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A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study
Original article
Annals of Oncology 16: 1811–1816, 2005 doi:10.1093/annonc/mdi365 Published online 8 August 2005
A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study G. K. Dy1, A. A. Miller2, S. J. Mandrekar1, M.-C. Aubry1, R. M. Langdon Jr.3, R. F. Morton4, S. E. Schild5, J. R. Jett1 & A. A. Adjei1* 1
Mayo Clinic and Mayo Foundation, Rochester, MN 55905; 2Wake Forest University School of Medicine, Winston-Salem, NC 27157; 3Missouri Valley Cancer Consortium, Omaha, NE 68106; 4Iowa Oncology Research Association CCOP, Des Moines, IA 50309-1014; 5Scottsdale CCOP, Scottsdale, AZ 85259-5404, USA
Background: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer. Patients and methods: Patients with c-kit-expressing SCLC (‡1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression ‡3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm. Results: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease ‡6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks. Conclusion: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kitexpressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development. Key words: c-kit, imatinib, kinase inhibitors, small-cell lung cancer
Introduction Small-cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15%–25% of all cases of primary lung cancers [1]. Although standard combination cytotoxic chemotherapy agents have shown antitumor activity with initial responses seen in 70%–90% for both limited and extensive stages of SCLC, long-term survival is low and most patients eventually develop progressive disease. Even among patients who achieve a complete response, there is a high rate of relapse [2]. Moreover, among patients who relapse, prognosis remains poor with second-line therapy. Response to sub-
*Correspondence to: Dr A. A. Adjei, Division of Medical Oncology, Mayo Clinic, 200 First St., SW Rochester, MN 55905, USA. Tel: +1-507-538-0548; Fax: +1-507-284-1803; E-mail: [email protected] Ó 2005 European Society for Medical Oncology
sequent therapy is influenced by the progression-free interval from cessation of initial therapy. Patients who relapse within 3 months are considered to have refractory disease and typically have response rates to second-line therapy that are inferior to patients considered to have ‘sensitive’ disease, generally defined as those who relapse more than 3 months after therapy [3]. Autocrine or paracrine activation of growth has been a popular hypothesis used to explain deregulated growth of SCLC. SCLC tumors and cultured cell lines produce a wide variety of peptide hormones and receptors that stimulate growth [4–6]. High level of expression of c-kit and its ligand, stem cell factor (SCF), has been widely found in both SCLC tumors and established cell cultures [7–9]. The role of the c-kit autocrine loop in SCLC has been well studied [10]. This autocrine loop not only functions cooperatively with other SCLC autocrine loops but, more importantly, seems to confer a tumor survival advantage in SCLC [10]. More importantly, in vitro treatment with c-kit tyrosine
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Received 18 May 2005; revised 17 June 2005; accepted 21 June 2005
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Patients and methods Eligibility/exclusion criteria The study was open for pre-registration screening to patients ‡18 years old with an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0–2 who had relapsed disease after, or refractory disease to one prior treatment regimen for a histologically or cytologically confirmed diagnosis of, small-cell lung cancer. Patients with tumors exhibiting mixed histology were not eligible. Prospective patients had to submit tumor tissue for c-kit evaluation and central pathology review. Patients were required to have measurable disease, defined as at least one lesion whose longest diameter could be accurately measured as ‡2 cm. Adequate hematologic [absolute neutrophil count (ANC) ‡1500/ll; platelet count ‡100,000/ll; hemoglobin ‡9.0 g/dl], renal [serum creatinine £1.5 · upper limit of normal (UNL)], and hepatic function (serum total bilirubin £1.5 · UNL or direct bilirubin £ UNL) had to be met prior to enrollment. Only patients with tumors that expressed c-kit as determined by immunohistochemistry (‡1+) were ultimately registered. Patients were excluded from the study if they had a concurrent or past history of another malignancy (except skin cancer or localized prostate cancer) within the preceding 3 years, had uncontrolled symptoms from
CNS metastasis (i.e. patients with treated CNS metastasis who were clinically stable were eligible), or had uncontrolled infection or precarious cardiovascular reserve (e.g. unstable angina pectoris, myocardial infarction or class III/IV heart failure within the preceding 3 months). Patients who received prior treatment with imatinib were not allowed to enroll in the study. Patients were also excluded if they had major surgery or preceding systemic chemotherapy within 21 days, or radiation therapy within 14 days prior to treatment. As the study involved an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn were unknown, men or women of childbearing potential who were unwilling to employ adequate contraception as well as pregnant or nursing women were excluded.
Pathology and immunohistochemistry Histology slides were reviewed and diagnosis of small-cell carcinoma confirmed, according to the 2004 World Health Organization Classification of Tumors of the Lung, by one of the authors (M.C.A.) prior to evaluation of c-kit expression in the tumor tissues. Nine cases were deemed ineligible for subsequent registration: six cases due to a change in the histologic diagnosis and three cases due to insufficient tumor tissue for evaluation. Immunohistochemical staining for KIT (CD117) was performed using a 1:250 dilution of the rabbit polyclonal antibody A4502 (DAKO, Carpinteria, CA) with the EnVision detection system. Appropriate positive and negative controls were used. The tumors were scored as 0 if <5% of cells were positive, as 1+ if 5%–25% of cells were positive, as 2+ if 26%–50% of cells positive and 3+ if >50% of cells were positive (Figure 1).
Treatment schema Patients were categorized into two groups depending on their prior response to treatment. Arm A included patients progressing <3 months after first-line therapy and arm B included patients progressing ‡3 months after completing one previous treatment regimen. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days and continued according to the schema shown in Figure 2. Patients who developed metastases in the central nervous system (CNS) as the only site of disease progression could receive therapeutic whole brain radiation therapy (WBRT) and after completion of WBRT continue on imatinib mesylate. Imaging studies were scheduled to be obtained after every other 28-day cycle. Response evaluation criteria for solid tumors (RECIST) [15] were used in the evaluation of treatment response. The National Cancer Institute Common Toxicity Criteria (NCI/CTC) version 2.0 was used for adverse event monitoring and reporting. Guidelines for dose reduction or interruption in the event of either hematologic and/or non-hematologic toxicities were instituted.
Study design and analysis In a phase III study of topotecan versus cyclophosphamide/doxorubicin/ vincristine (CAV) in recurrent SCLC, the median time to progression of the arms were 13.3 weeks (topotecan) and 12.3 weeks (CAV), respectively [2]. Based on this, the primary end point of this trial was the proportion of patients who were progression-free at 16 weeks. Progression-free survival was chosen as the primary end point, rather than response rate, as this is a more appropriate clinical end point for cytostatic agents such as imatinib. Moreover, reduction in tumor size may lag behind the cytostatic effect by months and thus objective tumor response rate was a secondary end point. A single-stage design with decision rules for a planned interim analysis based on a Simon Optimum two-stage design was used to assess the primary end point [16]. A treatment success was defined as a patient who was progression-free at 16 weeks. A sample of 37 evaluable patients provided 90% power to test the null hypothesis that the true success rate was at most 20% versus at least 40% in arm A with a type I error rate of 0.10. A sample
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kinase inhibitors reversed apoptosis resistance to growth factor deprivation in H526 cells, a SCLC cell line with co-expression of c-kit and SCF [11]. The ensuing growth inhibition was well correlated with the inhibition of c-kit tyrosine phosphorylation. Imatinib mesylate (STI571) is an orally bioavailable ‘promiscuous’ inhibitor of several tyrosine kinases due to the highly conserved structure of tyrosine kinase at the ATP binding site. Known targets of inhibition include the bcr-abl kinase, PDGF and c-kit. In a pivotal study, Krystal et al. [12] demonstrated that pretreatment of H526 cells with imatinib mesylate inhibited SCF-mediated kit activation. Inhibition of serum-dependent proliferation of multiple SCLC cell lines was established at an approximate IC50 of 5 lmol/l. It was also demonstrated that imatinib mesylate sufficiently blocked the signal transduction cascade triggered by c-kit activation. A separate study of SCLC cell lines documented a dose-dependent inhibition of tyrosine phosphorylation and in vitro kinase activity (at 5 lM) of c-kit using imatinib mesylate [13]. With the success of imatinib mesylate in the treatment of c-kit expressing gastrointestinal stromal tumor, a rare mesenchymal malignancy previously resistant to all treatment approaches, its use in other c-kit positive tumors such as SCLC presented a novel molecular therapeutic approach. Johnson et al. [14] reported their findings in 19 patients with SCLC, either with chemosensitive relapsed disease or previously untreated extensive stage, who were enrolled in a phase II trial using imatinib mesylate 600 mg daily for up to 12 months. There was no observed antitumor activity in this group of patients. However, the study was inconclusive, as it was weakened by at least two limitations: only 21% of the patients had c-kit positive tumors by immunohistochemstry and 26% of the patients had nonSCLC histology upon an unplanned post-hoc central pathology review. We therefore sought to evaluate clinical activity of imatinib in the treatment of patients with immunohistochemistryconfirmed c-kit + SCLC, utilizing a higher dose of 800 mg/day.
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Results Patient demographics and follow-up Only patients with c-kit positive SCLC by immunohistochemistry were allowed to be registered in the study. Out of 49 patients tested, 34 (69%) were c-kit positive (eight 1+, 11 2+, 15 3+). Four c-kit positive patients decided against enrollment in the study. Thus, a total of 30 patients (seven in arm A, 23 in arm B) entered the study between August 2003 and April 2004. One patient in arm B did not receive any treatment due to rapid deterioration in PS before starting treatment and was excluded from all analyses. The baseline characteristics of the 29 evaluable patients (seven in arm A, 22 in arm B) are given in Table 1. Treatment and follow-up data are summarized in Table 2. All patients were off active treatment at the time of this analysis. The median number of treatment cycles was one in both arms. The median follow-up for the nine alive patients in arm B is 8.2 months.
Adverse events (AE)
Figure 1. Immunohistochemical staining of small-cell carcinoma for c-kit. Intermediate photomicrographs showing immunoreactivity of (a) 1+, (b) 2+ and (c) 3+ (200·).
of 46 evaluable patients provided 90% power to test the null hypothesis that the true success rate was at most 30% versus at least 50% in arm B, with a type I error rate of 0.10. At the time of interim analysis, arm A was to be considered ineffective and accrual terminated if only three at most out of the first 17 evaluable patients
Grade 3+ non-hematologic adverse events, regardless of attribution, were seen in 52% of patients (Table 3). Grade 3+ nausea, vomiting, dyspnea, fatigue, anorexia and dehydration occurred in at least 10% (or three) of the patients. No grade 4 hematologic AEs were observed. The only grade 3 hematologic AE encountered in both treatment arms was anemia. One patient in arm A had left ventricular failure and subsequently died while on study, and one patient in arm B died from post-obstructive pneumonia. Both deaths were deemed to be due to progressive disease and unrelated to toxicities of treatment. One patient in arm A had a grade 5 event of acute respiratory distress syndrome (ARDS), deemed unrelated to study treatment.
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were progression free at 16 weeks. Similarly, arm B was to be considered ineffective and accrual terminated if only seven at most out of the first 22 evaluable patients were progression free at 16 weeks. Accrual was suspended during the interim analysis evaluation. The proportion of successes was estimated by the number of successes divided by the total number of evaluable patients and exact binomial confidence intervals for the true treatment success rate were constructed according to the method of Duffy and Santner for each arm [17]. Time to disease progression was defined as the time from registration to the date of first documented disease progression. Patients who died without disease progression were censored at the date of their last evaluation. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude that progression did not occur prior to death. Survival time was defined as the time from registration to death due to any cause. The distribution of time to disease progression and survival time was estimated in each arm using the method of Kaplan–Meier [18]. All adverse events, regardless of attribution, were summarized (overall and by arm). Presence of c-kit mutations in tumor tissue were to be analyzed and correlated with treatment response if any cohort of patients met the definition for treatment success.
1814
Figure 2. Treatment schema.
Table 2. Follow-up information
Variable
Arm A (n = 7)
Age, median (range)
68 (54–79)
Arm B (n = 22) 64.5 (45–84)
Gender Male
3 (43%)
12 (55%)
Female
4 (57%)
10 (45%)
White
7 (100%)
Black or African American
0 (0%)
21 (95%) 1 (5%)
Number cycles received, median (range) Time on treatment in months, median (range)
1 (1–2)
0 or 1
5 (71%)
21 (95%)
2
2 (29%)
1 (5%)
0 (0%)
7 (32%)
Brain metastasis (on registration), n (%)
7 (100%)
15 (68%)
Arm B (n = 22) 1 (1–2)
1.0 (0.6–1.9)
1.1 (0.3–1.9)
7 (100%)
22 (100%)
Progression status, n (%)
Follow-up status, n (%) Alive
0 (0%)
Dead
ECOG PS, n (%)
No
Arm A (n = 7)
Progression
Race, n (%)
Yes
Variable
7 (100%)
9 (41%) 13 (59%)
FU in months for alive patients, median (range)
–
8.2 (1.9–12.0)
Median survival, months Off active treatment, n (%)
3.9
5.3
Yes
7 (100%)
22 (100%)
Reason end treatment, n (%) Refused further treatment
3 (42%)
4 (18%)
Disease progression
2 (29%)
15 (68%)
Alternate treatment
0 (0%)
1 (5%)
11 (50%)
Died on study
2 (29%)
1 (5%)
6 (86%)
11 (50%)
Other
0 (0%)
1 (5%)
Yes
0 (100%)
9 (41%)
No
7 (100%)
13 (59%)
Previous chemotherapy, n (%) Yes
7 (100%)
22 (100%)
Previous TRT, n (%) Yes No
1 (14%)
Previous PCI, n (%)
PS, performance score; TRT, thoracic radiation therapy; PCI, prophylactic cranial irradiation.
Clinical activity Patient enrollment to arm A was temporarily suspended (seven patients accrued) as of 28 January 2004 prior to interim analysis due to rapid disease progression, early deaths or refusal (Table 2). On 16 April 2004, patient enrollment to arm B was temporarily suspended for interim analysis after the 22nd patient enrolled in that arm. The regimen was deemed ineffective and accrual to the arm was permanently terminated since only one patient was progression-free at 16 weeks (for 31 weeks; 95% CI 0 to 23%). Since arm B patients were likely to respond better to the treatment than arm A patients and arm B was deemed not
efficacious at interim analysis, the decision was made to close arm A permanently as well. There were no observed responses and no confirmed disease stability (‡6 weeks). There was one patient on arm B who had stable disease for 31 weeks. He refused further treatment after cycle 1 and was thus not subsequently evaluated for response. All other patients were either not evaluable for the primary end point as they went off study or progressed at their first evaluation (either cycle 1 or cycle 2). The median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively (Figure 3). There was no statistically significant association between the degree of c-kit expression and overall survival (log rank P value = 0.7). The mutational status of the c-kit receptor was not investigated further since there were no treatment successes, thus making it impossible to draw any relevant conclusions from such testing.
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Table 1. Patient characteristics
1815 Table 3. Adverse events (AE) regardless of attribution Patients with at least one:
Arm A (n = 7)
Arm B (n = 22)
Total (n = 29)
Grade 3 hematologic AE
1 (14%)
2 (9%)
3 (10%)
Grade 3+ non-hematologic AE
4 (57%)
11 (50%)
15 (52%)
Grade 4+ non-hematologic AE
2 (29%)
3 (14%)
5 (17%)
Grade 5 AE
2 (29%)
1 (5%)
3 (10%)
Grade 5 events were left ventricular failure (arm A), pneumonitis (arm B) and ARDS (arm A). These were deemed not to be related to the study medication.
This study demonstrates that in spite of selection of cases, imatinib mesylate does not have clinical activity in c-kit-expressing SCLC. The dosage selected was adequate based on data extrapolated from earlier pharmacokinetic studies [14, 19, 20], to achieve the inhibitory concentration for SCLC identified in preclinical studies. However, adverse events were significant using 400 mg twice daily dosing. This observation reinforces findings in trials of other tumor types of increased toxicities of daily doses at or above 800 mg. Although toxicities limited interpretation of clinical activity among arm A patients, treatment failure due to disease progression accounted for the majority of arm B patients. Based on historical data for drugs with other molecular targets (i.e. DNA or topoisomerases), arm B patients (sensitive relapse) were more likely to respond to treatment. More importantly, there are several other reasons to account for the observed results as explained below. c-kit is expressed by a variety of neoplasms, including SCLC [21]. Whether a c-kit tyrosine kinase inhibitor can induce tumor regression or growth inhibition depends largely on the degree of dependence on c-kit activity by the particular tumor cells under study. Single-agent therapy with tyrosine kinase inhibitors, such as imatinib mesylate, will be effective only against malignancies for which proliferation and/or survival are driven predominantly by the tyrosine kinase activity [22]. In this regard, clinical experience so far corroborates the mounting evidence that the greatest antitumor efficacy is seen in tumor types that have activating mutations of the tyrosine kinase [23–27]. KIT mutations are most commonly found in cell types (mast cells, germ cells, ICC and hematopoietic stem cells) for which development depends on normal activity of the SCF/KIT axis. On the contrary, the putative cells of origin of SCLC are not developmentally dependent on c-kit [21] and evidence to support the inference thereby of the lack of activating mutations in c-kit positive SCLC has been reported [28, 29]. Moreover, supporting evidence of lack of activity of imatinib in a murine xenograft model has been recently reported, in spite of activity demonstrable in corresponding in vitro studies using the same cell lines from which the xenografts were derived [30]. A potential limitation of the study is the use of tumor tissue obtained for initial diagnosis (prior to first-line chemotherapy) in the immunohistochemistry analyses. It has been reported that up to 50% of SCLC cases that were c-kit-positive at the time of
Figure 3. The Kaplan-Meier estimate of the time to disease progression by arm.
initial diagnosis were subsequently found to be c-kit-negative using a post-chemotherapy relapse specimen [31]. Moreover, current immunohistochemistry techniques are constrained to merely demonstrating c-kit expression, whereas most preclinical data of imatinib activity in SCLC were in cell lines that coexpressed its cognate ligand SCF [10–12]. Another condition controlled in the preclinical study of imatinib was serum deprivation [12, 13], which self-evidently cannot be achieved in the clinical setting. Our negative study serves as an important reminder of faulty assumptions that investigators need to be aware of in the design of future studies to test novel agents in solid tumors. Target expression by itself may not be enough to justify the study of kinase inhibitors in particular diseases. Evidence of activation of the relevant pathways need to be demonstrated. A more comprehensive preclinical evaluation must include in vivo studies of targeted agents to avoid waste of limited resources with conducting potentially ineffective trials [32]. Our data support the growing evidence that antitumor response to small molecule kinase inhibitors may not correlate with protein expression. Further understanding of the underlying molecular biology of SCLC is needed to facilitate the identification of appropriate targets for subsequent drug development and clinical testing. The redundancy and lack of dominance among the multiple aberrant growth and survival pathways make any single agent therapeutic intervention unlikely to be successful in SCLC. If imatinib is studied further in this disease, patients with tumors harboring c-kit mutations should be selected for testing.
Acknowledgements This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and the Cancer and Leukemia Group B was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-35431, CA-35269, CA-52352, CA-35101, CA-63849, CA-35431 and CA-35267.
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Discussion
1816 Additional participating institutions include: Medcenter One Health Systems, Bismarck, ND 58506 (E. J. Wos); Wichita Community Clinical Oncology Program, Wichita, KS 67214–3882 (S. Dakhil); Duluth CCOP, Duluth, MN 55805 (D. Nikcevich); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA 52403 (M. Wiesenfeld).
References
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1. Laskin J, Sandler A, Johnson DH. An advance in small-cell lung cancer treatment—more or less. J Natl Cancer Inst 2003; 95: 1099–1101. 2. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17: 658–667. 3. Ardizzoni A, Hansen H, Dombernowsky P et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997; 15: 2090–2096. 4. Sausville EA, Lebacq-Verheyden AM, Spindel ER et al. Expression of the gastrin-releasing peptide gene in human small-cell lung cancer. Evidence for alternative processing resulting in three distinct mRNAs. J Biol Chem 1986; 261: 2451–2457. 5. Nakanishi Y, Mulshine JL, Kasprzyk PG et al. Insulin-like growth factor-I can mediate autocrine proliferation of human small-cell lung cancer cell lines in vitro. J Clin Invest 1988; 82: 354–359. 6. Cuttitta F, Carney DN, Mulshine J et al. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 1985; 316: 823–826. 7. Sekido Y, Obata Y, Ueda R et al. Preferential expression of c-kit protooncogene transcripts in small-cell lung cancer. Cancer Res 1991; 51: 2416–2419. 8. Hibi K, Takahashi T, Sekido Y et al. Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene 1991; 6: 2291–2296. 9. Rygaard K, Nakamura T, Spang-Thomsen M. Expression of the protooncogenes c-met and c-kit and their ligands, hepatocyte growth factor/ scatter factor and stem cell factor, in SCLC cell lines and xenografts. Br J Cancer 1993; 67: 37–46. 10. Krystal GW, Hines SJ, Organ CP. Autocrine growth of small-cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res 1996; 56: 370–376. 11. Krystal GW, Carlson P, Litz J. Induction of apoptosis and inhibition of small-cell lung cancer growth by the quinoxaline tyrphostins. Cancer Res 1997; 57: 2203–2208. 12. Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small-cell lung cancer growth. Clin Cancer Res 2000; 6: 3319–3326. 13. Wang WL, Healy ME, Sattler M et al. Growth inhibition and modulation of kinase pathways of small-cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000; 19: 3521–3528. 14. Johnson BE, Fischer T, Fischer B et al. Phase II study of imatinib in patients with small-cell lung cancer. Clin Cancer Res 2003; 9: 5880–5887.
15. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 16. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 17. Duffy DE, Santner T. Confidence intervals for a binomial parameter based on multistage tests. Biometrics 1987; 43: 81–93. 18. Kaplan E, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 19. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–480. 20. Peng B, Hayes M, Resta D et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22: 935–942. 21. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002; 20: 1692–1703. 22. Heinrich MC, Griffith DJ, Druker BJ et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96: 925–932. 23. Cools J, DeAngelo DJ, Gotlib J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348: 1201–1214. 24. Rubin BP, Schuetze SM, Eary JF et al. Molecular targeting of plateletderived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002; 20: 3586–3591. 25. Lux ML, Rubin BP, Biase TL et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000; 156: 791–795. 26. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139. 27. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500. 28. Burger H, den Bakker MA, Stoter G et al. Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens. Eur J Cancer 2003; 39: 793–799. 29. Sihto H, Sarlomo-Rikala M, Tynninen O et al. KIT and plateletderived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 2005; 23: 49–57. 30. Wolff NC, Randle DE, Egorin MJ et al. Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small-cell lung cancer. Clin Cancer Res 2004; 10: 3528–3534. 31. Rossi G, Cavazza A, Marchioni A et al. Kit expression in small-cell carcinomas of the lung: effects of chemotherapy. Mod Pathol 2003; 16: 1041–1047. 32. Johnson BE. Imatinib for small-cell lung cancer, aiming for a target in vivo. Clin Cancer Res 2004; 10: 3235–3236.
Annals of Oncology 16: 1811–1816, 2005 doi:10.1093/annonc/mdi365 Published online 8 August 2005
A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study G. K. Dy1, A. A. Miller2, S. J. Mandrekar1, M.-C. Aubry1, R. M. Langdon Jr.3, R. F. Morton4, S. E. Schild5, J. R. Jett1 & A. A. Adjei1* 1
Mayo Clinic and Mayo Foundation, Rochester, MN 55905; 2Wake Forest University School of Medicine, Winston-Salem, NC 27157; 3Missouri Valley Cancer Consortium, Omaha, NE 68106; 4Iowa Oncology Research Association CCOP, Des Moines, IA 50309-1014; 5Scottsdale CCOP, Scottsdale, AZ 85259-5404, USA
Background: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer. Patients and methods: Patients with c-kit-expressing SCLC (‡1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression ‡3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm. Results: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease ‡6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks. Conclusion: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kitexpressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development. Key words: c-kit, imatinib, kinase inhibitors, small-cell lung cancer
Introduction Small-cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15%–25% of all cases of primary lung cancers [1]. Although standard combination cytotoxic chemotherapy agents have shown antitumor activity with initial responses seen in 70%–90% for both limited and extensive stages of SCLC, long-term survival is low and most patients eventually develop progressive disease. Even among patients who achieve a complete response, there is a high rate of relapse [2]. Moreover, among patients who relapse, prognosis remains poor with second-line therapy. Response to sub-
*Correspondence to: Dr A. A. Adjei, Division of Medical Oncology, Mayo Clinic, 200 First St., SW Rochester, MN 55905, USA. Tel: +1-507-538-0548; Fax: +1-507-284-1803; E-mail: [email protected] Ó 2005 European Society for Medical Oncology
sequent therapy is influenced by the progression-free interval from cessation of initial therapy. Patients who relapse within 3 months are considered to have refractory disease and typically have response rates to second-line therapy that are inferior to patients considered to have ‘sensitive’ disease, generally defined as those who relapse more than 3 months after therapy [3]. Autocrine or paracrine activation of growth has been a popular hypothesis used to explain deregulated growth of SCLC. SCLC tumors and cultured cell lines produce a wide variety of peptide hormones and receptors that stimulate growth [4–6]. High level of expression of c-kit and its ligand, stem cell factor (SCF), has been widely found in both SCLC tumors and established cell cultures [7–9]. The role of the c-kit autocrine loop in SCLC has been well studied [10]. This autocrine loop not only functions cooperatively with other SCLC autocrine loops but, more importantly, seems to confer a tumor survival advantage in SCLC [10]. More importantly, in vitro treatment with c-kit tyrosine
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Received 18 May 2005; revised 17 June 2005; accepted 21 June 2005
1812
Patients and methods Eligibility/exclusion criteria The study was open for pre-registration screening to patients ‡18 years old with an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0–2 who had relapsed disease after, or refractory disease to one prior treatment regimen for a histologically or cytologically confirmed diagnosis of, small-cell lung cancer. Patients with tumors exhibiting mixed histology were not eligible. Prospective patients had to submit tumor tissue for c-kit evaluation and central pathology review. Patients were required to have measurable disease, defined as at least one lesion whose longest diameter could be accurately measured as ‡2 cm. Adequate hematologic [absolute neutrophil count (ANC) ‡1500/ll; platelet count ‡100,000/ll; hemoglobin ‡9.0 g/dl], renal [serum creatinine £1.5 · upper limit of normal (UNL)], and hepatic function (serum total bilirubin £1.5 · UNL or direct bilirubin £ UNL) had to be met prior to enrollment. Only patients with tumors that expressed c-kit as determined by immunohistochemistry (‡1+) were ultimately registered. Patients were excluded from the study if they had a concurrent or past history of another malignancy (except skin cancer or localized prostate cancer) within the preceding 3 years, had uncontrolled symptoms from
CNS metastasis (i.e. patients with treated CNS metastasis who were clinically stable were eligible), or had uncontrolled infection or precarious cardiovascular reserve (e.g. unstable angina pectoris, myocardial infarction or class III/IV heart failure within the preceding 3 months). Patients who received prior treatment with imatinib were not allowed to enroll in the study. Patients were also excluded if they had major surgery or preceding systemic chemotherapy within 21 days, or radiation therapy within 14 days prior to treatment. As the study involved an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn were unknown, men or women of childbearing potential who were unwilling to employ adequate contraception as well as pregnant or nursing women were excluded.
Pathology and immunohistochemistry Histology slides were reviewed and diagnosis of small-cell carcinoma confirmed, according to the 2004 World Health Organization Classification of Tumors of the Lung, by one of the authors (M.C.A.) prior to evaluation of c-kit expression in the tumor tissues. Nine cases were deemed ineligible for subsequent registration: six cases due to a change in the histologic diagnosis and three cases due to insufficient tumor tissue for evaluation. Immunohistochemical staining for KIT (CD117) was performed using a 1:250 dilution of the rabbit polyclonal antibody A4502 (DAKO, Carpinteria, CA) with the EnVision detection system. Appropriate positive and negative controls were used. The tumors were scored as 0 if <5% of cells were positive, as 1+ if 5%–25% of cells were positive, as 2+ if 26%–50% of cells positive and 3+ if >50% of cells were positive (Figure 1).
Treatment schema Patients were categorized into two groups depending on their prior response to treatment. Arm A included patients progressing <3 months after first-line therapy and arm B included patients progressing ‡3 months after completing one previous treatment regimen. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days and continued according to the schema shown in Figure 2. Patients who developed metastases in the central nervous system (CNS) as the only site of disease progression could receive therapeutic whole brain radiation therapy (WBRT) and after completion of WBRT continue on imatinib mesylate. Imaging studies were scheduled to be obtained after every other 28-day cycle. Response evaluation criteria for solid tumors (RECIST) [15] were used in the evaluation of treatment response. The National Cancer Institute Common Toxicity Criteria (NCI/CTC) version 2.0 was used for adverse event monitoring and reporting. Guidelines for dose reduction or interruption in the event of either hematologic and/or non-hematologic toxicities were instituted.
Study design and analysis In a phase III study of topotecan versus cyclophosphamide/doxorubicin/ vincristine (CAV) in recurrent SCLC, the median time to progression of the arms were 13.3 weeks (topotecan) and 12.3 weeks (CAV), respectively [2]. Based on this, the primary end point of this trial was the proportion of patients who were progression-free at 16 weeks. Progression-free survival was chosen as the primary end point, rather than response rate, as this is a more appropriate clinical end point for cytostatic agents such as imatinib. Moreover, reduction in tumor size may lag behind the cytostatic effect by months and thus objective tumor response rate was a secondary end point. A single-stage design with decision rules for a planned interim analysis based on a Simon Optimum two-stage design was used to assess the primary end point [16]. A treatment success was defined as a patient who was progression-free at 16 weeks. A sample of 37 evaluable patients provided 90% power to test the null hypothesis that the true success rate was at most 20% versus at least 40% in arm A with a type I error rate of 0.10. A sample
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kinase inhibitors reversed apoptosis resistance to growth factor deprivation in H526 cells, a SCLC cell line with co-expression of c-kit and SCF [11]. The ensuing growth inhibition was well correlated with the inhibition of c-kit tyrosine phosphorylation. Imatinib mesylate (STI571) is an orally bioavailable ‘promiscuous’ inhibitor of several tyrosine kinases due to the highly conserved structure of tyrosine kinase at the ATP binding site. Known targets of inhibition include the bcr-abl kinase, PDGF and c-kit. In a pivotal study, Krystal et al. [12] demonstrated that pretreatment of H526 cells with imatinib mesylate inhibited SCF-mediated kit activation. Inhibition of serum-dependent proliferation of multiple SCLC cell lines was established at an approximate IC50 of 5 lmol/l. It was also demonstrated that imatinib mesylate sufficiently blocked the signal transduction cascade triggered by c-kit activation. A separate study of SCLC cell lines documented a dose-dependent inhibition of tyrosine phosphorylation and in vitro kinase activity (at 5 lM) of c-kit using imatinib mesylate [13]. With the success of imatinib mesylate in the treatment of c-kit expressing gastrointestinal stromal tumor, a rare mesenchymal malignancy previously resistant to all treatment approaches, its use in other c-kit positive tumors such as SCLC presented a novel molecular therapeutic approach. Johnson et al. [14] reported their findings in 19 patients with SCLC, either with chemosensitive relapsed disease or previously untreated extensive stage, who were enrolled in a phase II trial using imatinib mesylate 600 mg daily for up to 12 months. There was no observed antitumor activity in this group of patients. However, the study was inconclusive, as it was weakened by at least two limitations: only 21% of the patients had c-kit positive tumors by immunohistochemstry and 26% of the patients had nonSCLC histology upon an unplanned post-hoc central pathology review. We therefore sought to evaluate clinical activity of imatinib in the treatment of patients with immunohistochemistryconfirmed c-kit + SCLC, utilizing a higher dose of 800 mg/day.
1813
Results Patient demographics and follow-up Only patients with c-kit positive SCLC by immunohistochemistry were allowed to be registered in the study. Out of 49 patients tested, 34 (69%) were c-kit positive (eight 1+, 11 2+, 15 3+). Four c-kit positive patients decided against enrollment in the study. Thus, a total of 30 patients (seven in arm A, 23 in arm B) entered the study between August 2003 and April 2004. One patient in arm B did not receive any treatment due to rapid deterioration in PS before starting treatment and was excluded from all analyses. The baseline characteristics of the 29 evaluable patients (seven in arm A, 22 in arm B) are given in Table 1. Treatment and follow-up data are summarized in Table 2. All patients were off active treatment at the time of this analysis. The median number of treatment cycles was one in both arms. The median follow-up for the nine alive patients in arm B is 8.2 months.
Adverse events (AE)
Figure 1. Immunohistochemical staining of small-cell carcinoma for c-kit. Intermediate photomicrographs showing immunoreactivity of (a) 1+, (b) 2+ and (c) 3+ (200·).
of 46 evaluable patients provided 90% power to test the null hypothesis that the true success rate was at most 30% versus at least 50% in arm B, with a type I error rate of 0.10. At the time of interim analysis, arm A was to be considered ineffective and accrual terminated if only three at most out of the first 17 evaluable patients
Grade 3+ non-hematologic adverse events, regardless of attribution, were seen in 52% of patients (Table 3). Grade 3+ nausea, vomiting, dyspnea, fatigue, anorexia and dehydration occurred in at least 10% (or three) of the patients. No grade 4 hematologic AEs were observed. The only grade 3 hematologic AE encountered in both treatment arms was anemia. One patient in arm A had left ventricular failure and subsequently died while on study, and one patient in arm B died from post-obstructive pneumonia. Both deaths were deemed to be due to progressive disease and unrelated to toxicities of treatment. One patient in arm A had a grade 5 event of acute respiratory distress syndrome (ARDS), deemed unrelated to study treatment.
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were progression free at 16 weeks. Similarly, arm B was to be considered ineffective and accrual terminated if only seven at most out of the first 22 evaluable patients were progression free at 16 weeks. Accrual was suspended during the interim analysis evaluation. The proportion of successes was estimated by the number of successes divided by the total number of evaluable patients and exact binomial confidence intervals for the true treatment success rate were constructed according to the method of Duffy and Santner for each arm [17]. Time to disease progression was defined as the time from registration to the date of first documented disease progression. Patients who died without disease progression were censored at the date of their last evaluation. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude that progression did not occur prior to death. Survival time was defined as the time from registration to death due to any cause. The distribution of time to disease progression and survival time was estimated in each arm using the method of Kaplan–Meier [18]. All adverse events, regardless of attribution, were summarized (overall and by arm). Presence of c-kit mutations in tumor tissue were to be analyzed and correlated with treatment response if any cohort of patients met the definition for treatment success.
