Gefitinib

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].

Effects

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].