Amrubicin for the Treatment of Small Cell Lung Cancer: Does Effectiveness Cross the Pacific?

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David S. Ettinger, MD, FACP, FCCP

Despite the introduction of effective chemotherapeutic Abstract: Amrubicin is a synthetic 9-aminoanthracycline that has drugs in the treatment of untreated SCLC patients in the 1990s significant antitumor activity in Japanese patients with extensive (i.e., paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, stage small cell lung cancer (SCLC). Clinical trials ongoing in the gemcitabine), there has been no significant improvement in the Untied States and Europe will determine whether amrubicin will be survival of patients with SCLC (Table 1).4–11 effective in other ethnic groups (whites) or whether this will be an There is a need for new and effective agents to treat example of geographic and/or genetic variation. Genetic polymor- patients with SCLC. One such new agent may be amrubicin, phisms in the UGT1A1 gene have been identified as one of the a drug that has been studied in Japan and is now approved for causes of the increased diarrhea seen in white patients treated with both SCLC and non-small cell lung cancer (NSCLC). Am- irinotecan when compared with Japanese patients. Nicotinamide rubicin is being evaluated in the United States and Europe in adenine dinucleotide phosphate, reduced form–quinone oxidoreductase the treatment of patients with SCLC. (NQ01) is an enzyme that participates in the metabolism of amrubicin and polymorphisms of the enzyme, known to occur in the Asian AMRUBICIN population, might explain the effectiveness of the drug in Japanese Amrubicin (Figure 1) was discovered and developed by patients with small cell lung cancer. Studies to evaluate the drug in US Sumitomo Pharmaceuticals in Japan.12 It is a synthetic 9-ami- and European patients with extensive stage small cell lung cancer are noanthracycline with potent antitumor activity against vari- ongoing. Levels of NQ01 will also be determined in these studies. ous human tumor xenografts.13 Key Words: Amrubicin, Small cell, Extensive stage. Amrubicin is metabolized to the active metabolite amrubicinol, which has five to 200 times higher growth inhibi- (J Thorac Oncol. 2007;2: 160–165) tory activity against human tumor cell lines in vitro compared with doxorubicin. The in vitro growth inhibitor activity of amrubicinol was comparable with or higher than that of mall cell lung cancer (SCLC) accounts for approximately doxorubicin. In human xenograft models, antitumor effects S13% of new cases of lung cancer diagnosed in the United on administration of amrubicin were highly correlated with States.1 Sixty percent to 70% of patients with SCLC present the intratumor concentration of amrubicinol. In this regard, with extensive-stage SCLC (i.e., metastatic disease), whereas amrubicin is distinct from other anthracyclines for which 30% to 40% of patients have limited-stage SCLC, defined as metabolites have equal or decreased cytotoxic activity rela- disease confined to one hemithorax with or without regional tive to the parent compounds. In human xenograft models, lymph nodes (hilar or mediastinal), with or without ipsilateral amrubicin exhibited antitumor effects comparable with or supraclavicular lymph node involvement, and without ipsi- superior to those of doxorubicin, when both were adminis- lateral pleural effusions.2 tered at their maximum tolerated dose. SCLC is a rapidly proliferating tumor that responds Anthracyclines have been reported to have diverse molec- both to chemotherapy and radiation therapy. Unfortunately, ular effects (e.g., DNA intercalation, inhibition of topoisomerase although limited-stage SCLC is potentially curable with com- II, and stabilization of topoisomerase II␣ cleavable complexes). bined modality therapy (i.e., 15%–25% 5-year survival rate), Amrubicin demonstrates decreased DNA intercalation com- extensive stage, despite treatment with chemotherapy, has a pared with doxorubicin. The decreased DNA interaction appears poor long-term survival rate, with almost all such patients to influence the intracellular distribution because amrubicin and dead within 2 years from initial diagnosis.3 amrubicinol showed only 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution observed with doxorubicin. The cell growth inhibitory effects of amrubi- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. cin and amrubicinol appear to be primarily related to inhibition Research support from Cabrellis Pharmaceuticals. of topoisomerase II.14 Compared with doxorubicin, amrubicin, Address for correspondence: David S. Ettinger, M.D., Bunting-Blaustein and amrubicinol display stronger topoisomerase II–dependent CRB 1, Room G88, 1650 Orleans Street, Baltimore, MD 21231. E-mail: cleavage most probably due to the increased stability of the [email protected] Copyright © 2007 by the International Association for the Study of Lung complex formed by the drug, DNA, and the enzyme. Cancer The primary metabolite (amrubicinol) in rats and dogs ISSN: 1556-0864/07/0202-0160 is a product of reduction by cytoplasmic carbonyl reductase at

160 Journal of Thoracic Oncology • Volume 2, Number 2, February 2007 Journal of Thoracic Oncology • Volume 2, Number 2, February 2007 Amrubicin for the Treatment of SCLC

target organs of amrubicin toxicity were similar across spe- TABLE 1. Drugs for Previously Untreated Patients with Extensive-Stage Small Cell Lung Cancer cies. Histopathologic lesions were found in tissues with relatively rapid cellular turnover, i.e., hematopoietic and Patients Response Median lymphatic systems, the digestive tract, the reproductive sys- Agent (assessable) Rate (%) Survival (mo) tems, and hair follicles and were similar across species. In an Paclitaxel4 36 (32) 34 9.9 acute mouse study, a low incidence of kidney toxicity was Paclitaxel5 43 (37) 41 (68%)a 6.6 also observed. Docetaxel6 47 (43) 23 9 Clinical manifestations of toxicity observed on acute Topotecan7 48 (48) 39 9 and repeated administration of amrubicin in rats and dogs Irinotecan8 16 (15) 47 6.8 were dose related and reversible including fecal changes Irinotecan9 8 (8) 50 NR (mucoid or bloody feces/diarrhea), body weight decreases, Vinorelbine10 30 (27) 27 NR decreased food consumption, decreased activity, and alope- Gemcitabine11 29 (26) 27 12 cia. Similar ﬁndings were observed at doses of doxorubicin

a Ten additional regressions of assessable disease for an overall major response rate approximately one half those of amrubicin. of 68%. Results from the amrubicin toxicology program show that hematologic parameters are the most important parameters to monitor in clinical studies. In addition, studies in the C-13 carbonyl group. Other enzymes participating in the rabbits and dogs determined that amrubicin did not induce metabolism of amrubicin and amrubicinol were nicotinamide cardiomyopathy nor exacerbate doxorubicin-induced cardio- adenine dinucleotide phosphate, reduced form (NADPH)– myopathy.15,16 Amrubicin demonstrated reproductive and de- P450 reductase and nicotinamide adenine dinucleotide [phos- velopmental toxicity in rabbits and rats. It also was shown to phate] (NAD[P]H)-quinone oxidoreductase. Twelve additional be mutagenic. metabolites were detected in vivo and in vitro. These included Clinical development of amrubicin was initiated in four aglycone metabolites, two amrubicinol glucuronides, December 1986. It was approved for use in Japan for the deaminated amrubicin, and ﬁve highly polar unknowns. In treatment of NSCLC and SCLC in April 2002. vitro cell growth inhibitory activity of the minor metabolites The maximum tolerated dose of amrubicin was deter- was substantially lower than that of amrubicinol. Excretion of mined to be 130 mg/m2 in a single-dose schedule,17 25 amrubicin and its metabolites is primarily hepatobiliary. En- mg/m2/day (125 mg/m2 in total) in daily doses for 5 days, and terohepatic recycling was demonstrated in rats. 50 mg/m2/day (150 mg/m2 in total) for 3 days. The dose- Single-dose studies were conducted in mice, rats, and limiting toxicity was myelosuppression (neutropenia Ͼ dogs, and repeated-dose evaluations were conducted for dos- thrombocytopenia and anemia). Leukopenia and neutropenia ing periods up to 6 months in rats and dogs. Additional developed in Ͼ80% of the patients who received amrubicin. repeated-dose studies were conducted in rabbits and dogs to The incidence and severity were affected by previous treat- evaluate the cardiotoxicity potential of amrubicin compared ment, target lesion, and administration dose. Decreased he- with that of doxorubicin. moglobin level (71%) and thrombocytopenia (35%) also Based on acute intravenous dose toxicity studies, the developed at relatively high frequency. lethal dose to 50% of animals was estimated to be 42 mg/kg The plasma pharmacokinetics of amrubicin in cancer in mice, 14 mg/kg in rats, and 4 mg/kg in dogs. The primary patients are characterized by low total clearance (22% of total

FIGURE 1. Structure of amrubicin. Chemical name: (7S,9S)-9-acetyl-9- amino-7-[(2-deoxy-␤-D-erythro-pen- topyranosyl)oxy]-7,8,9,10-tetrahy- dro-6,11-dihydroxy-5,12- naphthacenedione hydrochloride. Molecular weight: 519.93.

liver blood ﬂow) and a moderate volume of distribution (1.4 21 times total body water). Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations ob- /dIV d 3–5; /d 2 2 served immediately after dosing followed by ␣ and ␤ half- 5 (5) — 80 80 Ϯ Ϯ Ϯ — 5; 3 sensitive; 2 refractory mg/m lives (t1/2) SD of 0.06 0.01 and 2.0 0.3 hours, topotecan 0.75 mg/m Shibayama et al. 0 Sen, 0 Ref Previously treated: respectively. Concentrations of amrubicin in red blood cells Amrubicin 30/40/45 (RBCs) were similar to those observed in plasma. Amrubicin plasma and red blood cell pharmacokinetic parameters were 19 linear over a 10- to 130-mg/m2 dose range as evidenced by Ն 2 /d IV d — 14 — — —

dose proportional increases in the area under the curve (AUC) 2 14 (14) and dose-independent t1/2. Amrubicin concentrations in 14 unfit or received regimens 1–3q 3 wk mg/m plasma and RBCs and t1/2 values after three and five Yamamoto et al. Previously treated: consecutive daily doses were similar to those observed Amrubicin 35–40 / after the first dose, suggesting that amrubicin pharmaco- 2 kinetic parameters were not altered on repeated adminis- 23 tration (amrubicin hydrochloride investigator’s brochure

[IND 22,883], 2005). 60 (60)

Peak plasma concentrations of the active metabolite Onoda et al. sensitive, 2 refractory dIV d 1–3q 3wk 43.5 Sen, 40.3 Ref Previouslytreated: 44 amrubicinol were observed from immediately after dosing to Amrubicin 40 mg/m 1 hour after dosing. Plasma concentrations of amrubicinol Previously Treated Patients / 2

were low compared with amrubicin plasma concentrations, 22 Ϯ Ϯ and the average plasma amrubicinol t1/2 SD was 15 8 hours. The plasma amrubicinol AUC was approximately —

10-fold lower than the amrubicin plasma AUC. Concentra- 26 (26) tions of amrubicinol were higher in RBCs as compared with sensitive, 17 refractory dIV d 1–3q 3 wk Hasegawa et al. 11.0 Sen, 5.7 Ref 11.6 Sen, 10.3 Ref 55.6 Sen, 41.2 Ref 52 Sen, 50 Ref — Sen, — Ref— Sen, — Ref 1.9 Sen, 2 Ref 50 Sen, 48 Ref plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold Amrubicin 40 mg/m higher in RBCs compared with plasma; however, the t1/2 of amrubicinol in RBCs was 14 Ϯ 3 hours and thus was similar 21 /d IV to the plasma value. Because amrubicinol distributes into 2 /d IV d — 50 — — RBCs to a greater extent than amrubicin, the concentrations — 2 of amrubicinol and amrubicin in RBCs were similar. The 4 (4) mg/m 3–5; topotecan 0.75 mg/m AUC of amrubicinol in RBCs was approximately twofold d1–5q3wk Shibayama et al. Chemonaive: 4 Previously treated: 9 lower than the amrubicin RBC AUC (amrubicin hydrochlo- Amrubicin 30/40/45 ride investigator’s brochure [IND 22,883], 2005).

Amrubicinol plasma and RBC AUCs increased in pro- 20 portion to amrubicin dose and t1/2 was independent of dose, 9.8 /dIV d 1–3; 13.6 87.8 78.0 56.1 suggesting linear PK. Upon repeated daily amrubicin admin- 2 44 (44) d1q3wk 2 istration, amrubicinol accumulation was observed in plasma Ohe et al. mg/m cisplatin 60 mg/ m Amrubicin 40–45 and RBCs. On day 3, the amrubicinol plasma AUC was Chemonaive 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 19 consecutive daily doses, plasma and RBC amrubicinol AUCs /dIV d — 71 — — were 1.2-fold to 2.0-fold higher than day 1 values (amrubicin — 2 hydrochloride investigator’s brochure [IND 22,883], 2005). 7 (7) 1–3q 3 wk mg/m Urinary excretion of amrubicin and amrubicinol after unable to tole rate combination chemotherapy Yamamoto et al. Amrubicin 35–40 administration of amrubicin accounted for 2.7% to 19.6% of Chemonaive: 7; / Chemotherapy-Naive Patients the dose. The amount of excreted amrubicinol was approxi- 2 18 mately 10-fold greater than excreted amrubicin (amrubicin a hydrochloride investigator’s brochure [IND 22,883], 2005). 11.0 78.8 The intravenous administration of amrubicin at a dose 15.2 63.6

