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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3936-3944 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.1336 Multicenter, Randomized, Phase II Trial of CI-1033, an Irreversible Pan-ERBB Inhibitor, for Previously Treated Advanced Non–Small-Cell Lung Cancer
From the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital; Department of Medicine, Massachusetts General Hospital, Boston, MA; Asklepios Fachklinik Fuer Lungenkrankheiten, Gauting, Germany; Fox Chase Cancer Center, Philadelphia, PA; Ospedale Silvestrini, Perugia, Italy; Cross Cancer Institute, Edmonton, Alberta, Canada; Pfizer Global Research & Development, Ann Arbor, MI; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and Rush Cancer Institute, Section of Oncology, Chicago, IL Address reprint requests to Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana Farber Cancer Institute, 820A, 44 Binney St, Boston, MA 02115; e-mail: pjanne{at}partners.org
Purpose To evaluate the efficacy of the pan-ERBB inhibitor, CI-1033, in platinum-refractory or recurrent advanced-stage non–small-cell lung cancer (NSCLC). Patients and Methods This open-label, randomized phase II trial evaluated CI-1033 in patients with advanced-stage NSCLC who experienced treatment failure after or were refractory to platinum-based chemotherapy. Three oral CI-1033 doses were evaluated in 21-day dosing cycles: 50 mg daily for 21 consecutive days, 150 mg daily for 21 consecutive days, and 450 mg daily for 14 consecutive days followed by 7 days of no treatment. The primary efficacy end point was the 1-year survival rate. Results One hundred sixty-six patients were randomly assigned to treatment. Baseline patient demographics were well balanced. The most common drug-related adverse events were rash and diarrhea. The 450-mg arm (14 days on/7 days off) was closed early due to an excessive rate of adverse events. The 1-year survival rates were 29%, 26%, and 29%, respectively, in the three arms. The response rates were 2%, 2%, and 4%, and stable disease was confirmed in 16%, 23%, and 18% of patients, respectively, in the three study arms. Exploratory analyses demonstrated a prolonged survival in patients who developed a rash and in those with baseline tumor ERBB-2 expression. Conclusion CI-1033 had modest activity in unselected NSCLC patients but did not meet its primary end point. Future studies should focus on identifying methods of patient selection.
Epidermal growth factor receptor (EGFR) inhibitors have emerged as attractive therapies for patients with previously treated advanced-stage non–small-cell lung cancer (NSCLC). EGFR is a member of a family of closely related receptors, including EGFR (ERBB1), human epidermal growth factor receptor 2 (HER-2)/neu (ERBB2), HER-3 (ERBB3), and HER-4 (ERBB4). EGFR is overexpressed in the majority of NSCLCs and is observed more frequently in squamous cell carcinomas (57% to 100%) than in adenocarcinomas (35% to 100%).1-4 In contrast, high ERBB2 protein expression is only observed in 1% of squamous cell carcinomas but is detected in approximately one third of adenocarcinomas.5 Expression of ERBB3 and ERBB4 have been less well studied, but both have been detected by immunohistochemistry (IHC) in approximately two thirds of NSCLC specimens and equally in adenocarcinomas and squamous cell carcinomas.6,7 Gefitinib and erlotinib are both reversible EGFR tyrosine kinase inhibitors (TKIs) that have been evaluated extensively.8-10 Both agents produce objective tumor regressions in 10% to 20% of previously treated NSCLC patients, and erlotinib has been associated with a survival prolongation in a phase III trial.8-12 Neither agent significantly inhibits the other ERBB family members.13,14 Studies on the role of EGFR expression, as detected by IHC, as a predictor of efficacy of gefitinib or erlotinib have been conflicting to date.15-17 More recently, expression of ERBB3 by IHC and increased ERBB2 copy number have been associated with efficacy of gefitinib.18,19 Given the presence of other ERBB family members in lung cancers, the development of agents capable of inhibiting these, in addition to EGFR, may provide an increase in therapeutic efficacy compared with pure EGFR inhibitors. CI-1033 is a 4-anilinoquinazoline that irreversibly inhibits all members of the ERBB family by covalently binding to cysteine 773 of EGFR (or the analogous cysteines 784 and 778 of ERBB2 and ERBB4, respectively).20 In vitro, covalent binding to EGFR results in more prolonged inhibition of EGFR phosphorylation compared with reversible kinase inhibitors.20 CI-1033 permanently inactivates the tyrosine kinase domain of ERBB receptors and induces receptor ubiquitination and degradation.21 Whether these biochemical differences will translate into clinical differences remains to be determined. Phase I clinical studies evaluated CI-1033 across a variety of doses and treatment schedules.22,23 A phase I study of intermittent dosing (7 days on/14 days off) found no differences in the extent of inhibition of EGFR phosphorylation in post-treatment tumor biopsies as a function on dose. However, the maintenance of EGFR inhibition was dose dependent, and was greatest with the maximum-tolerated dose of 450 mg.22 The maximum-tolerated dose of CI-1033 was 150 mg daily using a continuous-dosing schedule. Similar to gefitinib and erlotinib, the most common adverse events (AEs) observed with CI-1033 in the phase I studies were acneiform rash, diarrhea, and nausea. However, grade 3 thrombocytopenia and hypersensitivity reactions were observed occasionally in the phase I clinical studies of CI-1033, unlike gefitinib or erlotinib.22 In this study, we evaluated the efficacy of three dosing schedules of CI-1033 in a randomized phase II trial of patients with advanced-stage NSCLC who had experienced treatment failure after platinum-based chemotherapy.
