A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations


Abstract

Background:

A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21.

Methods:

Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival.

Results:

A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62–1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63–1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172).

Conclusions:

The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.

Main

Both gefitinib and erlotinib are first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) patients. Two phase III trials (the Iressa Survival Evaluation in Lung Cancer study and the BR.21 trial) comparing gefitinib or erlotinib to placebo in previously treated advanced NSCLC showed that erlotinib significantly prolonged median overall survival (OS; 6.7 vs 4.7 months, hazard ratio (HR) 0.70, P<0.001; Shepherd et al, 2005), but gefitinib did not (Thatcher et al, 2005). In 2004, two milestone studies identified somatic mutations in EGFR that predicted sensitivity and response to EGFR TKIs (Lynch et al, 2004; Paez et al, 2004). The frequency of these activating mutations, including EGFR exon 19 deletions and exon 21 (L858R) point mutations, was reported to be increased in specific NSCLC populations such as women, patients of Asian origin, and patients without a history of smoking (Fukuoka et al, 2003; Giaccone et al, 2004; Shepherd et al, 2005; Thatcher et al, 2005).

Until 2009, gefitinib and erlotinib had been considered valid treatment options for patients with advanced NSCLC who had received prior treatment (on the basis of several phase III trials (Shepherd et al, 2005; Thatcher et al, 2005; Kim et al, 2008) and were registered in many countries for this indication, particularly in Asian countries (Guan et al, 2005; Maruyama et al, 2008; Uhm et al, 2009). However, it was unclear how to choose between these two EGFR TKIs in the clinic. Although some differences in the trial results for erlotinib and gefitinib led to differences in regulatory policy, no head-to-head randomised controlled trials were published to provide a final treatment strategy. In addition, there were no significant differences in progression-free survival (PFS) or OS between first-line and second-line EGFR TKI treatment in EGFR-mutant NSCLC (Massuti et al, 2009). We were faced with the challenging problem of how to customise EGFR TKI treatment for advanced NSCLC patients with EGFR activating mutations.

Robust data were lacking, so it was difficult to make an informed choice, even though these two EGFR TKIs were available in the clinic. Therefore, in July 2009, we initiated a randomised controlled trial of erlotinib vs gefitinib in advanced NSCLC harbouring EGFR exon 19 or 21 mutations and enroled patients regardless of the line of treatment (Chinese Thoracic Oncology Group (CTONG) 0901) to determine whether erlotinib is superior to gefitinib in terms of response and survival.

Patients and methods

Eligibility criteria

Eligible patients were adults aged 18 years with histologically or cytologically confirmed and locally advanced or metastatic (stage IIIB without any indications for curative chemoradiation or other local treatments to stage IV) NSCLC (AJCC/UICC version 6) harbouring EGFR exon 19 or 21 mutations detected by direct DNA sequencing as previously described (Jiang et al, 2008); measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Eisenhauer et al, 2009); Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, liver, and kidney function. Patients without exposure to any EGFR inhibitors were eligible for recruitment. Those with clinically unstable brain metastases, a history of cardiac disease, uncontrolled hypertension, other active malignancies, or any active infectious diseases were excluded.

Treatment schedule

After screening, patients were randomly assigned at a 1 : 1 ratio to receive oral erlotinib 150 mg or gefitinib 250 mg once daily. Second- and further-line treatments were defined as second line in the present study. Treatment continued until unacceptable toxicity, disease progression, or another discontinuation criterion was met. Erlotinib or gefitinib dose delays of 14 days were permitted for grade 3 nonhaematological toxicities until resolution to grade 1 or baseline, and treatment was reintroduced at a reduced dosage depending on the toxicity.

Tumour response was assessed by investigators according to RECIST version 1.1 (Eisenhauer et al, 2009). The initial response was assessed after 5 weeks of treatment, and the baseline assessments were repeated every 2 months. Toxicities were assessed by the investigators based on the incidence and severity of adverse events (AEs), according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0.

Study design and objectives

In June 2009, this study was a head-to-head phase II randomised controlled trial (CTONG 0901; clinicaltrials.gov No. NCT01024413) comparing erlotinib with gefitinib for patients with exon 21 mutations. The primary end point was response rate (RR), and the secondary endpoints included PFS, OS, and safety. The sample size was 70 (35 in each arm).

However, the protocol was amended in January 2010, and the study was redesigned and approved as a phase III randomised controlled trial by the appropriate independent ethics committees at the Guangdong Lung Cancer Institute, Guangdong General Hospital; this study was conducted according to the Declaration of Helsinki. EGFR exon 19 or 21 mutation-positive patients with advanced NSCLC were allowed to be recruited into this phase III trial. All patients provided written informed consent before study participation.