2 35 (33)

of 45 mg/m /day for three consecutive days at 3-week inter- Yana et al. vals is the approved schedule used in Japan. dIV d 1–3q 3 wk

AMRUBICIN AS FIRST-LINE THERAPY Summary of Studies with Amrubicin in the Treatment of Extensive-Stage Small Cell Lung Cancer In the ﬁrst phase II study of amrubicin in previously untreated patients with extensive-stage SCLC, an overall Two-year survival rate. Sen, sensitive disease; Ref, refractory disease. 18 (no. assessable) response rate of 78.8% was reported ( Table 2). Thirty-ﬁve a Overall Complete Partial 1-y survival rate, % 46.9 (23.1) Mediansurvival, mo Response, % Dose of drugs Amrubicin 45 mg/m TABLE 2. Patient population Chemonaive patients were entered in the study of which 33 were eligible. No. of patients

The median age of the eligible patients was 66 years (range, bocytopenia occurred in 24% of patients, and grade 3/4 42–78), 29 were male and Eastern Cooperative Oncology hyponatremia was present in 22% of patients. Group performance statuses (PSs) were PS 0–5, PS 1–26, PS 2–2. Amrubicin was administered by intravenous injection of 45 mg/m2/day for three consecutive days every 3 weeks. The AMRUBICIN PLUS TOPOTECAN median number of courses of therapy was four (range, one to A phase I study of amrubicin and topotecan in patients six). Of the 33 eligible patients, five had a complete response who were either chemotherapy naive or relapsed with exten- (15.2%) and 21 patients had a partial response (63.6%), for an sive-stage SCLC was conducted.21 Topotecan was adminis- overall response rate of 78.8%. The median survival was 11.3 tered on days 1 to 5, and amrubicin was administered on days months (range, 2–21ϩ). The 1- and 2-year overall survival 3 to 5. Cycles were to be repeated every 4 weeks. Nine rates were 46.9% and 23.1%, respectively. The major toxicity patients (four chemonaive, five relapsed [three patients with was myelosuppression. Grade 3 and 4 leukopenia and neu- sensitive disease, two patients with refractory disease]) were tropenia was 39% and 39% and 12% and 39%, respectively. treated. The dose-limiting toxicity was neutropenia, febrile Nonhematologic toxicity of grade 3 and higher was not neutropenia, and thrombocytopenia. The maximum tolerated observed except for anorexia (9.1%) and alopecia (3%). dose for topotecan was 0.75 mg/m2 and 40 mg/m2 for Cardiac toxicity was not observed. amrubicin. Six patients (67%) had a partial response to the therapy (four of five [80%] relapsed patients and two of four AMRUBICIN IN MEDICALLY UNFIT OR HEAVILY [50%] chemonaive patients). The median time to progression PRETREATED PATIENTS was 4 months. Amrubicin monotherapy was also tested in patients with SCLC who were unable to tolerate combination chemo- AMRUBICIN AS SECOND-LINE THERAPY therapy because of old age, poor PS, or other contraindica- In a phase II study conducted in previously treated tions or patients who had previously undergone two or more 2 19 patients with SCLC, amrubicin 40 mg/m /day intravenously regimens of chemotherapy. Twenty-one patients were treated was administered for three consecutive days every 3 weeks.22 with amrubicin given on days 1, 2, and 3 every 3 weeks. 