The g
efitinib story
gefitinib
Rokuro Hama and Keiko Sakaguchi, Kusuri-no-Check (Check your pills to save your life) gec00724@nifty.ne.jp
Gefitinib (Iressa, ZD1839, AstraZeneca Japan) was approved by the Japanese Ministry of Health, Labor and Welfare (MHLW) in July 2002 forthe treatment of inoperable or recurrent non-small cell lung cancer (NSCLC). In Japan, up until the end of January 2003, approximately
23 500 people had received gefitinib and 183 deaths had been attributed to the drug. Acute lung disease and/or interstitial pneumonitis were
implicated in 173 deaths. In this article we shall give a brief description of gefitinib, an outline of the experience with this drug in Japan and inWestern countries, and also our opinion on what should be learnt from this story.

Mechanism of action
Epidermal growth factor receptor (EGFR) isa cell surface receptor. Tyrosine kinase actson this receptor within the cell to regulate cellproliferation and survival. Inactivation of
EGFR by tyrosine kinase inhibition induces
apoptosis (cell death), and reduces
angiogenesis and metastasis of cancer cells.1,2During anticancer therapy research,
AstraZeneca researchers noted that:
1. there was an increased EGFR-mediateddrive in a variety of solid tumours (egNSCLC, breast cancer)

deficient levels of EGFR have shown

results of a series of animal experiments that

impaired epithelial development in several

showed gefitinib increased bleomycin-organs, including skin, lung andinduced lung toxicity (alveolar damage andgastrointestinal tract 4, severe bleeding andfibrosis).7 This is currently being investigatedweight loss in newborn rats with laboratory-by the MHLW.8

induced necrotising enterocolitis 5, anddelayed corneal wound healing.6

Clinical Trials

Animal toxicity studies

IDEAL 1 and IDEAL 2

Six-month toxicity studies in dogs revealed

Results of two randomised double-blindan increase in hepatic necrosis after gefitinib

phase II trials (IDEAL 19 and IDEAL 210) were

was given at doses of 5 mg/kg/day, which

presented at the American Society of Clinicalapproximates the clinical dose in humans.

Oncology (ASCO) meeting in May 2002.

When doses of 15 mg/kg/day were given
after 10 days at 25 mg/kg/day, relative lung

IDEAL 1 (AstraZeneca Study 16) enrolled

cancer cell surface was associated withweight and white blood cell counts in dogs

210 patients with locally advanced oradvanced disease and a poor prognosis

increased dose-dependently3, indicating lungmetastatic NSCLC who had previously

in cancer patients.

inflammation that was possibly induced byreceived at least one chemotherapy regimen

gefitinib.

containing platinum.

target for anticancer therapy. AstraZeneca

In 6-month rat studies, 4 of 60 rats died after

IDEAL 2 (AstraZeneca Study 39) enrolled

screened 1500 EGFR-tyrosine kinase

being given gefitinib at a dose of 25 mg/kg/

216 patients (mostly Caucasians) with

inhibitor (TKI) derivatives and developed the

day for 8 weeks followed by 15 mg/kg/day

locally advanced or metastatic NSCLC whoorally active gefitinib as the most selective

for 4 months. The rats were shown to have

had previously failed at least two priorinhibitor.

renal papillary necrosis, liver necrosis andchemotherapy regimens containing

other lesions. These findings were considered

platinum and docetaxel therapy. In bothto be consistent with the mechanism of

trials, patients received gefitinib orally at aaction of gefitinib.3

dose of either 250 mg daily or 500 mg daily.

It was reported recently in the Japanese

Response and survival rates are shown inpress that AstraZeneca did not submit theTable 1 below.

2. excessive activation of EGFR on theInactivation of EGFR therefore became a3

Effect on normal cells
AstraZeneca has stressed gefitinib’s EGFRTKI selectivity and its efficacy on
experimental tumour models.1-3 However,3

they have not adequately addressed thepotentially harmful effects on normal tissue
and injured noncancer cells.