In this phase III trial, the primary end point was PFS, and the secondary end points included OS, RR, and safety. An exploratory end point was efficacy between the exon 19 and 21 mutation groups.

Statistical considerations

The study hypothesis was that erlotinib would improve PFS relative to gefitinib in advanced NSCLC harbouring EGFR exon 19 or 21 mutations. Based on the median PFS of 9.5 months with gefitinib and 14.0 months with erlotinib (Mok et al, 2008; Massuti et al, 2009), 80% power to detect a HR of 0.65 at a two-sided significance level of 0.05, 12 months of enrolment, 48 months of study duration, and a 5% rate of loss to follow-up, the appropriate sample size was calculated to be 254 patients with 127 in each arm, with statistical analysis of median survival time by log-rank test.

Chi-square or Fisher’s exact tests were used to compare qualitative data. PFS was defined as the time of randomisation to the first documentation of progressive disease (PD) or death from any cause. OS was calculated from randomisation to the last visit or death from any cause. Efficacy analyses were completed for the intent-to-treat population.

The Kaplan-Meier method was used to generate survival curves. The log-rank test was used to compare survival curves among patient groups. All statistical tests were two-sided, and 0.05 was deemed to indicate statistical significance. PASS version 11.0 (NCSS, Inc., Kaysville, Utah, USA) was used for the analyses.

Results

Patient population and characteristics

Between July 2009 and 2014, 256 patients at the Guangdong Lung Cancer Institute satisfied the inclusion or exclusion criteria and were randomly assigned (128 in each arm; Figure 1). The first and last patients with exon 21 mutations were recruited on 13 July 2009, and 11 July 2014, respectively. The first and last patients with exon 19 mutations were recruited on 26 February 2010 and 29 January 2014, respectively. In the erlotinib arm, 10 patients did not have an assessment of tumour response (three did not return to the hospital for evaluation; two discontinued treatment by themselves within one month; and two died within 1 month of treatment) or a confirmed response (three had an initial response of SD but did not undergo further imaging). In the gefitinib arm, eight patients did not undergo an assessment of tumour response (four died within 1 month of treatment, and four discontinued treatment by themselves within 1 month due to AEs or financial problems and refused to undergo imaging investigation). The compliance of the enroled patients was 95.3% (244/256).

Figure 1
Figure 1

Trial profile.The study flowchart is shown from randomisation to data cutoff.

Patient characteristics

The 256 randomized patients formed well-balanced treatment arms in terms of baseline demographics and clinicopathological characteristics (Table 1). The median age was 58.5 years (range, 30–85 years); 57.8% of the patients had EGFR exon 19 deletions, and 66.0% were in the first-line setting.

Table 1: Baseline demographics between the erlotinib and gefitinib arms

Efficacy analysis

The last follow-up was on 30 June 2015, and the median follow-up time was 22.1 months. When 218 progression events (85.2%) and 184 survival events (71.9%) had occurred, both PFS and OS were mature. PFS did not differ significantly between the treatment arms in the intent-to-treat population (HR 0.81, 95% CI 0.62–1.05, P=0.108; Figure 2A). Median PFS was 13.0 (95% CI 11.1–14.9) vs 10.4 (95% CI 8.8–11.9) months for the erlotinib and gefitinib arms, respectively (Figure 2A). Similarly, OS was not significantly different (median OS: erlotinib, 22.9 months; gefitinib, 20.1 months; HR 0.84, 95% CI 0.63–1.13, P=0.250; Figure 2B). Post-discontinuation therapies are listed in Supplementary Table S1. There was no significant difference in RR between the two arms in the intent-to-treat population (56.3% (76/128) vs 52.3% (67/128), P=0.530). The waterfall plots for the best percentage change in target lesion size are shown for the two arms (Figure 3).

Figure 2
Figure 2

Kaplan-Meier curves of PFS and OS in 256 patients.(A) Median PFS in the erlotinib and gefitinib arms. (B) Median OS in the erlotinib and gefitinib arms. (C) Median PFS in the EGFR exon 19 and 21 mutation arms. (D) Median OS in the EGFR exon 19 and 21 mutation arms. EGFR, epidermal growth factor receptor.

Figure 3
Figure 3

Waterfall plots of the best percentage change in target lesions at baseline.(A) Gefitinib arm. (B) Erlotinib arm. CR, complete remission; PR, partial response; SD, stable disease; and PD, progressive disease.

