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Yu-Yun Shao

Gefitinib or Erlotinib in the Treatment of Advanced Non-small Cell Lung Cancer

Abstract: Tyrosine kinase inhibitors of the epidermal growth factor receptor, gefitinib and erlotinib, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Many phase II or III studies have proven the efficacy of gefitinib or erlotinib as the first-line, second-line, or third-line treatment. However, it is not clear whether gefitinib or erlotinib has different activities in advanced NSCLC patients with different clinicopathological features or at different stages. We review the published clinical trials that used gefitinib or erlotinib in NSCLC and compare their efficacy. The selection criteria and efficacy measurement in these trials that might affect the final results of the studies are listed and discussed. The adequate-powered, direct comparisons of gefitinib against erlotinib under the same clinical scenarios are lacking. There is no evidence at present that the efficacy of these two agents in NSCLC is different.



Introduction

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, have shown efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). East Asian ethnicity, no smoking history, adenocarcinoma histology, and female gender are known factors predictive of response to these two agents (Chang et al., 2006; Yang et al., 2006). Recently, certain EGFR mutations emerged as an important predictor of response to or survival benefit of these two agents (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004).

Although both gefitinib and erlotinib target the same EGFR kinase domain, it remains to be explored that whether gefitinib and erlotinib provide the same treatment outcomes in advanced NSCLC patients. For example, two large randomized phase III trials compared an EGFR TKI to placebo for second- or third-line therapy of advanced NSCLC. Results showed that erlotinib (the BR.21 study) prolonged overall survival (OS) but gefitinib (the ISEL study) did not (Shepherd et al., 2005; Thatcher et al., 2005). Furthermore, case series showed that an objective response or stable disease can be observed in a few patients who took erlotinib after treatment failure of gefitinib for advanced NSCLC or vice versa (Kaira et al., 2010). A phase II study using erlotinib in such patients showed an overall response rate of 9.5% and a disease control rate of 28.6% (Cho et al., 2007). Third, gefitinib and erlotinib might not be biologically equivalent under the current approved doses. Although the approved daily dose of erlotinib (150 mg/day) is equal to the maximum tolerated dose and leads to a steady-state serum concentration of 3 µM (Hidalgo et al., 2001), the approved daily dose of gefitinib (250 mg/day) is approximately one third of the maximum tolerated dose and leads to a steady-state serum concentration of <1µM (Baselga et al., 2002).

Here we review the clinical experience of gefitinib and erlotinib, compare and contrast results from clinical trials, especially randomized phase III trials, corresponding to the same clinical scenarios, and discuss continuing trials of gefitinib and erlotinib to address the question of anticancer activity of gefitinib versus erlotinib.

Gefitinib or Erlotinib as the Third-line Therapy

As aforementioned, two phase III trials aiming at testing EGFR TKIs in second- or third-line therapy of advanced NSCLC yielded different results. Treatment outcomes of EGFR TKIs in both studies were summarized in Table 1. The two studies had similar percentages of smokers and female patients, but the ISEL study (gefitinib vs. placebo) had more Asians than the BR.21 study (erlotinib vs. placebo) (Shepherd et al., 2005; Thatcher et al., 2005). Besides, more patients in the ISEL study had prior platinum exposure than those in the BR.21 study (96% vs. 92%). However, in terms of chemo-sensitivity, two studies might have accrued different patient populations. Progression from prior chemotherapy within 90 days of last given dose was one of the inclusion criteria for ISEL study, thus, 45% of patients from ISEL had disease progression as the best response in previous chemotherapy whereas only 18% of patients from BR.21 had disease progression as best response (Blackhall et al., 2006). The response rate of gefitinib in the ISEL study (8%) is almost the same as that of erlotinib in the BR.21 study (9%). The disease control rate, median progression-free survival (PFS), and median overall survival (OS) of gefitinib were also similar to those of erlotinib.

Similar comparison with East Asian patients only can be made between two phase II studies in Taiwan using gefitinib (n = 428) and erlotinib (n = 299) (Chang et al., 2006; Perng et al., 2008). The percentage of never smokers (50 vs. 56%), female patients (45 vs. 47%), and adenocarcinoma (75 vs. 68%) were similar in the gefitinib study and the erlotinib study, respectively. Gefitinib and erlotinib offered very similar objective response rates of 27 and 29%, respectively.

