Journal of Chemotherapy
`
`ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
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`Gefitinib Treatment Is Highly Effective in Non-
`Small-Cell Lung Cancer Patients Failing Previous
`Chemotherapy in Taiwan: A Prospective Phase II
`Study
`
`Yuh-Min Chen, Reury-Perng Perng & Chun-Ming Tsai
`
`To cite this article: Yuh-Min Chen, Reury-Perng Perng & Chun-Ming Tsai (2005) Gefitinib
`Treatment Is Highly Effective in Non-Small-Cell Lung Cancer Patients Failing Previous
`Chemotherapy in Taiwan: A Prospective Phase II Study, Journal of Chemotherapy, 17:6,
`679-684, DOI: 10.1179/joc.2005.17.6.679
`
`To link to this article: http://dx.doi.org/10.1179/joc.2005.17.6.679
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`Published online: 18 Jul 2013.
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`AVENTIS EXHIBIT 2051
`Mylan v. Aventis, IPR2016-00712
`
`

`
`REPRINT
`
`Journal of Chemotherapy
`
`REVIEW
`
`Vol. 17 - n. 6 (679-684) - 2005
`
`Gefitinib Treatment Is Highly Effective in Non-Small-Cell
`Lung Cancer Patients Failing Previous Chemotherapy
`in Taiwan: A Prospective Phase II Study
`
`YUH-MIN CHEN - REURY-PERNG PERNG - CHUN-MING TSAI
`
`Chest Department, Taipei Veterans General Hospital, School of Medicine,
`National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
`Correspondence to: Dr. Yuh-Min Chen, Chest Department, Taipei Veterans General Hospital, Shih-pai Road,
`Taipei 112, Taiwan. Fax: +886-2-28763466 - Tel: +886-2-28763466. E-mail: ymchen@vghtpe.gov.tw
`
`Summary
`Gefitinib has shown activity in the treatment of non-small-cell lung cancer
`(NSCLC) patients who failed previous platinum-based combination chemotherapy
`and/or taxane treatment. Recently, gefitinib was documented to be more effective
`in an East Asian population, as well. Thus, we performed a gefitinib trial in
`Taiwanese patients to assess the efficacy of this regimen.
`Treatment consisted of gefitinib 250 mg one tablet daily until disease progres-
`sion.
`Thirty-six patients were enrolled from January 2003 to September 2004.
`Gefitinib was second-line treatment in 10, third-line in 15, fourth-line in 9, and
`fifth-line in 2. All patients were evaluable for toxicity profile and response rate.
`After 8 weeks of treatment, three patients had a complete response (CR) and nine
`had a partial response (PR), with an overall response rate of 33.3% (95% confi-
`dence interval 17.9% - 48.7%). All treatment-related toxicities were few and mild in
`severity, except that one patient suffered from reversible grade 3 interstitial pneu-
`monitis. The median time to disease progression was 4.7 months, and the median
`survival was 9.5 months. The one-year survival rate was 45.1%. Survival was sig-
`nificantly better in those who responded to treatment (CR and PR) than in those
`who did not (median 20.1 vs. 4.7 months, p=0.0002). Survival was also better in
`those who demonstrated disease control using gefitinib (CR, PR, and stable disease)
`than in those who did not (14.1 vs. 1.4 months, p<0.0001).
`The authors conclude that daily gefitinib treatment has high activity, is well tol-
`erated, and provides very good survival in Taiwanese NSCLC patients who have
`failed previous chemotherapy, especially in those who responded to gefitinib treat-
`ment or those whose disease was controlled by gefitinib treatment.
`
`Key words: Epidermal growth factor receptor (EGFR), gefitinib, non-small cell
`lung cancer, salvage therapy.