Baseline demographic characteristics for the EGFR exon 19 and 21 mutation arms are shown in Table 2. Except for age and line of EGFR TKI treatment, the other baseline demographics were well-balanced between the two arms. Upon receiving erlotinib or gefitinib treatment, patients with EGFR exon 19 mutations were superior to those with exon 21 mutations in terms of median OS (22.9 vs 17.8 months, HR 0.71, 95% CI 0.53–0.95, P=0.022; Figure 2D) and RR (62.2% vs 43.5%, P=0.003; Table 3), even though there was no significant difference in median PFS (11.4 vs 11.2 months, HR 0.82, 95% CI 0.63–1.08, P=0.160; Figure 2C).

Table 2: Baseline demographics between the exon 19 and 21 mutation arms
Table 3: Response to erlotinib or gefitinib between the exon 19 and 21 mutation arms

However, in the first-line setting, the erlotinib and gefitinib arms had an RR of 58.0% (47/81) vs 52.4% (44/84) (P=0.466), a median PFS of 13.2 vs 11.1 months (HR 0.96, 95% CI 0.69–1.35, P=0.827), and a median OS of 22.4 vs 20.7 months (HR 0.98, 95% CI 0.67–1.42, P=0.902).

Safety

In the safety population of 256 patients who received any dose of study drug, no significant difference was observed in the frequency of Grade 3 AEs in the erlotinib and gefitinib arms (5.4% vs 1.6%, P=0.172). No cases of interstitial lung disease were recorded. The treatment-emergent AEs that were observed in 10% of the patients in each arm are shown in Table 4.

Table 4: Treatment-emergent AEs10% of patients in either treatment arm

Discussion

To the best of our knowledge, the present study was the first head-to-head phase III randomised controlled trial comparing erlotinib with gefitinib in EGFR activating mutation-positive NSCLC. The results did not support the hypothesis described in the study design, namely, that the primary end point, PFS, would be significantly prolonged with erlotinib compared with gefitinib. These two EGFR TKIs produced similar results for RR, OS, and toxicity. To some extent, the conclusion of the present study was almost the same as that of the earlier randomised phase II study, in which gefitinib and erlotinib showed similar efficacy and tolerable toxicity profiles as second-line treatments for molecularly selected (EGFR activating mutations accounted for 17.7% (17/96) of all enroled patients) or clinically selected populations of patients with NSCLC (Kim et al, 2012). However, patients with EGFR exon 19 or 21 mutations in any line setting were enroled in the present study, leading to precision medicine in advanced NSCLC. In addition, the present study had a larger sample size (N=256; 128 in each arm) than the previous phase II study (N=96; 48 in each arm; Kim et al, 2012).

A prospective study showed no significant difference in PFS (14.0 vs 13.0 months, P=0.62) or OS (28.0 vs 27.0 months, P=0.67) between first- and second-line erlotinib treatment in EGFR-mutant NSCLC (Massuti et al, 2009; Rosell et al, 2009). Furthermore, in recent years, several phase III randomised controlled trials have demonstrated no significant difference in OS between first-line EGFR TKIs and chemotherapy for patients with EGFR-mutant advanced NSCLC, probably owing to subsequent EGFR TKI treatment for those receiving first-line chemotherapy (Mok et al, 2009; Maemondo et al, 2010; Mitsudomi et al, 2010; Zhou et al, 2011; Rosell et al, 2012; Sequist et al, 2013; Wu et al, 2014). Taken together, the design of the present study, comparing erlotinib with gefitinib in both first- and second-line settings, was evidence-based and could be rationalised in 2009.

In the present study, subgroup analyses showed that patients with EGFR exon 19 mutations had a significantly higher RR (62.2% vs 43.5%, P=0.003) and longer median OS (22.9 vs 17.8 months, P=0.022) than those with exon 21 mutations treated with erlotinib or gefitinib, similar to the results of several retrospective studies in which better efficacy was observed in patients with EGFR exon 19 deletions than in those with exon 21 L858R mutations (Jackman et al, 2006; Riely et al, 2006; Rosell et al, 2012); however, the present study had a relatively large sample size (N=148 vs N=108) and a prospective design based on our translational data (Zhu et al, 2008). Recently, an analysis of OS data from two randomised phase III trials suggested that EGFR del19-positive disease might be distinct from L858R-positive disease and that these subgroups should be analysed separately in future trials (Sequist et al, 2013; Wu et al, 2014; Yang et al, 2015). However, the above differences were found in subgroup analyses. Therefore, it could be very challenging to draw a definitive conclusion.