2 2 Twenty-six patients (nine sensitive-disease, 17 refractory- Amrubicin was administered at 40 mg/m (or 35 mg/m for disease patients), 22 men, four women; median age, 62.5 six patients in consideration of their general health). Seven years (range, 43–78) received a median number of three patients were chemonaive. The overall response rate was cycles of therapy. The response rate was 46.2% (55.6% 71% (five of seven patients) in chemonaive patients and 14% sensitive disease, 41.2% refractory disease). The median (two of 14) in patients with previous chemotherapy. Median survival time was 9.4 months (11.0 months for sensitive survival time was 9.4 months (95% confidence interval: disease, 5.7 months for refractory disease). Grade 4 leukope- 7.7–14.1) and 6 months (95% confidence interval: 2.6–8.6), nia and neutropenia occurred in 42.3% and 73.1% of patients, respectively. Hematologic toxicity was common and rela- respectively. Grade 3 or 4 thrombocytopenia occurred in 50% tively severe, whereas nonhematologic toxicity was relatively 19 of patients. mild. Therefore, amrubicin monotherapy could be consid- The Japanese Thoracic Oncology Research Group con- ered for patients with SCLC who are unfit for combination ducted a phase II study of amrubicin for the treatment of chemotherapy. previously treated SCLC.23 It is the largest study evaluating this drug in this patient population. Patients were eligible for AMRUBICIN PLUS CISPLATIN the study if they had measurable disease and an Eastern In a phase I/II study, amrubicin and cisplatin in previ- Cooperative Oncology Group PS of 0–2, were previously ously untreated patients with extensive-stage SCLC were treated with at least one platinum-based chemotherapy regi- studied.20 Amrubicin (40–45 mg/m2/day) on days 1 to 3 and men, and either had refractory disease (failed first-line treat- cisplatin 60 mg/m2) on day 1 were administered intrave- ment Ͻ60 days from discontinuing treatment) or sensitive nously every 3 weeks to patients with a good PS. Four and disease (progressed Ն60 days after discontinuing treatment). three patients received the amrubicin dose of 40 (level 1) and Amrubicin 40 mg/m2/day was administered as a 45 mg/m2/day (level 2), respectively. The maximum tolerated 5-minute intravenous injection for three consecutive days dose was determined to be the 45 mg/m2/day of amrubicin every 3 weeks.23 Sixty patients (16 with refractory disease plus cisplatin 60 mg/m2, whereas the recommended phase II and 44 with sensitive disease) were entered in the study. The dose was the lower dose of amrubicin plus cisplatin. No median number of cycles given was four (range, one to eight). dose-limiting toxicities were observed during the first course The overall response rates were 52% (1.9% complete re- of level 1, whereas at level 2, grade 4 febrile neutropenia sponse) in the sensitive-disease group and 50% (2% complete occurred in two patients. An additional 37 patients were response) in the refractory-disease group of patients. The entered in the study. A total of 41 patients were a treated at overall and 1-year survival rate in the sensitive-disease group the recommended phase II dose. The response rate was 87.8% were 11.6 months and 45.5%, respectively, whereas in the (10% complete response). The median survival time and refractory-disease group, they were 10.3 months and 40.3%, 1-year survival rate were 13.6 months and 56.1%, respec- respectively. The major toxicity was hematologic. Grade 3/4 tively. Grade 3/4 neutropenia and leukopenia occurred on toxicities occurred as follows: neutropenia, 83.3%; leukope- 95.1% and 65.9% of patients, respectively. Grade 3 throm- nia, 70.0%; anemia, 33.3%; thrombocytopenia, 20%; an-