`
`INTRODUCTION
`
`Gefitinib (Iressa; AstraZeneca Pharmaceuticals,
`Wilmington, DE) is a selective epidermal growth fac-
`tor receptor tyrosine kinase inhibitor (EGFR-TKI). It
`is an orally active agent for advanced non-small-cell
`lung cancer (NSCLC) in those who have failed a
`previous platinum-based regimen and taxane treat-
`
`ment 1-3. In two large phase II trials (IDEAL 1 and
`IDEAL 2), gefitinib was shown to have substantial
`effect as salvage treatment for patients who had
`failed at least one or two previous regimens of
`chemotherapy 1,2.
`The IDEAL 1 study found that Japanese patients
`had a better response to gefitinib treatment than
`Caucasian patients. Once it was found that the
`
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`EGFR mutation occurred more frequently in
`Japanese patients than in Caucasians, and that
`those patients with an EGFR mutation had a better
`response to gefitinib treatment, researchers under-
`stood why gefitinib had better efficacy in Japanese
`patients than in Caucasians 4-6.
`Based on the relatively good toxicity profiles and
`high activity found in the Japanese patients of the
`IDEAL-1 study, we decided to conduct a phase II
`trial using single-agent gefitinib in NSCLC patients
`failing previous chemotherapy, in order to investi-
`gate the efficacy and toxicity profile of this agent in
`Chinese patients who lived in Taiwan.
`
`PATIENTS AND METHODS
`The study was conducted according to existing
`rules for good clinical practice, and the study proto-
`col was approved by the local ethics committee.
`Patients with NSCLC who had failed previous plat-
`inum-based chemotherapy (age ≤80 years) or non-
`platinum-based chemotherapy (age >80 years), were
`entered into the study after giving informed consent.
`Eligibility criteria were: a histological or cytological
`diagnosis of stage IV NSCLC in those who had
`failed previous chemotherapy; clinically measurable
`disease, defined as bidimensionally measurable
`lesions; no previous radiotherapy on measurable
`lesion(s); and a life expectancy of more than 2
`weeks. Adequate bone marrow reserve and renal
`and liver functions, which are usually required in
`clinical trials with chemotherapy, were not required
`in the present study.
`Baseline evaluations included a documentation of
`the patient’s history, a physical examination, and a
`performance score. A complete blood cell count, uri-
`nalysis, serum biochemistry profile, ECG, chest
`roentgenography, whole body bone scan, brain CT
`scan, and chest (including the liver and adrenal
`glands) CT scan were also performed.
`Subsequent complete blood cell count and serum
`biochemistry studies were performed 2 weeks after
`the beginning of gefitinib treatment, and then, every
`4 weeks. Study drug-related adverse events and toxi-
`cities were recorded, according to established
`Eastern Cooperative Oncology Group (ECOG) crite-
`ria 7.
`All patients received gefitinib at a fixed daily oral
`dose of 250 mg. Concomitant use of other
`chemotherapeutic agents was not allowed. Palliative
`radiotherapy to the lesion not used as a measurable
`lesion(s) was allowed. Gefitinib was given until dis-
`ease progression or the presence of intolerable toxi-
`city. Treatment was temporarily stopped for one or
`two weeks if the patients suffered from grade 3 or
`worse toxicities; gefitinib could be re-started from a
`50% dose once the toxicity was reduced to grade 2
`or less, except in cases of drug-induced pneumonitis,
`in which the treatment would be permanently
`
`stopped if the patient suffered from grade 3 or
`worse toxicity. A subsequent dose escalation to the
`original level was allowed provided that the patient
`tolerated the doses given at the 50% level.
`Evaluation of response was performed after 4
`weeks of treatment, and every 8 weeks thereafter.
`Types of response were also assessed, according to
`established ECOG criteria 7. Responding patients
`and those with stable disease were continued until
`disease progression.
`A Simon two-stage phase II minimax design was
`used (α=0.1, β=0.1) to estimate patient accrual tar-
`gets. It was estimated that the power of this study to
`detect a true response rate of 20% was 0.9, requir-
`ing an accrual of at least 32 patients 8. Survival was
`measured from administration of the first dose until
`the date of death or last follow-up. For statistical
`analysis, the Kaplan-Meier method with a log-rank
`test was used for single-variate survival analysis. The
`Cox-regression test, including sex, smoking,
`response to treatment or not, adenocarcinoma or
`others, performance status, and present treatment
`as ≤ third-line or later, was performed for multivari-
`ate survival analysis. The SPSS statistical program
`was used.