Recently, first-line gefitinib was approved by the FDA for patients with EGFR-mutant advanced NSCLC (FDA approves targeted therapy for first-line treatment of patients with a type of metastatic lung cancer, 2015). The present study identified no significant differences in efficacy or toxicity profile between first-line erlotinib and gefitinib for patients with EGFR-mutant disease, and these results could be considered globally. Recently, in the LUX LUNG 7 trial, first-line afatinib (an irreversible ErbB family blocker) significantly improved PFS vs gefitinib in EGFR-mutant patients (HR 0.73, 95% CI 0.57–0.95, P=0.0165; Park et al, 2016). However, the LUX LUNG 7 trial was a global randomised phase IIb study, and the results will be validated by future phase III trials. The question remains as to the acceptable length of the survival benefit in the clinic. More investigations are warranted to determine which generation EGFR TKIs will be the best choice for the treatment of EGFR-mutant patients.

There are a few limitations to the present study. First, it took 5 years to complete recruitment at a single centre, and several competitive trials might have affected enrolment during this long period, possibly leading to an enrolment bias. Second, the present study was not sponsored by any pharmaceutical companies, and patients self-paid for study drugs and imaging investigations, so a few were not fully compliant. Finally, the efficacy data for erlotinib and gefitinib indicated that a much larger sample size was necessary in the present study.

In conclusion, the primary end point was not met in the present study, and erlotinib was not significantly superior to gefitinib in advanced NSCLC with EGFR exon 19 or 21 mutations in terms of response or survival, and it had similar toxicity. Meanwhile, upon treatment with erlotinib or gefitinib, patients with exon 19 mutations had markedly better outcomes than those with exon 21 mutations.

Genetic Testing in New NSCLC: Worth the Effort?


“If you build it, they will come,” the saying goes, but has that been the case with genetic/genomic testing in patients with newly diagnosed non-small cell lung cancer (NSCLC)? After all, research has shown that about 40% of patients with NSCLC have one of these molecular alterations in their tumor, and using these tests can help sort out those who have KRAS-mutated disease, versus epidermal growth factor receptor (EGFR) mutations, versus ALK, ROS1, or RET translocations, guiding patients to the most effective targeted therapy.

A recent international survey of oncologists revealed that while the use of genetic/genomic is on the rise, many clinicians are either bypassing testing altogether, or if the patient did undergo testing, the results were not used to make treatment decisions.

 Overall, genetic testing can help clinicians get a better handle on the subtype of NSCLC they are contending with, based on specific molecular alterations. This improved disease description will give patients a better chance of receiving the most effective treatment with the least toxicity and, ideally, at the right price point.

For instance, EGFR mutations are currently the most common genomically classified subgroup of NSCLC. These mutations tend to be more prevalent in tumors with adenocarcinoma histology, in patients who have never smoked tobacco, in patients of East Asian race, and women. Results of genetic/genomic testing can then set patients up for treatment with agents such as gefitinib (Iressa) and erlotinib (Tarceva).

Guidelines established by specialty groups, including the College of American Pathologists and the International Association for the Study of Lung Cancer, recommend testing for EGFR mutations (along with testing for ALK mutations) in patients with advanced-stage disease. Whether early-stage patients should undergo the same is uncertain.

“The question of whether or not to test a diagnostic specimen in early-stage disease is a local decision that must be made in conjunction with each institution’s oncology care team, as insufficient published evidence supports a universal recommendation,” according to 2013 guidelines from the groups mentioned above. “The benefits of testing all early-stage disease patients must be balanced against the cost of performing testing that may not be used to select therapy for the patients who never have relapse.”

But genetic screening in early NSCLC isn’t out of the question, wrote Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, in an email to MedPage Today. He pointed out that there is a debate over the risk of relapse in stage I-II cancer, but even if that risk is over a 5-year period, it “reaches 50%, so I also believe it could help.”

 Even in early-stage NSCLC, molecular testing can serve as a decisive factor in the choice of therapeutic strategies for patients, explained Frédérique Nowak, PhD, of the French National Cancer Institute (INCa) in Boulogne-Billancourt, France in an email to MedPage Today.

For example, early testing can rule out if a patient is simply ineligible for treatment with gefitinib, an EGFR tyrosine kinase inhibitor (TKI). Nowak cited a 2012 study that she and Soria co-authored that found that EGFR testing avoided a median of 8 weeks of administration of gefitinib for EGFR-negative patients.

An added benefit to testing? The potential for a significant reduction in treatment costs. “In France in 2010, about 15,000 of the 16,834 patients with lung cancer who benefited from EGFR screening were EGFR-mutation negative and thus were ineligible for TKI-EGFR treatment,” Nowak stated.

“As 8 weeks of gefitinib treatment costs €4,600 per patient in France [about $5,000], this would mean overall savings of €69 million [about $74 million]. According to the numbers of EGFR tests performed in 2011, the spared costs should be even greater,” she added.

