There are currently no randomised controlled trials that demonstrate a clinical benefit on overall survival with gefitinib.
First line setting:
The evidence supporting the use of gefitinib in the first line setting initially came from the IPASS study, a phase III, multicenter, randomised, study comparing gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia with advanced non-small cell lung cancer.
All patients had stage IIIB or IV NSCLC with histological features of adenocarcinoma, were nonsmokers (defined as patients who had smoked less than 100 cigarettes in their lifetime) or former light smokers (those who had stopped smoking at least 15 years previously and had a total of less than or equal to 10 pack-years of smoking), and had no previous chemotherapy or biologic or immunologic therapy.
Between March 2006 and October 2007, a total of 1217 patients were randomly assigned to receive gefitinib 250 mg/day (n=609) or carboplatin AUC=5 or 6 plus paclitaxel 200 mg/m2 every 21 days for 6 cycles (n=608).
The primary end point was progression-free survival and secondary end-points included overall survival, objective response rate, quality of life, symptom reduction and safety.r
More recently two phase III, randomised studies have compared gefitinib with platin-based doublet regimens in Asian patients with NSCLC and activating EGFR mutations.
The WJTOG3405 study (cisplatin and docetaxel) recruited 177 patients between March 2006 and June 2009 from 36 centres in Japan. The primary endpoint was progression free survival. Data from 172 (86 in each group) were analysed and the gefitinib group had significantly longer progression-free survival than the chemotherapy group.r
In another study, NEJ002, 230 patients with EGFR mutation positive NSCLC were randomly assigned to receive either gefitinib or chemotherapy (carboplatin and paclitaxel). The primary endpoint was progression free survival, with secondary endpoints included overall survival, response rate and toxic effects. The study was terminated early after the interim analysis of the first 200 patients demonstrated significantly longer progression free survival in the gefitinib group.r
Second or third line setting:
The activity of gefitinib was evaluated in a randomised, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). A total of 216 patients received gefitinib. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis.r
The Iressa® Survival Evaluation in Lung Cancer (ISEL) trial investigated gefitinib compared with placebo, in the second or third line setting. That study included 1,692 patients who had progressed or could no longer tolerate chemotherapy. The results showed a statistically significant greater tumour shrinkage in the gefitinib arm, but the overall survival durations were similar in the two arms: 5.6 months in treated patients versus 5.1 months in patients receiving placebo.
Efficacy
First line setting:
IPASS
The 12-month rates of PFS were 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the subgroup of 261 patients who had EGFR mutations, PFS was significantly longer among those who received gefitinib than those who received carboplatin/paclitaxel. (HR=0.48; p<0.001).r
Mature data from the IPASS study, presented at the 2010 ESMO congress, showed that overall survival (OS) was similar, with no significant difference, between gefitinib and doublet chemotherapy in the overall population (median OS 18.8 vs. 17.4 months; p=0.11). Analysis by EGFR mutation status confirmed that patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) had better outcomes, regardless of which treatment arm they were in, compared to patients with EGFR mutation-negative disease. Median survival times were around 22 months for EGFR mutation-positive patients, but only 11 to 12 months for EGFR mutation-negative patients. The majority of EGFR mutation-positive patients in IPASS received an EGFR-TKI at some point as 64% of those randomised to carboplatin/paclitaxel later received an EGFR-TKI as subsequent therapy.r
WJTOG3405 showed significantly longer progression free survival in the gefitinib group compared with the chemotherapy group. Median PFS of 9.2 months (95%CI 8.0-13.9)versus 6.3 months (5.8-7.8; HR 0.489 95% CI 0.336-0.710, log-rank p<0.0001).r
Maemondo et al demonstrated a significantly longer median progression free survival in the gefitinib group (10.8 months, vs. 5.4 months in the chemotherapy group; HR 0.30; 95% CI, 0.22 to 0.41; p<0.001) and a higher response rate 73.7 vs 30.7% p<0.001). Median OS was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group however this was not significant (p= 0.31).r
Second or third line setting:
Symptoms of NSCLC improved in 43% and 35% of patients receiving 250 mg/day and 500 mg/day of gefitinib respectively. Partial radiographic responses occurred in 12% and 9% of patients receiving 250 mg/day and 500 mg/day of gefitinib respectively. Responses were more frequent in females, Asians, adenocarcinomas and in non-smokers. The median duration of response was 7.0 months 4.
Kaplan-Meier Curves for Progression-free Survivalr
A: PFS for the overall population
B: PFS for patients who were positive for EGFR mutations
C: PFS for patients who were negative for EGFR mutations
D: PFS for patients with unknown EGFR status
© N Engl J Med 2009
Toxicity
First line setting:
When compared with carboplatin/paclitaxel in the first line setting, the most common adverse events were rash or acne (66.2%) and diarrhoea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%) and alopecia (58.4%) in the carboplatin/paclitaxel group.r
Second or third line setting:
The side effects of gefitinib were usually mild and mostly resolve within days after temporary cessation of gefitinib or improve despite ongoing treatment. Skin toxicity (62% in patients receiving 250mg/day) and diarrhoea (57% in patients receiving 250mg/day) were the 2 most common side effects with gefitinib. Other side effects included eye toxicities (19%), nausea (15%) and vomiting (10%). There were no cases of investigator-identified interstitial lung disease. There was one patient with grade 3 thrombocytopenia and one possible treatment-related death.r
Toxicityr
© New Engl J Med 2009
WJTOG3405r
© Lancet Oncol 2010
Maemondo et alr
Toxicity |
Gefitinib (n=114)
|
Carboplatin/Paclitaxel (n=113)
|
P Value for Grade >3 |
Grade |
3 |
4 |
>3 (%) |
3 |
4 |
>3 (%) |
P Value for Grade > 3 |
Diarrhoea |
1 |
0 |
1(0.9) |
0 |
0 |
0 |
<0.001 |
Appetite Loss |
6 |
0 |
6(5.3) |
7 |
0 |
7(6.2) |
<0.001 |
Fatigue |
3 |
0 |
3(2.6) |
1 |
0 |
1(0.9) |
0.002 |
Rash |
6 |
0 |
6(5.3) |
3 |
0 |
3(2.7) |
<0.001 |
Neuropathy (sensory) |
0 |
0 |
0 |
7 |
0 |
7(6.2) |
<0.001 |
Arthralgia |
1 |
0 |
1(0.9) |
8 |
0 |
8(7.1) |
<0.001 |
Pneumonitis |
2 |
1 |
3(2.6) |
0 |
0 |
0 |
0.02 |
Aminotransferase Elevation |
29 |
1 |
30(26.3) |
0 |
1 |
1(0.9) |
<0.001 |
Neutropaenia |
0 |
1 |
1(0.9) |
37 |
37 |
74(65.5) |
<0.001 |
Anaemia |
0 |
0 |
0 |
6 |
0 |
6(5.3) |
<0.001 |
Thrombocytopaenia |
0 |
0 |
0 |
3 |
1 |
4(3.5) |
<0.001 |
Any |
43 |
4 |
47(41.2) |
41 |
40 |
81(71.7) |
<0.001 |