`
`RESULTS
`Between January 2003 and September 2004,
`36 patients (20 males, 16 females) were enrolled
`into this study. The mean age was 62 years, with a
`range of 35-82 years. Seventy-five percent of the
`patients had a performance status of 2 or worse. All
`were stage IV patients. For those who received gefi-
`tinib as third-line or later treatment, cisplatin-based
`combination chemotherapy was given as first-line
`treatment and docetaxel as second-line treatment.
`The patients’ clinical characteristics are shown in
`Table 1. All were assessable for toxicity profile and
`treatment response.
`The mean number of treatment days was 223
`(median 140 days, range 8-779 days). After 8
`weeks of treatment, three patients had a complete
`response (CR) and nine patients had a partial
`response (PR), with an overall response rate of
`33.3% (95% confidence interval 17.9% - 48.7%).
`Stable disease was found in 14 patients (38.9%),
`and progressive disease was documented in the
`remaining 10 (27.8%).
`The median time to disease progression was 4.7
`months (95% confidence interval 0-10.6 months),
`and median survival was 9.5 months (95% confi-
`dence interval 4.1-14.9 months). The one-year sur-
`vival rate was 45.1%. Survival was significantly bet-
`ter in those who responded to treatment (CR and
`PR) than in those who did not (Figure 1, median
`20.1 vs. 4.7 months, p=0.0002). Survival was bet-
`ter in those who had disease control due to gefitinib
`treatment (CR, PR, and stable disease) than in those
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`GEFITINIB TREATMENT IS HIGHLY EFFECTIVE IN NON-SMALL-CELL LUNG CANCER PATIENTS FAILING PREVIOUS CHEMOTHERAPY ... 681
`
`TABLE 1 - Patient characteristics (n=36).
`
`Variable
`
`Male/female
`
`Mean age, Yr (range)
`
`Smoking, yes/no
`
`WHO performance status
`
`1
`2
`3
`4
`
`Histology
`
`Adenocarcinoma
`Squamous cell carcinoma
`NSCLC, type unspecified*
`
`Present treatment as
`
`2nd line
`3rd line
`4th line
`5th line
`
`N.
`
`20/16
`
`62 (35-82)
`
`14/22
`
`%
`
`55.6/44.4
`
`38.9/61.1
`
`9
`21
`5
`1
`
`25
`5
`6
`
`10
`15
`9
`2
`
`25
`58.3
`13.9
`2.8
`
`69.4
`13.9
`16.7
`
`27.8
`41.7
`25
`5.6
`
`*“NSCLC, type unspecified” means the pathologist could only make the diagnosis of NSCLC. However, further
`sub-classification was too difficult to make.
`
`Complete or partial response
`(n=12) median 20.1M
`Stable or progressive
`disease (n=24) median 4.7M
`
`treatment than in those with progressive disease in
`spite of treatment (Figure 2, median 9.4 vs 1.4
`months, p=0.0011). The Cox-regression test for
`multivariate analysis, including sex, smoking,
`response to treatment or not, adenocarcinoma or
`others, performance status, and present treatment
`as ≤ third-line or later, showed that only response to
`treatment (p=0.0003) and performance status
`(p=0.0001) had statistical significance.
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`% Survival
`
`Stable disease (n=14)
`median 9.4M
`Progressive disease (n=10)
`median 1.4M
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`% Survival
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`Months
`
`12
`
`14
`
`16
`
`18
`
`20
`
`FIGURE 2 - The Kaplan-Meier survival curve of 14
`patients who had stable disease versus 10 patients who
`had disease progression. The median survival was 9.4
`months and 1.4 months, respectively (p=0.0011).
