Gefitinib for the treatment of non-small-cell lung cancer

Figures & data

Box 1. Drug summary.

Drug name (generic)	Gefitinib, Iressa
Phase	Phase III/postmarketing
Indication	Advanced or metastatic NSCLC (stage IIIb/IV), selected EGFR-mutation-positive patients across all lines of therapy in Europe Widely used in advanced NSCLC in the pretreated setting in Japan and Asia
Pharmacology	Orally bioavailable, competitive, reversible EGFR-TKI, suitable for once-daily dosing. Linear dose-dependent pharmacokinetics. Metabolized by the liver and excreted via faeces
Route of administration	Oral
Chemical structure
Pivotal trials	1) The ISEL study compared gefitinib with placebo in heavily pretreated patients with advanced NSCLC; failed to demonstrate an overall survival benefit for gefitinib in an unselected population 2) The Phase III INTEREST study – Overall survival with gefitinib in unselected, pretreated patients, was not inferior to docetaxel; improved quality of life, superior toxicity profile with gefitinib therapy 3) The Phase III IPASS trial – Improved progression-free survival (PFS) with gefitinib compared with paclitaxel-carboplatin chemotherapy in chemotherapy-naive, never- or light smokers with adenocarcinoma histology. In subset of EGFR-mutation-positive patients, PFS was significantly prolonged with gefitinib compared with chemotherapy 4) The NEJ002 and WJTOG3405 Phase III studies in Japanese populations support the IPASS results, demonstrating superior response rate and significant improvement in PFS compared with paclitaxel-carboplatin and docetaxel-cisplatin respectively, in chemotherapy-naive, EGFR-mutation-positive patients with advanced or recurrent NSCLC postsurgery

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Table 1. Summary of prospective studies of gefitinib in EGFR-mutation-positive NSCLC patients.

Study	No. of patients with EGFR mutation	Ethnicity	Overall DCR rate (%)	Complete response	Partial response	Median PFS (months)
Yoshida et al. [91]	21	Japanese	91	3 (14%)	16 (76%)	7.7
Sunaga et al. [92]	21	Japanese	90	3 (14%)	13 (62%)	12.9
Inoue et al. [93]	16	Japanese	88	0 (0%)	12 (75%)	9.7
Asahina et al. [94]	16	Japanese	81	2 (13%)	10 (62%)	8.9
Sugio et al. [95]	19	Japanese	89.5	0 (0%)	12 (63.2%)	7.1
Tamura et al. [96]	28	Japanese	96	1 (3.6%)	20 (71.4%)	11.5
van Zandwijk et al. [97]	13	Caucasian	92	1 (8%)	10 (77%)	14
Sequist et al. [89]	31	Asian & others	94	1 (3%)	16 (52%)	9.2
Inoue et al. [88]	30	Japanese	90	1 (3%)	18 (62%)	6.5
Sutani et al. [90]	27	Japanese	NR	1 (3.7%)	20 (74%)	9.4

DCR: Disease control rate; EGFR: EGF receptor; NR: Not recorded; PFS: Progression-free survival.

Table 2. Summary of Phase III trial data for gefitinib in patients with advanced NSCLC.

Trial	Treatment arms	No. of patients	Object RR (%)	Median PFS (months)	Median survival (months)	Details
Gefitinib compared with best supportive care in pretreated, advanced NSCLC
ISEL [44]	Gefitinib 250 mg vs	1129	8.0 (p < 0.0001)	*3.0 (p = 0.0006)	5.6 (HR = 0.89, 95% CI 0.77 – 1.02, p = 0.09)	Included a population highly refractory to treatment Survival advantage in non-smokers and Asians *NB Time to treatment failure assessed rather than PFS
	Placebo	563	1.3%	2.6	5.1
Gefitinib compared with standard chemotherapy in pretreated, advanced NSCLC
INTEREST [45]	Gefitinib 250 mg vs	733	9.1 (p = 0.33)	2.2 (p = 0.47)	7.6 (HR = 1.020, 96% CI 0.905 – 0.15)	Gefitinib equivalent to docetaxel in OS, across all patient groups
	Docetaxel 75 mg/m^2	733	7.6	2.7	8
V-15 – 32 [49]	Gefitinib 250 mg vs	245	22.5 (p = 0.009)	2.0 (p = 0.34)	11.5 (p = 0.33)	Variable numbers crossing over on progression in each arm. Failed to demonstrate gefitinib is non-inferior to docetaxel in OS (HR1.12, 95.24%CI:0.89 – 1.4, non-inferiority criterion < 1.25)
	Docetaxel 60 mg/m^2	244	12.8	2.0	14.0
ISTANA [51]	Gefitinib 250 mg vs	82	28.1 (p = 0.0007)	3.3 (HR = 0.729, 90% CI 0.53 – 0.998, p = 0.04)	14.1 (p = 0.437)	Second- line therapy in Korean population. Primary end point of PFS significantly favoured gefitinib
	Docetaxel 75 mg/m^2	79	7.6	3.4	12.2	PFS favoured gefitinib.
Gefitinib compared with standard chemotherapy as first-line treatment for advanced NSCLC
IPASS [60]	Gefitinib 250 mg vs	609	43.0 (p = 0.001)	5.7 (HR: 0.74, 95% CI 0.65 – 0.85, p < 0.001)	18.6	Selected treatment-naïve, Asian patient population (adenocarcinoma, non-smokers). PFS favoured chemotherapy for first 6 months, then gefitinib, potentially due to EGFR mutational status OS data is from preliminary analysis, with only 37% maturity.
	Paclitaxel/carboplatin	608	32.2	5.8	17.3
Subgroups
Mutation positive	Gefitinib Chemotherapy			9.5 6.3
Mutation negative	Gefitinib Chemotherapy			1.5 5.5
First Signal [63]	Gefitinib vs	159	53.5 (p = 0.1533)	6.1 (HR = 0.813, 95% CI 0.641 – 1.031, p = 0.044)	21.3	Selected treatment-naïve, Asian patient population (adenocarcinoma, non-smokers)
	Gemcitabine/cisplatin	150	46.3	6.6	23.3	When EGFR mutant population selected, significant improvement in RR and PFS in favour of gefitinib (HR: 0.613, 95% CI: 0.308 – 1.22, p = 0.084)
WJTOG 3405 [61]	Gefitinib vs	88	62.1	9.2 (HR = 0.48, 95% CI 0.336 – 0.71, p < 0.0001)	NA	Selected, Japanese, chemo-naïve patients, stage IIIB/IV disease or recurrence postsurgical resection
	Cisplatin/docetaxel	89	32.2	6.3	NA	All EGFR-mutation-positive
NEJ002 [62]	Gefitinib vs	80	74.5	10.3 (HR = 0.357, 95% CI 0.25 – 0.51, p < 0.001)	NA	Selected, Japanese, chemo-naïve patients, stage IIIB/IV disease
	Carboplatin/paclitaxel	75	29	5.3	NA	All EGFR-mutation-positive
Gefitinib in combination with chemotherapy as first-line treatment of advanced NSCLC
INTACT-1 [53]	Gemcitabine/cisplatin + gefitinib 250 mg	365	51.2	5.8	9.9
	Gemcitabine/cisplatin + gefitinib 500 mg	365	50.3 (NS)	5.5 (p = 0.76)	9.9 (p = 0.46)
	Gemcitabine/cisplatin + placebo	363	47.2	6.0	10.9
INTACT-2 [52]	Paclitaxel/carboplatin + gefitinib 250 mg	345	30.4	5.3	9.8
	Paclitaxel/carboplatin + gefitinib 500 mg	347	30.0	4.6 (p = 0.06)	8.7 (p = 0.64)
	Paclitaxel/carboplatin + placebo	345	28.7	5	9.9
SWOG0023 [56]	Gefitinib 250 mg	118	NA	8.3 (p = 0.17)	23 (HR = 0.633, 95% CI 0.44 – 0.91, p = 0.01)	Phase III trial of maintenance gefitinib, following chemoradiation and consolidation docetaxel in stage III NSCLC.
	Placebo	125		11.7	35	The study was closed early following an unplanned interim analysis
WJTOG0203 [59]	Chemotherapy + gefitinib 250 mg	300	34.2	4.6 (HR = 0.68, 95% CI 0.57 – 0.8, p < 0.001)	13.7 (HR = 0.86, 95% CI 0.72 – 1.03, p = 0.11)	Phase III trial of sequential gefitinib following chemotherapy in stage IIIb/IV NSCLC
	Chemotherapy alone	298	29.3	4.3	12.9	Superior OS in gefitinib arm in adenocarcinomas

EGFR: EGF receptor; INTACT: Iressa NSCLC trial assessing combination treatment; INTEREST: Iressa NSCLC trial evaluating response and survival against taxotere; IPASS: Iressa Pan-Asia study; ISEL: Iressa survival evaluation in lung cancer; ISTANA: Iressa as second-line therapy in advanced NSCLC; NA: not applicable; NEJGSG: North-East Japan Gefitinib Study group; NSCLC: Non small cell lung cancer; OS: Overall survival; PFS: Progression-free survival; SWOG: South West Oncology Group.

Table 3. Randomized Phase III trials in progress with gefitinib.

Study	Population	Treatment arm	Primary end point
EORTC08021	First-line maintenance for advanced NSCLC in patients without disease progression on completion of chemotherapy	Gefitinib vs placebo	OS
CAN-NCIC-BR19	First-line maintenance after complete resection of stage I – IIIA NSCLC ± adjuvant chemotherapy	Gefitinib vs placebo	OS
NCT01017874	First-line, East Asian, chemo-naïve, stage IIIb/IV, non-squamous histology. Never-smokers	Pemetrexed-cisplatin, maintenance gefitinib vs gefitinib	PFS
NCT00891579	Second-line, relapsed metastatic NSCLC, previous platinum therapy, EGFR-mutation-negative. Chinese population	Gefitinib vs pemetrexed	PFS

EGFR: EGF receptor; EORTC: European Organisation for Research and Treatment of Cancer; NSCLC: Non small cell lung cancer; OS: Overall survival; PFS: Progression-free survival.

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