
  3. Socialstyrelsen. Cancer i siffror 2018. Socialstyrelsen [www]. [updated 2018-06-10, cited 2020-10-01]. länk
  4. IRESSA (gefitinib). Summary of Product Characteristics. European Medicines Agency (EMA) [updated 2019-02-22, cited 2020-06-04]
  5. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21(12):2237-46. PubMed
  6. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652):1809-18. PubMed
  7. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527-37. PubMed
  8. Schuette W, Eberhardt WE, Waller C, Schirmacher P, Dietel M, Zirrgiebel U et al. [Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy]. Pneumologie. 2016;70(9):579-88. PubMed
  9. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004;22(5):777-84. PubMed
  10. 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(5):785-94. PubMed
  11. Chen X, Liu Y, Røe OD, Qian Y, Guo R, Zhu L et al. Gefitinib or erlotinib as maintenance therapy in patients with advanced stage non-small cell lung cancer: a systematic review. PLoS One. 2013;8(3):e59314. PubMed
  12. Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, Yang S, Liu X, Liu Y, Lu S, Wang J, Zhang S, Zhou C, Zhang X, Hayashi N, Wang M; INFORM investigators. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol. 2012;13(5):466-75. PubMed
  13. Gaafar RM, Surmont VF, Scagliotti GV, Van Klaveren RJ, Papamichael D, Welch JJ et al. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer. 2011;47(15):2331-40. PubMed
  14. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk

Authors: Alan Fotoohi

Reviewed by: Diana Rydberg, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson