Kusuri-no-Check(Check-up your pills to save your life)
The death total related to the adverse reaction to "Iressa" (generic name: gefitinib, AstraZeneca) has reached 183 in Japan at the end of January 2003, the AstraZeneca Japan said on Feb 6 2003.
An estimated 23,500 people have so far been administered with Iressa in Japan. 644 of them suffered from the adverse reactions to Iressa. Of these, 183 have died. The AstraZeneca said that 473 of those patients with adverse effects had acute lung disease and/or interstitial pneumonitis. 173 of them have died.
They claimed that the safety measures issued by the MHLW on 26th Dec 2002 have effectively decreased the case mortality rate from 48percent at the beginning to 31 percent after the yellow letter issued at Oct 15th 2002, and to about 20 percent after the issue of safety measures of Dec. 2002.
But this is only a magic of calculation. Cumulative mortality rate has been constantly increasing (table 1) even after the issue of yellow letter on 15th Oct 2002 (the yellow letter has issued after regulatory body received 13 mortality cases related to Iressa).
|classified by the time|
|Patients||press released||doctor report|
|1.-Oct.13||before yellow letter on Oct 15th||7,000||14||20.2||30||45.3|
|2.-Oct.26||just after the yellow letter||10,000||42||42.4||64||64.2|
|3.-Dec.13||before safety measures by MHLW||19,000||124||65.3||160||84.2|
|4. -Jan31||after the safety measures by MHLW||23,500||183||77.9||183||77.9|
Cumulative mortality rate according to the spontaneous reports is about 65 in 10,000 at Dec 13th 2002 and 78 in 10,000 at Jan 31st 2003 based on the classification by the time press-released. Cumulative mortality rate increased up to 84 at Dec 13th 2002, based on the classification of adverse reaction by the time of doctorsﾕ reports. One never knows a true mortality rate (classified by the onset of reaction) at Jan 31st 2003 at this moment (Feb 7 2003), because many potential fatal cases have not been reported yet.
An officer of regulatory agency has claimed that the yellow letter issued at Oct 15th 2002 have effectively decreased the case mortality rate (from 48 percent to 15 percent) after about one month from the issue. But the case mortality in those with the onset of the reactions within two month after the yellow letter increased to 31 percent (from 15 percent) when calculated two months later (Table 1).
|A) 5/12/2002||B) 6/2/2003||C) after2M|
|Before Yellow letter ( -Oct.15)||41.3||→||48|
|After yellow letter (Oct.16-Nov.25)||14.7||→|
|After yellow letter (Oct.16-Dec.25)||?||→||31||?|
|After safety measures (Dec.26-Jan 31 2003)||?||20||→||?|
|*: Percent of death among reported adverse reactions cases to Iressa|
Iressa was approved on July 5th 2002, after only inspection for about 5 months in Japan even though INTACT 1 and 2 had failed the favorable effect of Iressa on overall survival when used as one of the first line agents with other cytotoxic chemotherapeutic agents. Median survival of the patients with 250 mg of Iressa showed a trend of 1.21 month shorter than of those with placebo (9.86 vs 11.07 months; p=0.3)(1). None of the median survival of the patients in four Iressa arm showed longer than non-Iressa treated arm.
While there are hints of drug activity, i.e. an objective response rate of 10.8% in the third-line treatment setting, the absence of a non-ZD1839 (Iressa) treated control group makes it difficult to evaluate these results. The fact that the study population was enriched for slowly growing, less aggressive cancers further complicates evaluation of results. Other confounding factors are failure to adhere to the eligibility criteria, limited number of measurable lesions, and relatively small tumor volumes (10 cm2) in 5 of 18 responders who had measurable disease in trial 39 and in 3 of 11 responding Caucasian patients and 11 of 28 responding Japanese patients in trial 16.
There are fundamental study design issue with the sponsorﾕs quality of life improvement and symptom benefit analyses including absence of a suitable control group, absence of blinding as all patients received ZD1839, dropout patients with early disease progression and meaningfulness of the criteria used to designate benefit.
Addendum: On August 19, 2002 the sponsor released the results of their phase III first-line NSCLC studies (INTACT 1 and 2; Iressa NSCLC Trials Assessing Combination Therapy). Two large randomized trials, accruing over 2000 patients, used an add-on design in which patients were randomized to receive either Iressa or placebo together with standard combination chemotherapy, gemcitabine/ cisplatin in one study and carboplatin/paclitaxel in the other. At the time this report study results were mature with approximately 70% of patients having died in each treatment arm. There was no survival benefit from Iressa treatment in either trial. Similarly, secondary endpoints, i.e. response rate and time to progression, also failed to show statistically significant differences. Results were unambiguous.