1814
Figure 2. Treatment schema.
Table 2. Follow-up information
Variable
Arm A (n = 7)
Age, median (range)
68 (54–79)
Arm B (n = 22) 64.5 (45–84)
Gender Male
3 (43%)
12 (55%)
Female
4 (57%)
10 (45%)
White
7 (100%)
Black or African American
0 (0%)
21 (95%) 1 (5%)
Number cycles received, median (range) Time on treatment in months, median (range)
1 (1–2)
0 or 1
5 (71%)
21 (95%)
2
2 (29%)
1 (5%)
0 (0%)
7 (32%)
Brain metastasis (on registration), n (%)
7 (100%)
15 (68%)
Arm B (n = 22) 1 (1–2)
1.0 (0.6–1.9)
1.1 (0.3–1.9)
7 (100%)
22 (100%)
Progression status, n (%)
Follow-up status, n (%) Alive
0 (0%)
Dead
ECOG PS, n (%)
No
Arm A (n = 7)
Progression
Race, n (%)
Yes
Variable
7 (100%)
9 (41%) 13 (59%)
FU in months for alive patients, median (range)
–
8.2 (1.9–12.0)
Median survival, months Off active treatment, n (%)
3.9
5.3
Yes
7 (100%)
22 (100%)
Reason end treatment, n (%) Refused further treatment
3 (42%)
4 (18%)
Disease progression
2 (29%)
15 (68%)
Alternate treatment
0 (0%)
1 (5%)
11 (50%)
Died on study
2 (29%)
1 (5%)
6 (86%)
11 (50%)
Other
0 (0%)
1 (5%)
Yes
0 (100%)
9 (41%)
No
7 (100%)
13 (59%)
Previous chemotherapy, n (%) Yes
7 (100%)
22 (100%)
Previous TRT, n (%) Yes No
1 (14%)
Previous PCI, n (%)
PS, performance score; TRT, thoracic radiation therapy; PCI, prophylactic cranial irradiation.
Clinical activity Patient enrollment to arm A was temporarily suspended (seven patients accrued) as of 28 January 2004 prior to interim analysis due to rapid disease progression, early deaths or refusal (Table 2). On 16 April 2004, patient enrollment to arm B was temporarily suspended for interim analysis after the 22nd patient enrolled in that arm. The regimen was deemed ineffective and accrual to the arm was permanently terminated since only one patient was progression-free at 16 weeks (for 31 weeks; 95% CI 0 to 23%). Since arm B patients were likely to respond better to the treatment than arm A patients and arm B was deemed not
efficacious at interim analysis, the decision was made to close arm A permanently as well. There were no observed responses and no confirmed disease stability (‡6 weeks). There was one patient on arm B who had stable disease for 31 weeks. He refused further treatment after cycle 1 and was thus not subsequently evaluated for response. All other patients were either not evaluable for the primary end point as they went off study or progressed at their first evaluation (either cycle 1 or cycle 2). The median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively (Figure 3). There was no statistically significant association between the degree of c-kit expression and overall survival (log rank P value = 0.7). The mutational status of the c-kit receptor was not investigated further since there were no treatment successes, thus making it impossible to draw any relevant conclusions from such testing.
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Table 1. Patient characteristics
1815 Table 3. Adverse events (AE) regardless of attribution Patients with at least one:
Arm A (n = 7)
Arm B (n = 22)
Total (n = 29)
Grade 3 hematologic AE
1 (14%)
2 (9%)
3 (10%)
Grade 3+ non-hematologic AE
4 (57%)
11 (50%)
15 (52%)
Grade 4+ non-hematologic AE
2 (29%)
3 (14%)
5 (17%)
Grade 5 AE
2 (29%)
1 (5%)
3 (10%)
Grade 5 events were left ventricular failure (arm A), pneumonitis (arm B) and ARDS (arm A). These were deemed not to be related to the study medication.
This study demonstrates that in spite of selection of cases, imatinib mesylate does not have clinical activity in c-kit-expressing SCLC. The dosage selected was adequate based on data extrapolated from earlier pharmacokinetic studies [14, 19, 20], to achieve the inhibitory concentration for SCLC identified in preclinical studies. However, adverse events were significant using 400 mg twice daily dosing. This observation reinforces findings in trials of other tumor types of increased toxicities of daily doses at or above 800 mg. Although toxicities limited interpretation of clinical activity among arm A patients, treatment failure due to disease progression accounted for the majority of arm B patients. Based on historical data for drugs with other molecular targets (i.e. DNA or topoisomerases), arm B patients (sensitive relapse) were more likely to respond to treatment. More importantly, there are several other reasons to account for the observed results as explained below. c-kit is expressed by a variety of neoplasms, including SCLC [21]. Whether a c-kit tyrosine kinase inhibitor can induce tumor regression or growth inhibition depends largely on the degree of dependence on c-kit activity by the particular tumor cells under study. Single-agent therapy with tyrosine kinase inhibitors, such as imatinib mesylate, will be effective only against malignancies for which proliferation and/or survival are driven predominantly by the tyrosine kinase activity [22]. In this regard, clinical experience so far corroborates the mounting evidence that the greatest antitumor efficacy is seen in tumor types that have activating mutations of the tyrosine kinase [23–27]. KIT mutations are most commonly found in cell types (mast cells, germ cells, ICC and hematopoietic stem cells) for which development depends on normal activity of the SCF/KIT axis. On the contrary, the putative cells of origin of SCLC are not developmentally dependent on c-kit [21] and evidence to support the inference thereby of the lack of activating mutations in c-kit positive SCLC has been reported [28, 29]. Moreover, supporting evidence of lack of activity of imatinib in a murine xenograft model has been recently reported, in spite of activity demonstrable in corresponding in vitro studies using the same cell lines from which the xenografts were derived [30]. A potential limitation of the study is the use of tumor tissue obtained for initial diagnosis (prior to first-line chemotherapy) in the immunohistochemistry analyses. It has been reported that up to 50% of SCLC cases that were c-kit-positive at the time of
Figure 3. The Kaplan-Meier estimate of the time to disease progression by arm.
