 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Journal of Cancer Research and Therapeutics, Vol. 6, No. 3, July-September, 2010, pp. 249-254 Review Article Geftinib Ajay Gupta, Vinod Raina Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India Correspondence Address:Ajay Gupta, P-41, South Extension-2, New Delhi - 110 049, India ajayajaygupta2002@rediffmail.com Code Number: cr10058 PMID: 21119248 DOI: 10.4103/0973-1482.73330 Abstract Gefitinib is an orally active, highly selective, reversible inhibitor of the tyrosine kinase domain associated with the epidermal growth factor receptor (EGFR). EGFR gene mutations, never smoking status, Asian origin and adenocarcinoma histology are associated with good clinical responses to geftinib. Geftinib has generally been tried in the setting of chemotherapy refractory disease in patients who have failed at least one line of therapy. Trials are exploring use of geftinib as first line therapy in patients harboring EGFR mutations and also in the elderly. The most exciting feature of geftinib use is its potential for Lazarus responses in patients with poor performance status. Its use is associated with little toxicity. The success of geftinib suggests that it is important to understand the basic mechanisms underlying lung cancer in order to evolve better therapies. The review has been prepared after conducting extensive PubMed and Medline search for related articles.Keywords: Geftinib, lung cancer, tyrosine kinase inhibitor Introduction Gefitinib is an orally active, highly selective, reversible inhibitor of the tyrosine kinase domain associated with the epidermal growth factor receptor (EGFR). It is a low-molecular-weight (447-dalton) synthetic anilinoquinazoline [4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline]. [1],[2] It is particularly efficacious in patients harboring EGFR mutations - the mutation status and consequently sensitivity to the drug correlates strongly with favorable clinical parameters including non smoker status, female sex, East Asian ethnic background and adenocarcinoma (especially bronchioloalveolar histology). The most exciting feature is its potential for dramatic clinical (Lazarus) responses in patients with poor performance status. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11] The review has been prepared after conducting extensive Pubmed and Medline search for all related articles. Mechanism of Action It inhibits the intracellular phosphorylation and signaling of EGFR-tyrosine kinase through competitive binding of the ATP-binding domain of the receptor. It acts at the G0/G1 boundary of the cell cycle. Up-regulation of p27 and p21 cyclin-dependent kinase inhibitors results in inhibition of cell proliferation, metastasis and invasion. Its oral bioavailability is 60% and is not affected by food. Peak plasma levels are achieved in 3 to 7 h, steady-state levels are achieved in 7 to 10 days. The terminal half-life is 48 h. Excretion is primarily by hepatobiliary mechanisms: renal mechanisms play a minor role (less than 4%). Drugs stimulating the liver microsomal CYP3A4 system (phenytoin, carbamazepine, rifampicin, phenobarbital and St. John′s wort) result in increased metabolism and inactivation of geftinib. Inhibitors of this system (ketoconazole, itraconazole, erythromycin and clarithromycin) decrease the rate of metabolism resulting in increased drug levels. [3],[4] Adverse events The most common adverse events are diarrhea, mucositis, mild nausea, vomiting and skin rash: usually an acneiform rash present on the face and upper trunk. Elevations in blood pressure, especially in patients with underlying hypertension, and mild to moderate transient elevations in serum transaminases are also observed. [5],[6] Interstitial lung disease (ILD) is one of the most serious adverse events. The overall incidence is approximately 1%. The median time to onset of ILD was 24 days in Japanese patients and 42 days in U.S. patients. Approximately one-third of cases were fatal. The development of dyspnea, cough and fever while on treatment with gefitinib calls for immediate evaluation and consideration for discontinuation of drug therapy. [7] EGFR Gene Mutations and Response to Geftinib EGFR is expressed in 40% to 80% of lung cancers, making it an attractive target for molecular intervention. The presence of EGFR mutations confers sensitivity to geftinib. [8] Exon 19 or 21 L858R deletions or mis-sense mutations have been associated with greater responses to geftinib. [9] These mutations occur near the ATP cleft of the Tyrosine Kinase (TK) domain and facilitate the action of the 4-anilinoquinazoline compounds which compete with ATP. Patients with EGFR amplification show much lesser rates of response as compared to patients having EGFR mutations. [10] However, increased EGFR gene copy number detected by fluorescent in situ hybridization (FISH) predicts outcome in patients treated with a combination of cetuximab and chemotherapy. [11] Geftinib resistance has been ascribed to EGFR T790M (threonine-to-methionine mutation at codon 790) mutation. MET gene mutations have been associated with geftinib resistance. Exon 20 and K-ras mutations are also associated with poor response to geftinib. [12],[13] Sensitivity to gefitinib correlates strongly with activating mutations in the EGFR kinase domain which correlate strongly with favorable clinical parameters including non smoker status, female sex, East Asian ethnic background, adenocarcinoma (especially bronchioloalveolar histology). [14] Frequency of EGFR mutations in Asian populations is higher and apparently results in better responses to geftinib. In a study in an Asian population, EGFR mutations (predominantly exon 18-21) were found in 19.2% patients. [15] Mutation rates were significantly higher in adenocarcinoma, adenosquamous carcinoma, bronchi alveolar carcinoma (26.1%-50%) than in squamous cell carcinoma - 0%) and significantly higher in non-smokers (41.8% v/s 8.6%). In European and American populations, EGFR mutations have been found in approximately 12% populations. [16],[17],[18] [Table - 1] shows major trials (geftinib in pre treated patients with advanced NSCLC) ISEL trial evaluated the efficacy of geftinib in patients who were refractory to or could not tolerate chemotherapy. Geftinib did not improve overall survival. ISEL study Asian data revealed improved survival in the geftinib therapy arm: median survival 9.5 months v/s 5.5 months. On subgroup analysis, significant survival benefit was seen in patients who never smoked and were of Asian origin. [17] Initial phase 2 trials evaluated the role of geftinib in patients who had failed at least two lines of therapy in two different dosages 250 mg and 500 mg. IDEAL 1 (patient number = 216) was conducted in Japan, Australia, Europe and South Africa. [18] IDEAL 2 (patients number = 221) was conducted in USA. [19] These trials reported objective response rates varying from 8.8 to 19%, symptom improvement rate from 35.1 to 43.1%, median survival 5.9-8 months and one year survival 24-35%. Median time to symptom improvement was very rapid (9-10 days). Diarrhea and acne were the most common side effects, but less than 2% patients stopped therapy on account of an adverse drug reaction. ISEL specimens were analyzed for EGFR copy number and EGFR mutations: high copy number and presence of mutations were associated with better survival: EGFR mutations had higher response rates: 37.5% v/s 2.6%. [20] Geftinib in Asian Populations In ISEL and IDEAL 1 trials, the overall 1 year survival was 27% and 35%, respectively, but in the Asian populations the 1 year survival was 41% and 57%, respectively. [17],[18] In a study in Singapore involving 110 patients, 32% partial response rates (PR) were achieved. Never smoking status was predictive of response: achievement of PR and good performance status were associated with improved survival. [21] These response rates are also seen in immigrant Asian populations. PR rates of 22.9% and stable disease rates (SD) of 40.9% were obtained in a study of 61 patients in Vancouver.: Better responses were seen in Asian females, non-smokers, adenocarcinomas (also bronchio- alveolar variant). [22] In Korean patients, the objective response rate (ORR) was 26%, disease control rate was 40% and 1 year OS was 44%. [23] Adenocarcinoma, good performance status and female gender were associated with better survival. An analysis conducted in previously treated NSCLC Chinese patients revealed that 1 year survival ranged between 19.7 and 40% in the chemotherapy arm depending upon the regimen used and 40.8% in the geftinib arm which also had a very favorable toxicity profile. [24] In Taiwanese patients 1 year OS of 45.1% and median survival of 9.5 months have been seen. [25] Another study demonstrated no difference in overall survival between docetaxel or geftinib in previously treated Japanese patients. [26] Indian Study One retrospective analysis has found median survival of 6.4 months and response rates of 14% to geftinib in refractory advanced NSCLC in India. [27] Geftinib in Predominantly Caucasian Populations In a major European study involving 83 Spanish patients, EGFR mutations were found in 10 (12%) patients and were strongly associated with adenocarcinomas, female gender and nonsmokers. Response was observed in 60% of patients with mutations and 8.8% of patients with wild-type EGFR (P=0.001). Time to progression and median survival for patients with mutations was 12.3 months and 13 months respectively compared with 3.6 months and 4.9 months, respectively, for patients with wild-type EGFR (P=0.002). [28] In another study, EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemo refractory, advanced NSCLC patients from the United States, Europe, and Asia were studied and their presence correlated with response and survival. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR. [15] Geftinib as second line therapy in advanced NSCLC [Table - 1] Gefitinib was evaluated against docetaxel in the SIGN study: a multicenter, randomized, parallel-group, and open-label, phase II trial that investigated oral gefitinib (250 mg/day) or i.v. docetaxel (75 mg /m 2 every 3 weeks) in patients with advanced NSCLC who had previously received one chemotherapy regimen. The primary objective was assessment of symptom improvement, response rate, overall survival and safety. This trial recruited 141 patients (68 to gefitinib and 73 to docetaxel) who received treatment for a median duration of 3.0 (gefitinib) and 2.8 (docetaxel) months. Similar efficacy was observed with gefitinib and docetaxel, 36.8 and 26.0% symptom improvement rates, 33.8 and 26.0% quality-of-life (QOL) improvement rates, 13.2 and 13.7% objective response rates, and 7.5 and 7.1 months median OS, respectively. [29] The INTEREST ( IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study was a randomized, open-label, parallel-group, phase III trial evaluating survival with geftinib versus docetaxel in 1,466 patients with locally advanced or metastatic recurrent NSCLC who had previously received platinum-based chemotherapy. Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (median survival 7.6 vs 8.0 months). This trial suggested that geftinib was a valid treatment option in pre-treated patients with advanced non-small-cell lung. [30] V-15-32 trial similarly evaluated geftinib and docetaxel in pretreated Japanese patients. Non inferiority in OS could not be demonstrated. The median survival and the 1-year survival rates were 11.5 months and 47.8%, respectively, for gefitinib and were 14.0 months and 53.7%, respectively, for docetaxel. Gefitinib significantly improved objective response rate and quality of life versus docetaxel; PFS, disease control rates, and symptom improvement were similar for the two treatments. Grades 3 to 4 adverse events occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of patients. Incidence of interstitial lung disease was 5.7% (gefitinib) and 2.9% (docetaxel). [27] ISTANA (Iressa as Second Line Therapy in Advanced NSCLC-Asia) was a Phase III study that compared gefitinib and docetaxel in pre-treated advanced NSCLC in 161 Korean patients. PFS was significantly longer with gefitinib compared with docetaxel as was the overall response rate (objective response rate: 28.1% vs 7.6%). [31] Geftinib in combination with chemotherapy as first line in advanced lung cancer [Table - 2] Two major trials: the Intact Trial 1 and Intact Trial 2 were conducted to determine if addition of geftinib to first line therapy in advanced NSCLC resulted in improved survival. Addition of geftinib (in dosages of 250mg or 500 mg) to gemcitabine / cisplatin (in Intact 1 involving 1093 patients) or to paclitaxel / carboplatin (in Intact 2) was not associated with any survival benefit. However in the Intact 2 trial involving 1037 patients, there was a trend toward improved survival in the subgroup of patients with adenocarcinoma who had received chemotherapy for 90 days in the geftinib 250 mg/ day arm (P=0.05) suggesting a possible role of geftinib monotherapy in maintenance. [17],[32] Geftinib monotherapy as first line in advanced lung cancer [Table - 3] In a study involving 53 chemotherapy naοve patients with advanced NSCLC geftinib administered as first line therapy ORR - 32.1%, overall disease control rates - 52.8% and I year OS of 41.5% were obtained. ILD was seen in 4 patients (7.5%). [33] In another study involving 196 patients (96 non-smokers, 144 adenocarcinomas or bronchioalveolar histology) 42% ORR, total disease control rates (ORR and Stable disease of 61%) and median survival of 11.1 months was seen. One year survival was 47.5% in patients with good PS. Female gender, adenocarcinoma histology and non smoking status were independent predictors of response. [34] Spigel et al.′s US Phase II study of 70 chemotherapy-naοve patients with poor performance status and advanced NSCLC receiving gefitinib 250 mg/day first-line reported a median PFS and OS of 3.7 and 6.3 months, respectively. [35] IPASS (IRESSA Pan-Asia Study) was a phase 3, open-label study in which treatment naοve, non smokers / light smokers with advanced pulmonary adenocarcinoma were randomized to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival (PFS). The 12-month rates of PFS were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study showed the superiority of geftinib with respect to PFS. In the subgroup of 261 patients who were positive for the EGFR mutation, PFS was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation PFS was significantly longer among those who received chemotherapy (P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. [36] Thus the presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib and such patients are candidates for upfront therapy with geftinib. [36] First line Geftinib in NSCLC in elderly patients Gefitinib was compared with vinorelbine in elderly patients in a randomized, Phase II Study (INVITE). The disease control rates were 43.3% and 53.5% respectively and were not statistically different. There was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib - a result which was considered intriguing and merits further study. [37] Studies Showing Geftinib Responsiveness in EGFR Mutated Populations [Table - 4]In a Japanese study involving 82 patients of advanced lung cancer, 20 (24%) had EGFR mutations (16 were treated) and response rate was 75%. Median progression free survival was 8.9 months. [38] In another Japanese study, geftinib was given upfront or as second/ third line to patients with EGFR mutations which were found in 32/118 patients (28 enrolled). The overall response rate was 75%. Median PFS was 11.5 months with 1 year OS of 79%. [39] Sequist et al. (iTarget trial) prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations. 34 / 98 (35%) patients had EGFR mutations. 31 received gefitinib with RR: 55%, median PFS 9.2 months. 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients exhibited de novo gefitinib resistance and had T790M EGFR mutation and MET amplification. [40] First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. [40] A Phase II Japanese study reported by Kimura et al., [41] showed that 78% of NSCLC patients showing a partial response to first-line gefitinib treatment had EGFR mutations and mutation-positive patients showed a longer median survival compared with mutation-negative patients (611 versus 232 days, respectively). Inoue et al., [42] reported an overall response rate of 75% and a disease control rate of 88% in 16 mutation-positive NSCLC patients. I-CAMP examined the efficacy and safety of gefitinib mono-therapy for advanced NSCLC patients with EGFR mutations in a combined analysis of 7 prospective Phase II trials conducted in Japan. There were 148 patients in 7 trials; 57% received gefitinib as first line. Median OS and PFS were 24.3 months and 9.7 months, respectively. Age, histology and PS were significantly related to longer PFS. The combined response rate was 76% and only 6% of the patients had progressive disease, indicating that gefitinib produced significant anti-tumor activity and prolonged survival in this selected NSCLC population. [43] Geftinib Maintenance Maintenance with geftinib resulted in poor overall survival in patients with geftinib after chemo radiotherapy and treatment with docetaxel. [44] Sequential administration of docetaxel followed by geftinib maintenance as salvage treatment in patients with advanced NSCLC was feasible but showed only modest activity. [45] Thus geftinib maintenance does not seem to offer much clinical benefit. In the phase III West Japan study patients were randomized to platinum doublet therapy for 6 cycles or geftinib maintenance after 3 cycles. Though PFS was better in the geftinib arm, OS was not. However, on subset analysis in patients with adenocaricnoma had better OS. [46] Lazarus Responses Patients with poor performance status (PS of 2 or more) and brain or liver metastases fare badly and are often excluded from chemotherapy clinical trials. [47] Dramatic complete and partial remissions (Lazarus responses) have been documented in patients with lung adenocarinoma having multiple brain, lung and bone metastases on geftinib. [48] In some studies, 60%-90% response rates (RR) have been described in chemotherapy-resistant NSCLC patients with PS - 2 and liver, bone and brain metastases harboring EGFR mutations, with time to progression (TTP) of 12 to 21 months. [16],[28] This is significantly beyond the 10% RR and 3-month TTP observed in the general population of NSCLC patients with second- or third-line gefitinib or erlotinib. [48] Conclusion The most exciting feature of geftinib use is its potential for Lazarus responses in patients with poor performance status. Geftinib also exhibits good responses in patients with EGFR mutations and its use is associated with little toxicity. This raises hopes that future drugs will be able to elicit better and more sustained responses even as the mechanisms underlying lung cancer are better understood. References
Copyright 2010 - Journal of Cancer Research and Therapeutics The following images related to this document are available:Photo images[cr10058t4.jpg] [cr10058t2.jpg] [cr10058t3.jpg] [cr10058t1.jpg] |
| |||||||||
![[Table - 1]](/showimage?cr/photo/cr10058t1.jpg){kind=link}
![[Table - 2]](/showimage?cr/photo/cr10058t2.jpg){kind=link}
![[Table - 3]](/showimage?cr/photo/cr10058t3.jpg){kind=link}
![[Table - 4]](/showimage?cr/photo/cr10058t4.jpg){kind=link}