Copyright © 2007 by the International Association for the Study of Lung Cancer 163 Ettinger Journal of Thoracic Oncology • Volume 2, Number 2, February 2007 orexia, 15%; and asthenia, 15%. Nonhematologic toxicity addition, 2% of Japanese patients developed interstitial lung was relatively mild. No cardiac toxicity was observed. disease associated with gefitinib administration, whereas no U.S. patients developed the toxicity. Does geographic and/or ethnic variation apply to the DISCUSSION effectiveness of irinotecan plus cisplatin compared with eto- The only drug approved for second-line treatment of poside plus cisplatin for extensive-stage SCLC? In a Japanese SCLC in the United States is topotecan (Hycamtin). The U.S. phase III study, the median survival 12.8 months for SCLC Food and Drug Administration approved it on November 30, patients treated with irinotecan/cisplatin compared with 9.4 1998. In part, their decision was based on the results of a months (p ϭ 0.002) for the patients treated with etoposide/ phase III multicenter study of SCLC patients who relapsed cisplatin. The survival rate at 2 years was 19.5% for the Ͼ60 days after completion of first-line chemotherapy and patients treated with irinotecan/cisplatin and 5.2% for the then were randomized to receive either topotecan or cyclo- patients treated with etoposide/cisplatin.29 phosphamide, doxorubicin, and vincristine (CAV).24 The In a U.S. phase III study comparing irinotecan/cisplatin patient population was considered as having SCLC sensitive with etoposide/cisplatin in SCLC patients, there was no disease. The response rate to topotecan-treated patients was improvement in survival in the patients receiving irinotecan/ 24.3% compared with 18.3% for the patients receiving CAV cisplatin.30 The median survival was 9.3 months versus 10.2 ϭ (p 0.285). The median survival was 25.0 weeks for the months (p ϭ 0.74). In this study, the patients appeared to topotecan-treated patients and 24.7 weeks for the CAV- ϭ have more advanced disease compared with the patients in treated patients (p 0.795). There was greater symptom the Japanese study. In addition, a different dose and schedule improvement (shortness of breath, anorexia, hoarseness, and of irinotecan/cisplatin was used in the U.S. study. fatigue) and less toxicity associated with topotecan treatment There is an ongoing Southwest Oncology Group study compared with CAV treatment. 25 comparing irinotecan/cisplatin with etoposide/cisplatin using In an earlier phase II study, SCLC patients were the same dose and schedule as in the Japanese study to treat stratified as having refractory or sensitive disease and given patients with extensive-stage SCLC. topotecan as second-line therapy. In the study, patients with Why are there these differences between the Japanese refractory disease were defined as patients who relapsed Ͻ90 patients and U.S. patients? Is it geographic variations in days after first-line chemotherapy for the treatment of SCLC. treatment? In the former study, this may be operative because Patients with sensitive disease was defined as SCLC patients Ͼ of health care economics, the influence of regulatory agen- who relapsed 90 days after completion of initial chemo- 31 therapy. In sensitive-disease SCLC patients, the response rate cies, and physician biases. In addition, in both the former was 37.8%, whereas in refractory-disease patients, it was and latter studies, another explanation could be biologic 6.4%. The median survival for all patients was 5.4 months, differences between Japanese and U.S. patients in regard to and for sensitive-disease patients, it was 6.9 months. pharmacogenomic aspects of drug metabolism or differences 31 Although studies have shown that topotecan is effective in tumor susceptibility affecting efficacy and toxicity. as a second-line treatment of SCLC patients, especially those What genetic variations might explain the effectiveness who have chemosensitive disease, it has not had a significant of amrubicin in Japanese patients with SCLC? It is known impact on the survival of such patients. New therapies are that polymorphisms of NQ01 subunits affect doxorubicin needed to inhibit distant metastasis and thereby improve efflux transporters, thereby increasing the risk of anthracy- survival rates of SCLC patients. cline-induced cardiotoxicity.32 In addition, NQ01 detoxifies Is amrubicin one of these new therapies? In Japan, as a quinones derived from the oxidation of phenolic metabolites single agent and in combination with other agents, it appears of benzene. Individuals homozygous for the 609C-T poly- to be effective in treating extensive-stage SCLC patients morphisms (T/T genotype) have an increased risk of benzene especially as second-line therapy. However, thus far, the poisoning. In cells with the T/T genotype, NQ01 was not studies reported of its effectiveness are small and there has detected. The prevalence of the T/T genotype was highest in been no phase III study to evaluate its effectiveness compared the Asian populations.33 NAD(P)H-quinone oxidoreductase with standard treatments. is an enzyme that participates in the metabolism of amrubicin In addition, can its effectiveness in treating Japanese and amrubinol. Will polymorphisms of NAD(P)H oxidase patients with extensive-stage SCLC be reproduced in West- possibly explain the effectiveness of amrubicin in treating ern patients with the disease? If not, will this be another Japanese patients? situation of possible geographic and/or ethnic variation in the Because amrubicin appears to be the most effective effectiveness of the same treatment given to patients with single agent to treat SCLC, at least in Japan, and has not yet geographic and ethnic differences. been tested outside Japan, it is necessary to confirm its The most striking example of the above has been seen effectiveness in U.S. patients with SCLC. Recently, a ran- in both the activity and toxicity of the tyrosine kinase inhib- domized phase II tried comparing amrubicin with topotecan itor gefitinib in the treatment of NSCLC patients in Japan and as second-line treatment in patients with extensive-stage the United States.26–28 Japanese patients had a higher re- SCLC sensitive to first-line chemotherapy has been initiated sponse rate (28%) and longer median survival (12 months) sponsored by Cabrellis Pharmaceuticals Corporation, San compared with U.S. patients who had a response rate of 10% Diego, CA. A phase II single-arm study will evaluate the and median survival of 6 to 7 months receiving gefitinib. In effectiveness of the drug in patients refractory to first-line

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