Table 1. Tumour response rate and median survival in patients treated withgefitinib after previous treatment with platinum-based chemotherapy

Almost all cells have EGFRs.4 So gefitinib
not only inhibits the growth of cancer cells
but also inhibits physiological replacement of
normal cells, particularly after injury whenrecovering tissues require more epidermal
growth factor.
This effect has been demonstrated in animalmodels. Studies in mice and rats with

Objective tumour

IDEAL 1 (Study 16)

IDEAL 2 (Study 39)

250 mg/day 500 mg/day

250 mg/day 500 mg/day

18.4%

19.0%

11.8%

8.8%

7.6

8.1

6.1

6.0

response rate
Median survival(months)•

patients must remain in hospital for four

A subsequent evaluation of Study 16 by the

NSCLC were presented at the European

Japanese Pharmaceutical and Medical

Society for Medical Oncology Congress inweeks after the commencement ofDevices Evaluation Centre showed that the

October 2002.

therapy

response rate in Japanese patients (23.5%
in both 250 mg and 500 mg arms) was
higher than in non-Japanese patients (5.8%
in 250 mg arm, 9.3% in 500 mg arm).
Although the reason for this difference is notentirely clear, the less intensive and shorter

12,13

Gefitinib (250 mg/day or 500 mg/day) or•

doctors must exercise caution in using

placebo was combined with gemcitabine andgefitinib in patients who have a history ofcisplatin in INTACT 1 (1093 patients) andinterstitial pneumonitis or other lungwith paclitaxel and carboplatin in INTACT 2

diseases.

12(1037 patients).

13

In February 2003, AstraZeneca Japan

duration of chemotherapy regimens often

Neither study showed an improvement inannounced that the number of deaths as aused in Japanese patients may influence theresponse rate or survival benefit whenresult of adverse reactions to gefitinib in

response to subsequent therapy.

gefitinib was added to standard treatment.

Japan had reached 183 by 31 January

Adverse reactions

Pharmacokinetics

received gefitinib in Japan by this date, andIn Study 39 the most frequent adverse

Gefitinib is mainly metabolised by liver

Of these, acute lung disease and/or

events in patients receiving 250 mg gefitinib

CYP3A4. CYP3A4 activity varies more thaninterstitial pneumonitis were implicated indaily were diarrhoea (57%), rash (48%),

40-fold between individuals.14,15

473 cases and, of these, 173 patients had

Subsequently, there is wide (30- to 100-fold)died.

asthenia (28%), dyspnoea (28%), nausea(27%) and acne (26%).11

2003.16 Approximately 23 500 patients had
there had been 644 adverse reaction reports.

interindividual variation in maximum

AstraZeneca Japan claims that the safety

The mortality rate in this study due toconcentration and area under the curvemeasures introduced by the MHLW on 26

adverse events was reported as 5.1%

values after repeated gefitinib dosing.3 Time

December 2002 have effectively decreased(11/216).3,11 However, another 4 deaths due

to maximum concentration (Tmax) in cancer

the case mortality rate but the cumulative

to adverse events—pneumonia (1), acutepatients varied from 1 to 24 hours andmortality rate continues to rise.

respiratory distress syndrome (ARDS) (1),elimination half-life varied from 10 to 90

dyspnoea (2)—were described in a notehours in healthy volunteers and patients.3

outside the relevant table. The true mortality
rate due to adverse events was therefore
almost 7% (15/216).

Japanese experience

Case reports
The following cases were presented to theJapanese panel considering the safety

Gefitinib was approved on 5 July 2002 inproblem of gefitinib in late 2002.8

Japan, five months after the application was

Case 1. A woman in her sixties was

submitted by AstraZeneca.

admitted with progression of lung cancer.

(25%) in Study 39 and in 39 of the 107

On 15 October 2002, the Japanese MHLW

Three weeks after admission, treatment with

Caucasian patients (36%) in Study 16. Of

issued a ‘yellow letter’ alerting prescribers

gefitinib was commenced. Her lung cancer

these, 15 patients (6.9%) in Study 39 and 4

that the use of gefitinib had been linked to 13

responded well and her tumour decreased in

Caucasian patients (3.7%) in Study 16 dieddeaths. More detailed adverse effectsize within one week, but the next day she

due to adverse events.

warnings were also imposed at this time.

had diarrhoea and dyspnoea. Typical diffuse

In one of the phase I/II trials (AstraZeneca

However, the mortality rate continued to rise,

Study 11), 9 of 69 patients (13%) died due towith 124 deaths due to adverse reactions toan adverse event. Of these, 7 had

gefitinib notified by 13 December 2002.

Serious adverse events such as ARDS and/or pneumonia or pneumonitis (or acute lunginjuries) were seen in 55 of the 216 patients

respiratory tract complications: pulmonary
insufficiency (2), pneumonia (2), bleedingfrom respiratory tract (2), and ARDS (1). Of
the 9 deaths due to adverse events, gefitinib
had been withdrawn in 5 of the patients, but
none of these events were classified as
drug-related.

INTACT 1 and INTACT 2
Results of two large randomised, double-

opaque appearance on the chest X-ray was

Stricter safety measures were announced by
the MHLW on 26 December 2002. These
measures were recommended by a panel,comprising experts in medicine andfound and gefitinib was withdrawn. She
failed to improve with oxygen andcorticosteroid pulse therapy. She died 8 days
after the withdrawal of gefitinib frommultiorgan failure involving lung,gastrointestinal tract, liver, kidneys andheart.

pharmacy, which had been convened to
examine the safety of gefitinib.

Case 2. An ambulant woman in her
seventies with NSCLC was admitted to

The new measures require that:•

hospital and gefitinib therapy was initiatedinformed patient consent must be

the next day. Seven days later, the woman

obtained before gefitinib is administeredcomplained of dyspnoea and a chest X-ray

gefitinib must only be prescribed byindicated interstitial pneumonitis. Gefitinib

blind, placebo-controlled, phase III trials in

doctors experienced in treating patientswas withdrawn and she was treated withchemotherapy-naive patients with advancedwith lung cancer

corticosteroids, but she died later that day.

•Case 3. A man in his seventies with severe

other health professionals and patients to theGefitinib inhibits the normal repair processcongestive heart failure experienced

adverse drug-related effects that havewhen tissue is injured. Many patients

abdominal discomfort the evening after

occurred with gefitinib. Such information hasreceived chemotherapy and/or radiationcommencing gefitinib. On day 3, he

not been forthcoming from the drug company.

therapy before starting gefitinib and there

developed an ileus and gefitinib waswithdrawn. However, severe hypoxaemia

may be residual tissue damage. Although

Experience in othercountries

this injury may be predictable, it is in

gefitinib with multiorgan failure involving the

A submission for approval of gefitinib in

during the treatment course and the ensuinglungs, gastrointestinal tract, and kidneys.

NSCLC is currently before the Food andsystemic inflammatory response syndrome

The elimination of gefitinib by CYP3A4 liver

Drug Administration (FDA) in the US.11 In

may induce tissue injury in the lungs andand intestinal enzymes may have been

September 2002, the FDA’s Oncologic

various other organs. The process ofcompromised in this patient as a result of his

Drugs Advisory Committee recommended

repairing this injured lung tissue may be

severe congestive heart failure.

accelerated approval of gefitinib based on

inhibited by gefitinib, with resulting

IDEAL 1 and IDEAL 2 study results.

pulmonary toxicity.

and pulmonary symptoms progressed. He
died one week after the withdrawal of

The panel noted that of the 17 patients who
experienced adverse symptoms within one
week of commencing gefitinib, 13 (76%) died.

Published case reports

precisely these patients that gefitinib has
been used. In addition, infection may occur

However, FDA reviewers were concernedthat there was no non–gefitinib-treatedcontrol group, that there were a number ofpatients with slowly growing, less aggressive
cancers that made evaluation of results

Extensive promotion andwide use of unapproved
gefitinib

An article published in The Lancet in Januarycomplicated, and that there were a number

Use of unapproved gefitinib commenced in2003 described four Japanese patients withof other confounding factors. This concern

December 2000, when it was provided freeadvanced NSCLC who developed severe

was reinforced with the release of theof charge on a compassionate basis. Brief

acute interstitial pneumonia in association

INTACT 1 and INTACT 2 study results,

product information was provided.

with gefitinib.17 Two patients recovered but

which showed no survival benefit withthe other two died from progressive

gefitinib when used as first-line therapy in

respiratory dysfunction. The authors

combination with standard chemotherapy

concluded that gefitinib induces pulmonary

regimens.19 It appears that the accelerated

toxic effects, especially in patients withprocess has been put on hold and a decisionpulmonary comorbidities.

from the FDA is not expected until May 2003.

AstraZeneca response

Meanwhile, AstraZeneca announced in

The price in Japan is now ¥7216(approximately US$60, €56 or £38) per
250 mg tablet, or more than ¥210 000(approximately US$1800) for one month’s
treatment at a dose of 250 mg daily.
AstraZeneca has several websites including

AstraZeneca has queried the association
between gefitinib and the deaths in Japan. A
spokeswoman from their London
headquarters said:
ILD [interstitial lung disease] has been
observed in patients, but causality hasn’t
been established. The problem with ILD isthat it’s a well-known phenomenon inpatients that have advanced non-small celllung cancer, and it is associated with otheranticancer treatments such as
chemotherapy and radiotherapy. We
believe that the benefits of the drug far

their own, www.astrazeneca.com, a site

February 2003 that a Marketing

specifically devoted to gefitinib (Iressa),

Authorisation Application for gefitinib had

www.iressa.com, and one with information

been submitted in Europe for the treatment

on EGFRs, www.egfr-info.com, whichof locally advanced or metastatic NSCLC in

includes a special journal, Signal. Thesepatients who had failed prior chemotherapy.

sites can be accessed by patients and theirGefitinib has also been used for NSCLC in

families and appear to us to give a false

Western countries through expanded accessexpectation about the safety and efficacy of

programs, and has been trialled in patientsthe drug.

with prostate, colorectal, breast, and headand neck cancers.1

Risk factors

Conclusion
The regulation of information on websites isvery difficult but premarketing promotion of

Various risk factors may contribute to theunapproved drugs should be strictly

adverse reactions to gefitinib. Large

controlled.

interindividual variation in the metabolism of

Expanded access programs, whereby new

gefitinib may be one of the most important

products are made available before approval

The two independent drug bulletins infactors. But we believe another factor may

on the grounds of compassionate use, areJapan—The Informed Prescriber and Kusuri-

be more important and this is related to thelegal in the US and in European Union

no-Check—have published widely on thisdrug’s mechanism of action.

countries. However, it is very doubtful thatoutweigh the potential risks.18

Independent view

issue and have helped to alert prescribers,prescribers and patients can accesssufficient information about unapproved

6.

drugs to make informed decisions about theiruse. Increased access to new products
before approval is never ethical unless full
information including animal toxicity studies
and clinical trial results are disclosed. It is

7.

Nakamura Y, Sotozono C, Kinoshita S. The

Available from: http://

epidermal growth factor receptor (EGFR):

ex2.excerptamedica.com/ciw-02esmo/role in corneal wound healing andindex.cfm?fuseaction=CIS2002&hoofdnav

homeostasis. Exp Eye Res=Abstracts&content=abs.details&what

2001;72(5):511-7.

=FREE%20TEXT&searchtext

Mainichi Daily News (in Japanese). 7
February 2003. Available from: http://

time to debate whether ‘compassionate use’www12.mainichi.co.jp/news/search-news/

is ethical, even if full information is disclosed.

871241/83C838c83b83T-0-4.html [accessed
7 February 2003].

It is our opinion that the efficacy and safetyof gefitinib and the regulatory approval

8.

Documents released at the panel on theprocess should be completely re-examinedsafety problem of gefitinib (in Japanese).

using data accumulated through clinical
trials, expanded access programs and thepostmarketing experience in Japan.
In the meantime gefitinib should be
withdrawn, both in Japan and in Westerncountries where it is available throughexpanded access programs.
Further information about gefitinib and theexperience in Japan can be obtained fromthe authors.

Ministry of Health, Labor and Welfare.

25 December 2002.
9.

1.

Iressa (ZD1839, gefitinib). Available from:http://www.astrazeneca.com/mainnav1/
s_products/s_ptherapy/s_oncology/c_oncology/iressa.html [accessed 25
February 2003].

2.

3.

13. Johnson DH, Herbst R, Giaccone G, Schiller
J, Natale RB, Miller V, et al. ZD1839(‘Iressa’) in combination with paclitaxel &carboplatin in chemotherapy-naïve patientswith advanced non–small-cell lung cancer(NSCLC): results from a phase III clinical
trial (INTACT 2) [abstract]. 27th European
Society for Medical Oncology Congress;

Nakagawa K, Douillard J-Y, et al. Final

2002 Oct 18-22; Nice, France. Abstract

results from a phase II trial of ZD1839

468O. Available from: http://(‘Iressa’) for patients with advanced non–ex2.excerptamedica.com/ciw-02esmo/

small-cell lung cancer (IDEAL 1) [abstract].

index.cfm?fuseaction=CIS2002&hoofdnav

38th Annual Meeting of the American=Abstracts&content=abs.details&what

Society of Clinical Oncology (ASCO); 2002

=FREE%20TEXT&searchtext

May; Orlando, US. Abstract 1188. Available=ZD1839&topicselected

from: http://www.asco.org/ac/1,1003,_12-=*&selection=ABSTRACT&qryStartRowDetail=6002326-00_18-002002-00_19-001188-[accessed 25 February 2003].