These results raise a question regarding accelerated approval of Iressa. Accelerated approval regulations require additional studies that demonstrate clinical benefit. Can FDA consider accelerated approval when it has already demonstrated in the INTACT trials that there is no survival advantage?
Objective tumor response rate to Iressa was 11.8% (95%CI: 6.2, 19.7%) for the 250mg/day group and 8.8% (95%CI: 4.3, 15.5%) for the 500mg/day group in trial 39 (most of the patients enrolled were Caucasians). Overall response rate was 10.2% (2). In the No 16 phase II clinical trial, Japanese patients showed 23.5% of response rate (95%CI: 12.8, 37.5%, 12/51 in 250 mg arm, 95%CI: 15.7, 33.0%, 24/102 for total), while Non-Japanese patients (Caucasians) showed 5.8%(3/52; 95%CI; 1.2-15.9%) in 250mg/day arm and 9.3%(5/54; 95%CI; 3.1-20.3%) in 500mg/day arm, after the evaluation of Japanese inspection center. Response rate in 250mg arm was 14.6% (15/103; 95%CI: 8.4, 22.9%) and 16.2% (32/208; 95%CI: 9.7, 24.7%) in phase II trial No16 (2, 3).
On the other hand severe adverse event such as ARDS and/or pneumonia or pneumonitis (or acute lung injuries) etc were seen in 25.5% in Trial 39 patients and 36.4% in Trial 16 Caucasian patients. Among these 6.9% in Trial 39 and 3.7% in Trial 16 Caucasian patients were deaths due to adverse events.
In one of the phase I/II trial (No11), deaths due to adverse event(s) are 9(13.0%) in 69 patients. Of these 7 had any of the respiratory tract complications: 2 pulmonary insufficiency, 2 pneumonia, 1 ARDS and 2 bleeding from respiratory tracts. Of 9 deaths due to adverse event(s), Iressa was withdrawn in 5 patients. But none of the adverse events were classified in drug-related adverse event, though doctors stopped to administer Iressa because they thought the any possibility of adverse reaction to Iressa.
In the No39 clinical trial, mortality rate due to adverse events were reported as 5.1% (11/216). But another 4 death cases (*a) due to adverse events were described as a note outside the table. As these 4 cases should be included in the death cases due to adverse events, true mortality rate due to adverse events is almost 7% (15/216).
*a: pneumonia 1, ARDS 1, dyspnea 2
The pharmaceutical company claimed that Iressa inhibits the tyrosine-kinase of the Epidermal Growth Factor Receptor (EGFR)(EGFR-TKI) which non-small cell lung cancer(NSCLC) cell express much more than other tissues including normal cells. Industry claims that it is safe for normal tissue when used as anti-cancer agents for NSCLS.
Almost all of the cells except blood cells have EGFR (4) (blood cell might not be an exception). So Iressa not only inhibit the growth of cancer but also inhibit physiological replacement of normal cells. Especially repairing tissues after injury require more EGF and express more EGFR than normal tissues.
1) Mice lacking EGFR survive for up to 8 days (or up to 18days) after birth and suffer from impaired epithelial development in several organs, including skin, lung and gastrointestinal tract (4).
2) Maternal milk plays an important protective role against necrotizing enterocolitis (NEC) and is the major source of epidermal growth factor (EGF) for neonates. After induction of NEC by exposure to asphyxia and cold stress, new born rats were divided into tree groups: Dam fed group, artificial rat milk substitute (RMS) fed groups with and without EGF. Dam fed pups with sufficient EGF showed steady increase in body weight throughout the experiments showing no or minimal blood in the stool. However newborn rats fed with RMS without EGF bleed severely and lost body weight (5).
3) Wound healing of rat cornea was delayed dose-dependently and at 48 hr post wounding, epithelial thickness was also significantly less in treated rats compared with control rats (6).
These results indicate that EGFR inhibition affects epithelial cell proliferation and stratification during corneal epithelial healing and may play a role in maintaining normal corneal epithelial thickness.
Moreover Iressa is mainly metabolized by liver CYP3A4. Activities of CYP3A4 vary more than 40 folds interindividually (7, 8). Subsequently Cmax and/or AUC differ more than 30 to one hundred times interindividually after repeated dosing (3).