`
`All patients enrolled into the study were eligible
`for toxicity evaluation. The toxicities were few and
`mild in severity. No more than grade 2 toxicity
`
`0
`
`3
`
`6
`
`12
`9
`Months
`
`15
`
`18
`
`21
`
`FIGURE 1 - The Kaplan-Meier survival curve of 12
`patients with complete or partial response versus 24
`patients who had stable or progressive disease after treat-
`ment. The median survival was 20.1 months and 4.7
`months, respectively (p=0.0002).
`
`who did not (median 14.1 vs 1.4 months,
`p<0.0001), and was also better in those patients
`who had a better performance status (p=0.0014).
`Survival was longer in females and non-smokers,
`however, without statistical significance, and survival
`was not related to histology or present treatment as
`≤ third line or later (Table 2). Survival was also bet-
`ter in those who had stable disease after gefitinib
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`
`682
`
`Sex
`
`Smoking or not
`
`Histology
`
`Response or not*
`
`Disease controlled or not#
`
`Performance status
`
`Present treatment as
`
`Skin rash
`
`Dry skin
`
`YUH-MIN CHEN - REURY-PERNG PERNG - CHUN-MING TSAI
`
`TABLE 2 - Survival status of the patients treated with gefitinib.
`
`N. Patients
`
`Median
`survival
`(months)
`
`Male
`Female
`Yes
`No
`Adenocarcinoma
`Non-adenocarcinoma
`Yes
`No
`Yes
`No
`
`1
`2
`3
`4
`≤ 3rd line
`≥ 4th line
`Yes
`No
`Yes
`No
`
`20
`16
`14
`22
`25
`11
`12
`24
`
`26
`10
`9
`21
`5
`1
`25
`11
`12
`24
`8
`28
`
`9.3
`13.7
`3.4
`13.7
`9.4
`13
`20.1
`4.7
`
`14.1
`1.4
`20.1
`5.1
`4.7
`16.5
`9.3
`13.9
`19.1
`5.1
`26
`5.1
`
`p value
`(log-rank)
`
`0.3914
`
`0.2022
`
`0.4176
`
`0.0002
`
`<0.0001
`
`0.0014
`
`0.7441
`
`0.011
`
`0.0065
`
`*complete response and partial response.
`#complete response, partial response, and stable disease.
`
`occurred in the present study, except for one patient
`with grade 3 drug-induced interstitial pneumonitis.
`This patient responded well to steroid treatment.
`Other toxicity profiles included skin rash: ten grade
`1, and two grade 2; dry skin: two grade 1, and six
`grade 2; liver enzyme elevation: one grade 1, and
`one grade 2; diarrhea: four grade 1, and four grade
`2; and paronychia in 4. The response rate was
`higher in those with skin rash (p=0.0295) and dry
`skin (p<0.001), but not in those with paronychia
`(p=0.064). Survival was significantly better in those
`with skin rash (n=12, median 19.1 months) versus
`those without skin rash (n=24, median 5.1 months)
`(p=0.011). Survival was also better in those with dry
`skin (n=8, median 26 months) versus those without
`dry skin (n=28, median 5.1 months) (p=0.0065),
`but was not correlated with the occurrence of
`paronychia or not (p=0.1853).
`
`DISCUSSION
`Because the chemotherapy response rate for
`those who have failed previous chemotherapy is usu-
`ally low, at a level at or below 20%, the options
`available to patients with advanced NSCLC resistant
`or refractory to first-line chemotherapy are very lim-
`
`ited. The only chemotherapeutic agents that have
`been documented in phase III studies to be effective
`in second-line treatment were docetaxel and peme-
`trexed 9,10. In contrast, EGFR-TKI is a new class of
`anti-cancer agents that has been found effective,
`since 2003, in the salvage treatment of NSCLC
`patients who failed previous chemotherapy, includ-
`ing tarceva in second-line treatment 11 and gefinitib
`for patients after failure with both platinum-based
`and docetaxel chemotherapies 2,3.