Gefitinib or Erlotinib as the Second-line Therapy

Four trials compared gefitinib to docetaxel as second-line therapy (Table 2). The global INTEREST study enrolled 80% smokers, 36% women, and only 21% Asians in the trial (Kim et al., 2008). The primary objective, the non-inferiority of gefitinib to docetaxel in terms of overall survival, was met. The response rate (9%) and median PFS (2.2 months) of the gefitinib group were very similar to those in the ISEL study. These results may represent the general treatment outcomes in unselected patients in the Western countries.

The two studies in East Asia showed somewhat different results. Sixty to seventy percents of patients were smokers. The Japanese V-15-32 study, which aimed at testing the non-inferiority of gefitinib compared to docetaxel in patients’ OS, failed to demonstrate the non-inferiority since the confidence interval of the OS hazard ratio exceeded the predetermined margin (Maruyama et al., 2008). However, at the same time, log rank test showed that the OS of the two groups was not statistically significantly different either. In the Korean ISTANA study, the OS was not significantly different between the two treatment arms (Lee et al., 2010b). In both studies, gefitinib provided response rates around 25% and median PFS around 2 to 3 months. The treatment outcomes are better than those reported in the INTEREST study. These results may represent the general treatment outcomes in unselected East Asian patients.

Currently, the result of a similar study testing erlotinib in second-line advanced NSCLC treatment (the TITAN study, erlotinib vs. docetaxel or pemetrexed) is not yet available.

There was only one randomized study that focused on the comparison of gefitinib and erlotinib in the second-line setting. A randomized phase II study enrolled 96 advanced NSCLC patients to receive gefitinib or erlotinib if they had failed or were intolerable to first-line chemotherapy (Uhm et al., 2009). The enrolled patients had to meet at least two of the three criteria: female, non-smoker, and adenocarcinoma, to increase the chance of treatment response. There was no statistically significant difference between the response rates of gefitinib (47.9%) and erlotinib (39.6%). The median PFS was also similar in gefitinib (4.9 months) and erlotinib (3.1 months).

Gefitinib or Erlotinib as the First-line Therapy

Phase II trials

Because of the encouraging results in second- or third-line advanced NSCLC treatment, gefitinib and erlotinib were tested as the front-line therapy in several phase II trials. Comparing the efficacy of gefitinib to that of erlotinib in these studies needs to be cautious, since the patient selection and enrichment criteria are diverse and could interfere with the results.

In Asian studies with relatively unselected patient cohorts, both gefitinib and erlotinib provided a response rate of 20 to 30% as the first-line therapy (Lee et al., 2010a; Niho et al., 2006; Suzuki et al., 2006). With enrichment of female patients, non-smokers, or adenocarcinoma histology, gefitinib can yield a response rate as high as 50 to 70% (Lee et al., 2005; Yang et al., 2008).

In studies performed in Western countries without obvious enrichment of patients by good clinicopathological predictors, both gefitinib (Spigel et al., 2005) and erlotinib (Giaccone et al., 2006; Jackman et al., 2007; Akerley et al., 2009) as the first-line therapy showed disappointing low response rates from 8 to 23% and median PFS from 2.0 to 3.5 months. Therefore, the response rates and PFS of the first-line EGFR TKI treatment in unselected NSCLC patients, no matter Asians or Caucasians, are similarly poor between gefitinib and erlotinib.

A Spanish phase II study used erlotinib to treat advanced NSCLC patients with EGFR mutations (Rosell et al., 2009). The response rate and the disease control rate were also high (Table 3). However, this study was hampered by its registry nature without strict criteria to evaluate the tumor response and to follow up the patients.

Phase III trials

There are three phase III studies compared gefitinib to platinum-based chemotherapy as the first-line treatment in NSCLC patients either unselected (but enriched) (Mok et al., 2009) or selected (with EGFR mutations) (Kobayashi et al., 2009; Mitsudomi et al., 2010) (Table 3). In the gefitinib-treated arms of the three randomized trials, response rates were between 62% and 75% in patients with EGFR mutations. Disease control rates were also encouraging, around 90%. Median PFS was approximately nine months.

No randomized phase III trials of erlotinib vs. platinum-based chemotherapy as the first-line therapy were available for comparison. Studies randomizing chemo-naive NSCLC patients with EGFR mutations to erlotinib or chemotherapy are ongoing.