Tmax in cancer patients vary 1hr to 24 hrs (3). Elimination half life (t1/2) in healthy volunteers and various patients vary 10 to 90 hrs (3).
76 percent of the patients (13/17) who experienced their first adverse symptoms within one week died. It may be impossible to save the patients who suffer from adverse reaction occurring within one week after start of Iressa (9).
Various risk factors may contribute inducing adverse reactions to Iressa. Large interindividual variance of the metabolism may be one of the most important risk factors. But I think another factors may be more important.
The important factor may be related to the mechanism of Iressa. It inhibits the normal repairing process when tissues are injured. Many patients have had received chemotherapy and/or radiation previously before starting Iressa. In addition they may have infection during the treatment course. Infection with systemic inflammatory response syndrome (SIRS) induces injury of tissues including lungs and various organs in any extent. The process of repairing of injured tissues may be inhibited by treating Iressa.
Injury from chemotherapeutics and/or radiation is predictable but those patients are those who indicated with Iressa.
Six months-repeated animal toxicity tests (rats and dogs) revealed the increase of hepatic necrosis with 5mg/kg/day of Iressa which is the same dose as human clinical dose. One among 8 dogs treated with 5mg/kg/day of Iressa (clinical dose) died (sacrificed) at 18th week. One dog among 14 dogs of 25mg/kg group died (sacrificed) at 10th day. Dose was reduced to 15mg subsequently (3).
One of the 60 rats treated with 25mg/kg of Iressa died (sacrificed) in 8th week. Dose was reduced to 15mg/kg subsequently. But three more rats died (sacrificed) even at dose of 15mg/kg/day (3).
They had renal papillary necrosis, liver necrosis and other lesions. These findings were considered as related to the mechanism of action of Iressa (EGFR-TKI) (3).
In the dog toxicity test for 6 month, relative lung weight increased dose-dependently and WBC counts also increased dose dependently (3). These data indicate that these animals had inflammation in lung possibly induced by Iressa.
But AstraZeneka claimed that ﾒwe have never observed Iressa related abnormal findings in pulmonary system.ﾓ They never deny the presence of abnormal findings in pulmonary system.
Lately it was reported (10) that AstraZeneca did not submit the results of a series of animal experiments; i.e. Iressa increased bleomycin-induced lung toxicities (alveolar damage and fibrosis) (9, 10). This is clearly related to the action of Iressa inhibiting the EGFR-TK.
Case1. A woman in sixties was admitted with progression of lung cancer. Three weeks after admission, she was administered with Iressa. Her lung cancer responded well and decreased in size within one week. But the next day she diarrhoeaed and had dyspnea. Typical diffuse opaque appearance on the chest XP was found and Iressa was withdrawn. O2 inhalation, Corticosteroids pulse-therapy failed to improve her. She died at 8th day after the withdrawal of Iressa. Her lung cancer was treated but she died with multi-organ-failure including lung, GI tracts, liver, kidney and heart failure induced by Iressa.
Case2. A woman in seventies with NSCLC was admitted. She could walk then. She was treated with Iressa since the next day. In the 7th day morning of commencement, she complained of dyspnea. Chest XP indicates the interstitial pneumonitis. Iressa was withdrawn, and she was treated with corticosteroids, but died at 21 oﾕclock of the day.
Case3. A man in seventies with severe congestive heart failure experienced an abdominal discomfort in the next day evening after the commencement of Iressa. On the day 3, he had ileus. Iressa was withdrawn because he could not take due to ileus. But sever hypoxemia and pulmonary symptoms progressed. He died one week after the withdrawal of Iressa with multi-organ-failure including lungs, GI-tracts, renal insufficiency. Elimination of Iressa by liver and intestine by CYP3A4 might have decreased because of the severe congestive heart failure.
The ministry set up a panel on Iressa comprising experts in medicine and pharmacy. The panel decided that informed consent must be obtained from patients in advance of administering them with Iressa, and that patients must be hospitalized for at least four weeks at an institution that has a doctor specializing in treating lung cancer patients. It also required that doctors exercise caution in using Iressa on patients who have suffered from interstitial pneumonitis and other lung diseases.
These recommended measures by the panel could hardly prevent death from Iressa effectively.
Iressa should be stop to use in Japan. It may be true in other western countries where Iressa is being prescribed as an expanded access program before approval.
And efficacy and safety of Iressa and process of approval by regulatory agency should be re-examined completely by using the data stored at present. It could well be done because data have already been sufficiently stored during clinical trials and clinical use after approval.