`After a series of clinical trial reports and labora-
`tory studies, it was found that female gender, non-
`smoker, adenocarcinoma (especially those with a
`bronchioloalveolar carcinoma component), EGFR
`mutation, and East Asian ethnicity were known fac-
`tors predicting a better response to EGFR-TKI treat-
`ment, including gefitinib and tarceva 4,5,12. A previ-
`ous study also found that response to gefitinib treat-
`ment predicted a better survival 12, as in this study.
`The toxicity of gefitinib has been minimal and
`mild in degree, in both previous studies and this one
`1,2. The median survival and one-year survival of
`patients in this study was better than in the IDEAL-1
`and IDEAL-2 studies. Gefitinib has the advantage of
`a relatively rapid tumor response and a lot fewer
`severe side effects. In the IDEAL-1 study, 68% of
`NSCLC patients met the criteria for objective
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`GEFITINIB TREATMENT IS HIGHLY EFFECTIVE IN NON-SMALL-CELL LUNG CANCER PATIENTS FAILING PREVIOUS CHEMOTHERAPY ... 683
`
`response by the 4th week, as in our patients.
`The female patients and non-smokers of this
`study had a better prognosis, similar to other phase
`II studies, although this was not statistically signifi-
`cant in our study 1,4,5. The objective response rate in
`the present study was 33.3%, which is close to the
`data from other East Asian regions, including Japan
`(35.2%) and Singapore (38.8%) 13,14. The overall
`response rate of the IDEAL-1 trial was 27.5% for
`Japanese and 10.4% for non-Japanese (including
`patients from Europe, Australia and South Africa) 1.
`Thus, the response rate of East Asian NSCLC
`patients was around 30%, while it was only 10% for
`Caucasians.
`It has been recently reported that EGFR muta-
`tions played a critical role in predicting tumor
`response in patients receiving gefitinib, and that the
`frequency of EGFR mutations was strikingly different
`in East Asian and Caucasian populations 4,5. While
`the response rate of first-line combination
`chemotherapy is around 20-45%, it was only 10-
`15% in a second-line setting, and even less than
`10% in third-line regimens and thereafter 15. While
`the response rate to gefitinib was around 30% in an
`East Asian population, regardless of whether it was
`used as first-line or later treatment, and the response
`correlated with the patient’s survival, this response
`rate was much better than that of chemotherapeutic
`agents in a second-line or later setting, so gefitinib is
`deserving of use in the East Asian region for second-
`line or later treatment without further study of
`patient EGFR mutation status outside of clinical tri-
`als. This is especially useful in female non-smokers
`with an adenocarcinoma histology, who will have
`around a 60% EGFR mutation rate. The response
`rate of those with an EGFR mutation is around
`80%-84%, thus, there will be a response rate of
`around 50% 4,5,16-19. The usefulness of gefitinib in
`salvage therapy holds true even in EGFR mutation-
`negative patients who had about a 14% response
`rate to gefitinib treatment, which is similar to or bet-
`ter than chemotherapy in a second-line or later
`treatment. For first-line treatment, the detection of
`the EGFR mutation is still not valuable in female
`non-smokers with adenocarcinoma, because they
`will have a response rate of around 50%, which is
`still better than that of combination chemotherapy.
`However, the EGFR mutation status in other patient
`populations who will undergo first-line treatment is
`still worthy of determination. The issue of time con-
`sumption, the need of tissue or cytologic samples,
`and the costs for mutation analysis should not be
`forgotten, when comparing the use of a short
`course of gefitinib to look for a response and to
`assess mutation. The future will tell us which will be
`the better choice.
`In summary, gefitinib is an effective and rather
`safe salvage regimen for NSCLC patients who have
`failed previous chemotherapy. Tumors respond to
`the treatment rapidly, and there is a better predicted
`
`survival when an objective response is found.
`Gefitinib can be given to patients even when they
`have a poor performance status, which is completely
`different from the experience we have had with
`chemotherapeutic agents. Short-term gefitinib usage
`to determine whether or not to continue treatment
`is more effective and logical than determining the
`EGFR mutation, outside of clinical trials.
`
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