Seven years ago, INCa, along with the French Ministry of Health, launched a campaign to implement molecular testing for all cancer patients across the French national healthcare system. The network is made up of 28 regional molecular genetic centers that perform tests for free for all patients in their regions.

 Nowak reported that the network now “is fully deployed in the country. For lung cancer, the tumors of more than 24,000 patients were screened for EGFR mutation and ALK rearrangement in 2014. It roughly corresponds to all non-epidermoid NSCLC patients at a metastatic stage in France.”

Back to the survey results, which revealed that one of the impediments to implementing genetic testing in newly diagnosed patients may be the wait for the results – the turnaround time for test findings can range from 1 to 2 weeks. About a quarter of U.S.-based survey respondents stating that was too long.

In general, lung cancer takes some time to develop before a diagnosis is made; a few extra days of waiting for test results that can have a major impact on treatment course and patient outcomes shouldn’t be that onerous, noted survey leader James Spicer, PhD, MBBS, of King’s College London.

“Personally — and I think this is a fairly common viewpoint — turnaround within 1 week — 5 working days — would definitely be acceptable; 2 weeks or more becomes a problem,” he said.

While Spicer told MedPage Today that he wasn’t surprised by the survey results, his group also did not find any evidence that clinicians were skeptical about EGFR testing overall. Instead, it may be a matter of continual education to emphasize the benefits of genetic testing in NSCLC patients across the board.

“We should be aiming for every suitable NSCLC patient to be tested, and every patient receiving an appropriate treatment for their type of lung cancer,” Spicer said in a written statement about the survey results. He added that “there is still work to be done in emphasizing the importance of obtaining EGFR test results prior to the initiation of treatment, and using this vital information to select optimum therapy.”

Afatinib outperforms gefitinib in Asian patients with EGFR-positive NSCLC


The pan-ERB inhibitor afatinib improves progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) compared with gefitinib among Asian patients with EGFR-positive non-small cell lung cancer (NSCLC) included in the LUX-Lung 7 trial. [APLCC 2016, ABS068]

“Median PFS and TTF were significantly longer with afatinib [11 and 13.7 months] than with gefitinib [10.9 and 11·5 months],” said study investigator Professor Kenneth O’Byrne, consultant medical oncologist at the Princess Alexandra Hospital in Brisbane, Queensland, Australia, at the recent APLCC 2016 held in Chiang Mai, Thailand. “Among Asian patients, PFS was prolonged by 24 percent. OS [overall survival] data are not mature yet.”

The secondary endpoint of ORR by independent review was also higher with afatinib (70 vs 56 percent for gefitinib). ORR in Asian patients was 70 percent with afatinib versus 57 percent for gefitinib.

“Results were consistent across all subgroups evaluated, including Asian patients,” O’ Byrne reported. “The improvement in efficacy was observed in both del19 and L858R populations.” Among Asian patients with del19 mutation, ORR was 72 and 68 percent, in favour of afatinib. In those with L858R mutation, ORR was also higher with afatinib (68 vs 42 percent with gefitinib).

Professor Kenneth O'Byrne

Professor Kenneth O’Byrne

LUX-Lung 7 was an international, phase IIb, randomized, open-label trial investigating the efficacy and safety of afatinib vs gefitinib in untreated patients with advanced, EGFR-positive NSCLC. The trial was done at 64 centres in 13 countries. [Lancet Oncol 2016;pii: S1470-2045(16)30033-X]

Patients were randomized to receive afatinib 40 mg once daily (n=160) or gefitinib 250 mg once daily (n=159) until radiological disease progression or beyond, by investigator decision. Median follow-up was 27.3 months. The coprimary endpoints were PFS by independent review, TTF, and OS. Over half of the participants were Asians (59 percent with afatinib; 55 percent with gefitinib). Baseline characteristics such as ethnicity and type of EGFR mutation were similar between arms.

“Adverse events in both groups were consistent with previous experience using the drugs and were manageable, leading to equally low rates of treatment discontinuation (6 percent for both),” said O’Byrne.

The most common grade ≥3 adverse events reported were diarrhoea, rash and acne with afatinib, and liver enzyme elevations with gefitinib.

“LUX-Lung 7 confirms the benefit of irreversible ErbB blockade with afatinib over reversible EGFR inhibition with gefitinib in the treatment of EGFR-positive NSCLC,” he concluded.

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.


Background

Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.

Methods

In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18—75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.

Findings

400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67—1·05; median progression-free survival 4·6 months [95% CI 3·5—6·3] vs 3·4 months [2·3—3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).

Interpretation

Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

Source: Lancet