initial diagnosis were subsequently found to be c-kit-negative using a post-chemotherapy relapse specimen [31]. Moreover, current immunohistochemistry techniques are constrained to merely demonstrating c-kit expression, whereas most preclinical data of imatinib activity in SCLC were in cell lines that coexpressed its cognate ligand SCF [10–12]. Another condition controlled in the preclinical study of imatinib was serum deprivation [12, 13], which self-evidently cannot be achieved in the clinical setting. Our negative study serves as an important reminder of faulty assumptions that investigators need to be aware of in the design of future studies to test novel agents in solid tumors. Target expression by itself may not be enough to justify the study of kinase inhibitors in particular diseases. Evidence of activation of the relevant pathways need to be demonstrated. A more comprehensive preclinical evaluation must include in vivo studies of targeted agents to avoid waste of limited resources with conducting potentially ineffective trials [32]. Our data support the growing evidence that antitumor response to small molecule kinase inhibitors may not correlate with protein expression. Further understanding of the underlying molecular biology of SCLC is needed to facilitate the identification of appropriate targets for subsequent drug development and clinical testing. The redundancy and lack of dominance among the multiple aberrant growth and survival pathways make any single agent therapeutic intervention unlikely to be successful in SCLC. If imatinib is studied further in this disease, patients with tumors harboring c-kit mutations should be selected for testing.
Acknowledgements This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and the Cancer and Leukemia Group B was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-35431, CA-35269, CA-52352, CA-35101, CA-63849, CA-35431 and CA-35267.
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Discussion
1816 Additional participating institutions include: Medcenter One Health Systems, Bismarck, ND 58506 (E. J. Wos); Wichita Community Clinical Oncology Program, Wichita, KS 67214–3882 (S. Dakhil); Duluth CCOP, Duluth, MN 55805 (D. Nikcevich); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA 52403 (M. Wiesenfeld).
References
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1. Laskin J, Sandler A, Johnson DH. An advance in small-cell lung cancer treatment—more or less. J Natl Cancer Inst 2003; 95: 1099–1101. 2. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17: 658–667. 3. Ardizzoni A, Hansen H, Dombernowsky P et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997; 15: 2090–2096. 4. Sausville EA, Lebacq-Verheyden AM, Spindel ER et al. Expression of the gastrin-releasing peptide gene in human small-cell lung cancer. Evidence for alternative processing resulting in three distinct mRNAs. J Biol Chem 1986; 261: 2451–2457. 5. Nakanishi Y, Mulshine JL, Kasprzyk PG et al. Insulin-like growth factor-I can mediate autocrine proliferation of human small-cell lung cancer cell lines in vitro. J Clin Invest 1988; 82: 354–359. 6. Cuttitta F, Carney DN, Mulshine J et al. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 1985; 316: 823–826. 7. Sekido Y, Obata Y, Ueda R et al. Preferential expression of c-kit protooncogene transcripts in small-cell lung cancer. Cancer Res 1991; 51: 2416–2419. 8. Hibi K, Takahashi T, Sekido Y et al. Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene 1991; 6: 2291–2296. 9. Rygaard K, Nakamura T, Spang-Thomsen M. Expression of the protooncogenes c-met and c-kit and their ligands, hepatocyte growth factor/ scatter factor and stem cell factor, in SCLC cell lines and xenografts. Br J Cancer 1993; 67: 37–46. 10. Krystal GW, Hines SJ, Organ CP. Autocrine growth of small-cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res 1996; 56: 370–376. 11. Krystal GW, Carlson P, Litz J. Induction of apoptosis and inhibition of small-cell lung cancer growth by the quinoxaline tyrphostins. Cancer Res 1997; 57: 2203–2208. 12. Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small-cell lung cancer growth. Clin Cancer Res 2000; 6: 3319–3326. 13. Wang WL, Healy ME, Sattler M et al. Growth inhibition and modulation of kinase pathways of small-cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000; 19: 3521–3528. 14. Johnson BE, Fischer T, Fischer B et al. Phase II study of imatinib in patients with small-cell lung cancer. Clin Cancer Res 2003; 9: 5880–5887.
15. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 16. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 17. Duffy DE, Santner T. Confidence intervals for a binomial parameter based on multistage tests. Biometrics 1987; 43: 81–93. 18. Kaplan E, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 19. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–480. 20. Peng B, Hayes M, Resta D et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22: 935–942. 21. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002; 20: 1692–1703. 22. Heinrich MC, Griffith DJ, Druker BJ et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96: 925–932. 23. Cools J, DeAngelo DJ, Gotlib J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348: 1201–1214. 24. Rubin BP, Schuetze SM, Eary JF et al. Molecular targeting of plateletderived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002; 20: 3586–3591. 25. Lux ML, Rubin BP, Biase TL et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000; 156: 791–795. 26. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139. 27. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500. 28. Burger H, den Bakker MA, Stoter G et al. Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens. Eur J Cancer 2003; 39: 793–799. 29. Sihto H, Sarlomo-Rikala M, Tynninen O et al. KIT and plateletderived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 2005; 23: 49–57. 30. Wolff NC, Randle DE, Egorin MJ et al. Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small-cell lung cancer. Clin Cancer Res 2004; 10: 3528–3534. 31. Rossi G, Cavazza A, Marchioni A et al. Kit expression in small-cell carcinomas of the lung: effects of chemotherapy. Mod Pathol 2003; 16: 1041–1047. 32. Johnson BE. Imatinib for small-cell lung cancer, aiming for a target in vivo. Clin Cancer Res 2004; 10: 3235–3236.