Eligibility Criteria Patients had pathologically confirmed, progressive or recurrent advanced-stage (IIIB or IV) NSCLC; had experienced treatment failure after platinum-based therapy for advanced NSCLC; had IHC evidence of expression of at least one ERBB family member (ERBB1, ERBB2, or ERBB4); had measurable disease as defined by Response Evaluation Criteria in Solid Tumors Group; were age  18 years; had Eastern Cooperative Oncology Group performance status of 0 to 1; and had adequate organ and bone marrow function.24 Exclusion criteria included prior exposure to agents targeting any member of the ERBB family, more than two prior chemotherapy regimens, or an unknown response to prior platinum-containing chemotherapy. Patients with brain metastases were eligible as long as they were neurologically stable, had completed definitive treatment, and had discontinued corticosteroids for 4 weeks. All patients provided written informed consent and approval was obtained from the institutional review boards at each of the investigational centers participating in this study. The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki.
Trial Design
Toxicity assessments were performed using the National Cancer Institute Common Toxicity Criteria version 2.0. Dose reductions were made for grade 4 hematologic toxicity, grade
Statistical Analysis All time-to-event variables, including overall survival, duration of objective response, progression-free survival, and 26-week progression-free survival, were analyzed using Kaplan-Meier product-limit survival estimates. Objective response rates were calculated using exact 95% two-sided CIs using standard methods based on the binomial distribution.
Assessment of Biomarkers Expression was assessed using a standard histopathologic semiquantitative scale that scored staining as 0 (absent staining), 1+ (slight staining in at least 10% of cells), 2+ (moderate staining in at least 10% of cells), or 3+ (marked staining in at least 10% of cells). In addition, the hybrid-score (H-score) method was also used to demonstrate expression and was calculated based on total number of malignant cells in each field and the number of cells stained at each intensity.26 An H-score between 0 and 300 was obtained, where 300 was equal to 100% of tumor cells staining strongly (3+). Statistical comparisons based on H-score were performed using the Mann-Whitney test. All P values were two sided.
Patient Characteristics Between January 2003 and April 2005, 262 patients were screened and 166 patients were randomly assigned to treatment with CI-1033 from 32 centers in eight countries from North America (n = 2) and Europe (n = 6). Reasons for not randomly assigning the remaining 96 patients were lack of tumor staining for any ERBB family member (n = 25); patient did not meet all eligibility criteria (n = 23); the submitted tumor specimens did not contain tumor (n = 11) or was insufficient for analyses (n = 1); or performance status was declining (n = 36). Of the randomly assigned patients, 163 were treated with CI-1033: 59 patients in arm A, 59 patients in arm B, and 45 patients in arm C (Fig 1). Table 1 lists the baseline characteristics of all randomly assigned patients. The baseline patient characteristics were similar in all three treatment arms. No patients of Asian ethnicity were enrolled onto this study and no information on smoking history was collected during this study.
Adverse Events All patients who received at least one dose of CI-1033 were analyzed for safety. The delivered treatment is listed in Table 2. Dose reductions were more frequent in arm C and more patients discontinued treatment in arm C due to a CI-1033 related AE (14 of 19; 74%) compared with either arm A (three of 13; 23%) or arm B (nine of 19; 47%). The most common reasons for discontinuation were rash and diarrhea. The high rate of AEs led to the discontinuation of arm C from the trial after 46 patients were randomly assigned. Patients already receiving treatment on this arm were allowed to continue to receive this dose at the discretion of the treating physician or have their dose reduced based on protocol-defined criteria. The remaining study patients were randomly assigned 1:1 to either arm A or B.
Table 3 lists the AEs for patients treated in the study arms. The most common grade 3/4 toxicities were diarrhea, rash, nausea, asthenia, and dyspnea. The incidence of grade 3/4 AEs was dose dependent and involved seven patients (12%) in arm A, 18 patients (31%) in arm B, and 33 patients (73%) in arm C. Hematologic and chemistry abnormalities were also noted but no grade 3/4 toxicities occurred in 10% of patients (Table 3).
One patient treated in arm B died as a result of an AE. The patient was a 72-year-old white female who developed severe shortness of breath 8 days after initiation of treatment. She had ingested six doses of CI-1033. Radiographic evaluation demonstrated diffuse interstitial infiltrates in all lung lobes consistent with pneumonitis. She was treated with corticosteroids and broad-spectrum antibiotics, and her family decided not to pursue additional treatments or diagnostic procedures.
Efficacy
There were no CRs in this study (Table 4). There were four confirmed PRs (one in arm A, one in arm B, and two in arm C).
Correlation of Rash With Efficacy
Expression of ERBB Family Members and Correlation With Efficacy
This multicenter, randomized, phase II trial evaluated the efficacy of an irreversible ERBB inhibitor, CI-1033, in patients with previously treated advanced NSCLC. To our knowledge, this is the first report of a phase II clinical study of an irreversible ERBB inhibitor and of a pan-ERBB inhibitor in patients with advanced NSCLC. The study demonstrated marginal efficacy of the agent, with a response rate of 2% to 4% in each arm, but failed to meet its primary statistical end point. These observations suggest a lower efficacy (response rate and disease control rate [patients with PR + SD]) for CI-1033 than for gefitinib or erlotinib in similar patient populations.8-10 It will be important to understand the determinants of efficacy differences for the future development of irreversible pure EGFR or pan-ERBB inhibitors for NSCLC. This is especially true in light of recent in vitro observations suggesting that irreversible EGFR inhibitors may be effective therapies for patients who have developed acquired resistance to gefitinib or erlotinib.30,31 Several possibilities may account for the observations in this study. The findings in the current study may be due in part to the patients entered onto the trial. There are clear clinical determinants of the efficacy (as measured by radiographic regression and/or survival) of gefitinib and erlotinib.32 Radiographic responses to gefitinib or erlotinib in patients with squamous cell carcinoma are rare. In our study, the percentage of patients with squamous cell carcinoma was slightly higher (24% in the entire study) than in the gefitinib and erlotinib studies (15% to 20%), which may have contributed to our findings. Twenty percent of patients in the BR.21 trial were never-smokers, and this subgroup of patients had the largest response rate and derived the greatest survival benefit from erlotinib.11 No information on cigarette smoking was collected in this study, and the higher frequency of patients with squamous cell carcinomas in the present study suggests that the majority of patients were either former or current smokers. Furthermore, unlike in the BR.21 trial, there were no patients of Asian ethnicity (which is associated with increased efficacy of EGFR TKIs) in the current study.8,11 Thus, although in vitro, CI-1033 is more effective than reversible EGFR TKIs, these differences did not translate into an improved clinical efficacy, perhaps due in part to the patient composition in the current trial. Recent molecular studies have identified EGFR somatic mutations and/or increased copy number as predictors for response and prolonged survival with gefitinib and erlotinib.16,17,33-36 These molecular analyses have not been performed from patients on this study, but it is possible that they may be revealing and help us understand the low rate of PRs in this study and also aid in the design of future clinical studies with pan-ERBB inhibitors. Patient selection using either clinical or molecular parameters will be important in future trial designs of this class of agents. Similar to previous studies of EGFR inhibitors, patients who developed a rash had a significantly longer survival than those who did not develop a rash. Thus for an agent (CI-1033) with only modest clinical activity, rash still emerges as a predictor for survival. However, given the modest clinical activity, it is possible that the development of skin rash only identifies a better prognostic group of patients, those with a better performance status, or those with less aggressive tumors; thus, these patients are able to take CI-1033 for a longer period of time and as a result develop a skin rash. In support of this hypothesis, the median duration of treatment in patients who did not develop a skin rash was 26 days (range, 1 to 253 days) compared with 56 days (range, 9 to 479 days) for those who developed any grade rash. These differences are statistically different (P = .028; log rank). Continued investigation into the mechanisms and prognostic significance of skin rash in patients treated with ERBB inhibitors is warranted. Recent studies have revealed the importance of the concurrent presence of other ERBB family members to the efficacy of the EGFR inhibitor gefitinib.18,19 Increased ERBB2 copy number is associated with a better response rate, disease control rate (CR, PR, and SD patients), and longer time to progression with gefitinib.19 It is of interest that higher levels of ERBB2 expression (as measured by the H-score) are found in patients with either PR or SD in this study compared with those with PD. Similarly, a positive H-score was associated with prolonged survival. It should be noted that this study examined ERBB2 expression rather than gene copy number, as was examined by Cappuzzo et al.19 Most of the tumors in our study also demonstrated low ERBB2 expression (Fig 3), suggesting that even the low-level presence of ERBB2 may be sufficient to confer a clinical benefit to CI-1033. These findings are in contrast to studies examining selective ERBB2-targeted agents (trastuzumab), which have not been successful even when restricted to 2+ or 3+ ERBB2-expressing tumors as assayed by IHC.37-39 Alternatively, it is possible that ERBB2 expression only serves as a prognostic marker, given that all patients in this study received CI-1033 treatment. Additional studies are needed to confirm the association of ERBB2 expression and/or increased copy number as a prognostic marker and/or a predictive marker of efficacy of ERBB inhibitors.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Steven S. Olson, Pfizer; Irene A. Eisman, Pfizer; Peter F. Lenehan, Pfizer; Kathy Dasse, Pfizer; Meredith Sheeran, Pfizer Leadership: N/A Consultant: Charles A. Butts, Pfizer; Philip D. Bonomi, Pfizer, Genentech, OSI Pharmaceuticals, AstraZeneca Stock: Steven S. Olson, Pfizer; Irene A. Eisman, Pfizer; Peter F. Lenehan, Pfizer; Kathy Dasse, Pfizer; Meredith Sheeran, Pfizer Honoraria: Pasi A. Jänne, AstraZeneca, Roche; Charles A. Butts, Pfizer; Philip D. Bonomi, Pfizer, Genentech, OSI Pharmaceuticals, AstraZeneca Research Funds: Roger Cohen, Pfizer; Alberto A. Chiappori, Pfizer; Philip D. Bonomi, Pfizer, Genentech, OSI Pharmaceuticals, AstraZeneca Testimony: N/A Other: N/A
Conception and design: Peter F. Lenehan Financial support: Steven S. Olson, Irene A. Eisman, Peter F. Lenehan, Kathy Dasse, Meredith Sheeran Provision of study materials or patients: Pasi A. Jänne, Joachim von Pawel, Roger Cohen, Lucio Crino, Charles A. Butts, Alberto A. Chiappori Collection and assembly of data: Steven S. Olson, Irene A. Eisman, Kathy Dasse, Meredith Sheeran Data analysis and interpretation: Pasi A. Jänne, Beow Y. Yeap Manuscript writing: Pasi A. Jänne, Philip D. Bonomi Final approval of manuscript: Pasi A. Jänne, Joachim von Pawel, Roger Cohen, Lucio Crino, Charles Butts, Steven S. Olson, Irene A. Eisman, Alberto A. Chiappori, Beow Y. Yeap, Peter F. Lenehan, Kathy Dasse, Meredith Sheeran, Philip D. Bonomi
We thank the other investigators who participated in this clinical trial: E. Vokes, MD, A. Sandler, MD, P. Fidias, MD, J. Bitran, MD, G. Kalemkerian, MD, F. Robert-Vizcarrondo, MD, W. Akerley, MD, P. Stella, MD, J. Hamm, MD, J. Crawford, MD, M. Kies, MD, G. Otterson, MD, H. Raftopoulos, MD, P. Eisenberg, MD, F. Greco, MD, R. Mercier, MD, H. Kreisman, MD, D. Dunlop, MD, P. Ellis, MD, G. Scagliotti, MD, G. Giaccone, MD, O. Breathnach, MD, D. Carney, MD, U. Gatzmeier, MD, C. Manegold, MD, and F. Cardenal, MD.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