Gefitinib or Erlotinib as Maintenance Therapy

Since gefitinib was efficacious as second-line treatment in Asian patients, researchers were enthusiastic to test its use as a maintenance therapy after completion of the first-line chemotherapy. The WJTOG0203 study allocated advanced NSCLC patients to receive either six cycles of chemotherapy or three cycles of chemotherapy followed by gefitinib until disease progression if patients achieved disease control after the first three cycles of chemotherapy (Takeda et al., 2010). The median PFS of the gefitinib maintenance group was significantly longer than that of the chemotherapy alone group (4.6 vs. 4.3 months), but OS was similar. Intriguingly, subgroup analysis with adenocarcinoma histology showed significantly longer PFS and OS in the gefitinib maintenance arm. On the contrary, non-adenocarcinoma patients had similar PFS and OS with either treatment.

Two phase III trials tested erlotinib as the maintenance therapy. The SATURN study randomized advanced NSCLC patients who had disease control after four cycles of chemotherapy to either erlotinib or placebo (Cappuzzo et al., 2010). The median PFS was significantly prolonged with erlotinib compared to placebo (12.3 vs. 11.1 weeks). The OS data were not yet mature. The PFS benefit of erlotinib maintenance was shown not only in adenocarcinoma and non-smokers but also in non-adenocarcinoma and smokers.

The ATLAS study had a similar scheme as the SATURN study. However, the initial four cycles of chemotherapy were combined with bevacizumab. Therefore, bevacizumab was given to both the erlotinib maintenance arm and the control arm (Miller et al., 2009). Again, the PFS was significantly improved by the gefitinib plus bevacizumab maintenance therapy (4.8 vs.3.7 months). The subgroup analysis showed this benefit occurred only in patients with adenocarcinoma.

All three trials demonstrated improved PFS by EGFR TKI maintenance after chemotherapy. However, it is difficult to compare gefitinib with erlotinib in these trials since the WJTOG0203 study had a very different treatment scheme compared to the other two studies with erlotinib. The gefitinib arm, by the protocol, can only receive up to 3 cycles of chemotherapy while the other arm had up to 6 cycles. Because the standard first-line chemotherapy of NSCLC remains four to six cycles, such a design resulted in a genuine imbalance of the first-line therapy between the two arms. Therefore, the comparisons between the two groups cannot be regarded only as gefitinib maintenance or not, but also the duration of the first-line therapy. Currently, the maintenance therapy is still under active investigation. Further comparison of gefitinib and erlotinib in this setting will be conducted in more details after the complete results of the above studies are available.

Activity of Gefitinib or Erlotinib in EGFR Mutation Positive or Negative Patients in Phase III Studies

In vitro drug testing indicates a stronger potency in inhibiting wild-type EGFR activity by erlotinib than gefitinib. Although efficacy of gefitinib or erlotinib was highest in patients with EGFR mutations, in order to minimize the selection bias of most phase II studies, the activity of these drugs in EGFR mutation positive and negative patients can best be observed in randomized phase III studies that contain both EGFR mutation positive and negative patients as listed in Table 4.

The response rates of gefitinib in NSCLC with wild-type EGFR range from 0 to 6.6% in several phase III trials (Douillard et al., 2010; Hirsch et al., 2006; Maruyama et al., 2008; Mok et al., 2009). The response rate of erlotinib in NSCLC with wild-type EGFR was 7% in BR.21 (Zhu et al, 2008) and seemed to be higher than that of gefitinib in EGFR wild-type patients (1.1%) in IPASS (Mok et al., 2009). However, one should be cautious in interpreting these results since the detection method of EGFR mutations have not been standardized and varied from study to study (Table 4). The method used in IPASS study was very sensitive so that the false negative rate of EGFR mutation detection was very small. That may contribute to the very low response rates of gefitinib in EGFR wild type patients. On the contrary, in patients with EGFR mutations, the response rates of gefitinib range from 37.5% to 75% but was only 27% in BR.21 study (Zhu et al., 2008). The reason for the low response rate of patients with EGFR mutations in BR.21 study was not clear.

Conclusion

Currently, there is no evidence that the efficacy of gefitinib and that of erlotinib in advanced NSCLC are different; since adequate-powered, direct comparisons of gefitinib against erlotinib under the same clinical scenarios are lacking.

Disclosure

The authors declare no conflicts of interest.

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