00_29-00A,00.asp?cat=LUNG+CANCER&returnpid=2325[accessed 25 February 2003].

14. Westlind A, Lofberg L, Tindberg N,
Andersson TB, Ingelman-Sundberg M.
Interindividual differences in hepatic
expression of CYP3A4: relationship to

10. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr,

genetic polymorphism in the 5'-upstream

Prager D, Belani CP, et al. A phase II trial of

regulatory region. Biochem Biophys Res

ZD1839 (‘Iressa’) in advanced non–small cellCommun 1999;259(1):201-5.

lung cancer (NSCLC) patients who had
failed platinum- and docetaxel-based

15. Guengerich FP. In: Ortis de Montellano PR,
editor. Cytochrome P450: structure,

regimens (IDEAL 2) [abstract]. 38th Annual

target in cancer. Available from: http://

Meeting of the American Society of Clinicalwww.egfr-info.com/member/

Oncology (ASCO); 2002 May; Orlando, US.

index.asp?p=958673634_6119 [accessed

Abstract 1166. Available from: http://

25 February 2003].

www.asco.org/ac/1,1003,_12-002326-

2003. Available from: http://00_18-002002-00_19-001166-00_29-

www.yomiuri.co.jp/iryou/news_i/

00A,00.asp?cat

20030207so11.htm [accessed 7 February=Non%2DSmall%2DCell+Lung+Cancer&parent

2003].

Summary basis of approval of Iressa 250 by
020904. Available from: http://
211.132.8.246/shinyaku/g0207/06/
67022700_21400AMY00188.html [accessed
30 October 2003].
Miettinen PJ, Berger JE, Meneses J, Phung
Y, Pedersen RA, Werb Z, et al. Epithelial
immaturity and multiorgan failure in micelacking epidermal growth factor receptor.
Nature 1995;376(6538):337-41.

5.

[accessed 25 February 2003].

The epidermal growth factor as a clinicalAstraZeneca (in Japanese). Iressa-SIRYOU-

4.

=*&selection=ABSTRACT&qryStartRowDetail=9

Fukuoka M, Yano S, Giaccone G, Tamura T,=Non%2DSmall%2DCell+Lung+Cancer&parent

References=ZD1839&topicselected

Dvorak B, Halpern MD, Holubec H, Williams
CS, McWilliam DL, Dominguez JA, et al.
Epidermal growth factor reduces thedevelopment of necrotizing enterocolitis in aneonatal rat model. Am J Physiol
Gastrointest Liver Physiol
2002;282(1):G156-64.

=LUNG+CANCER&returnpid=2325[accessed 25 February 2003].
11. Cohen MH, medical reviewer. Briefing
document NDA 21-399. Available from: http://www.fda.gov/ohrms/dockets/ac/02/briefing/
3894B1_03_FDAMedical%20Officer%20Review.doc[accessed 25 February 2003].
12. Giaccone G, Johnson DH, Manegold C,
Scagliotti GV, Rosell R, Wolf M, et al. A
phase III clinical trial of ZD1839 (‘Iressa’) in
combination with gemcitabine and cisplatinin chemotherapy-naive patients withadvanced non-small-cell lung cancer(INTACT 1) [abstract]. 27th European
Society for Medical Oncology Congress;
2002 Oct 18-22; Nice, France. Abstract 4O.

mechanism and biochemistry. New York:
Plenum Press; 1995. p. 473-535.
16. Yomiuri On-line (in Japanese). 7 February

17. Inoue A, Saijo Y, Maemondo M, Gomi K,
Tokue Y, Kimura Y, et al. Severe acuteinterstitial pneumonia and gefitinib. Lancet
2003;361(9352):137-9.
18. McCurry J. AstraZeneca defends cancer
drug linked to deaths in Japan. Lancet
2003;361(9354):320.
19. Williams G. NDA 21-399, ZD1839 (Iressa).
Team leader comments and regulatory
background for the ODAC. Available from:http://www.fda.gov/ohrms/dockets/ac/02/
briefing/3894B1_02_FDATeam%20Leader%20Comments.pdf[accessed 25 February 2003].