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Prospective Multicentric Randomized Phase III Study of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors Comparing Interruption Versus Continuation of Treatment Beyond 1 Year: The French Sarcoma Group

Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Florence Duffaud, Catherine Delbaldo, Antoine Adenis, Patrice Viens, Maria Rios, Emmanuelle Bompas, Didier Cupissol, Cecile Guillemet, Pierre Kerbrat, Jérome Fayette, Sylvie Chabaud, Patrice Berthaud, David Perol

From the Unité INSERM U590 Centre Léon Bérard & Université Claude Bernard Lyon I & Hopital Edouard Herriot; Département de Médecine & UBET, Centre Léon Bérard; Hopital Edouard Herriot, Lyon; Institut Gustave Roussy, Villejuif; Institut Bergonié, Bordeaux; Hopital La Timone, Marseille; Centre Oscar Lambret, Lille; Institut Paoli Calmettes, Marseille; Centre Alexis Vautrin, Nancy; Centre René Gauducheau, Nantes; Centre Val D'Aurelle Montpellier; Centre Henri Becquerel, Rouen; and Novartis Pharma, Rueil Malmaison, France

Address reprint requests to Jean-Yves Blay, MD, INSERM U590, Centre Léon Bérard & Université Claude Bernard Lyon I & Unité d'Oncologie Médicale, Hôpital Edouard Herriot, 28, rue Laennec, 69008 Lyon, France; e-mail: blay{at}lyon.fnclcc.fr; or Axel Le Cesne, MD, Institut Gustave Roussy, Villejuif, France; e-mail: lecesne@igr.fr

	ABSTRACT

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Purpose Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled.

Methods This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses.

Results Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients.

Conclusion Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity.

	INTRODUCTION

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GI stromal tumors (GISTs) are malignant tumors that arise from precursor cells of the interstitial cells of Cajal in the GI tract.^1-3 Eighty-six percent of GISTs harbor activating mutations of the KIT or PDGFR genes, leading to ligand-independent activation of these receptor tyrosine kinases and tumor growth in vitro. These mutations are likely to be very early events in the oncogenesis of these tumors.^3-12 Although resistant to conventional chemotherapy, these tumors have been shown to be extremely sensitive to targeted therapy with imatinib, a tyrosine kinase inhibitor selectively blocking KIT and PDGFR.^13-18 Eight-five percent to 90% of GIST patients experience tumor control with imatinib, including objective tumor response and stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), both being correlated with a similar prolonged overall survival.¹⁵ A strong correlation between the antitumor activity of imatinib and the site of KIT and PDGFR mutations has been reported.^11,12 Secondary resistance has been reported to occur at a median time of 24 months, and may be related to the emergence of tumor clones with additional imatinib-resistant KIT mutations.¹⁹

It is unclear whether imatinib treatment for metastatic GISTs should be continued until progression or intolerance. Although the toxicity of chronic imatinib administration is limited, with mild to moderate nausea, rash and edema, these adverse effects are occasionally difficult to handle. In addition, asymptomatic patients in whom tumor is controlled by imatinib treatment sometimes request treatment interruption. Finally, it has been shown that long-term exposure to imatinib is associated with decreased blood levels of imatinib.²⁰ Whether treatment interruption is safe and feasible for patients with advanced GIST in whom disease is controlled by imatinib treatment is not known.

The objective of this study was to determine whether interruption of imatinib treatment is feasible in patients with advanced GIST who achieved 1 year of tumor control.

	METHODS

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Overall Study Design
BFR14 is an open-label, multicentric, randomized phase III clinical trial randomizing treatment interruption versus maintenance after 1 year in patients with metastatic or unresectable malignant GIST in relapse who have received oral imatinib 400 mg/d during 1 year. After 1 year of imatinib treatment, patients with controlled disease under imatinib 400 mg per day (ie, complete response [CR], partial response [PR], or stable disease [SD]) were proposed for random assignment between (1) interruption of imatinib until progression according to RECIST and then reintroduction of imatinib (INT arm) or (2) maintenance of imatinib until progression or intolerance (CONT arm). Patients who refused random assignment were offered either option and followed similarly.

Objectives of the Study
The primary objective was to compare progression-free survival (PFS) in the INT and the CONT groups^21,22 Secondary objectives included overall survival, response rate using RECIST after reinitiation of imatinib in the INT arm, and patient quality of life before and during treatment.

Patients
The protocol was reviewed and validated by a national ethics committee according to national and European directives. Inclusion criteria were age at least 18 years, histologically proven metastatic GIST, immunohistochemical documentation of c-kit (CD117) expression, and Eastern Cooperative Oncology Group performance status of 0 to 3. Patients had to be previously untreated with imatinib, with no previous malignancy, and with normal renal, cardiac, and hepatic function. No concurrent therapy was allowed, and patients were required to give a written informed consent before inclusion.

Statistics
When written in April 2002, we assumed that the 1-year PFS rate of patients treated with maintenance of imatinib (CONT arm) would be 90%; the objectives were to show that the 1-year PFS of patients in whom imatinib was interrupted and restarted at progression (INT arm) was not less than 75%. With a two-sided test significance level of 10% ( = .10), and a power (1-ß) of 0.90, the requested number of patients was 76 in each arm, (ie, total of 152 randomly assigned patients). An value of 0.1 was selected to favor a higher power of the study (1-ß = 0.9) while conserving reasonable number of patients. Considering both a 70% PFS rate after a 1-year period of treatment, and a 20% rate of refusal of randomization, the number of patients to be included was 284. Patients were stratified according to (1) the treatment center (2) and the presence or absence of residual disease on computed tomography (CT) scan.

Stopping Rules
During the study, an interim monitoring stopping scheme using Lee-type boundaries was used. Accordingly, it was possible to stop the trial if the 3-month progression rate exceeded 20% in the experimental arm (INT group): (1) A first analysis was scheduled when the first 14 patients would be evaluable for response in the INT group; if six or more progressions were observed, a data monitoring committee would assess the results and, if confirmed, the trial would be stopped with the conclusion that the interruption of imatinib was associated with a higher risk of progression. (2) If five or fewer progressions were observed, random assignment would continue until 29 patients would be assessable for response in the INT group. At this date, a second analysis would be performed: if 10 or more progressions were observed, the DMC would again assess the results and decide whether to continue random assignment.

Analysis
Survival curves were plotted according to the Kaplan-Meier method and compared using the log-rank test. For randomly assigned patients, PFS is calculated from the date of random assignment to the date of progression or last follow-up, time to imatinib resistance is calculated from the date of random assignment to the date of progression under imatinib 400 mg/d or date of last follow-up, and overall survival is calculated from the date of random assignment to the date of death or last follow-up. Quality of life was assessed on the 30-item Quality of Life Questionnaire (QLQ30) by the patient. All analysis were performed on an intent-to-treat basis. Statistical analyses were performed using the SPSS 11.5.1 (SPSS Inc, Chicago, IL) and SAS 8.2 software (SAS Institute, Cary, NC).

	RESULTS

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Between May 2002 and April 2004, 182 patients were enrolled (Table 1). Random assignment after 1 year of imatinib treatment started from May 2003 until March 2004; during this timeframe, 98 patients had been included for more than 1 year: 18 (18.4%), were in CR, 29 (29.6%) in PR, and 27 (27.6%) in SD. The rate of CR at 1 year is superior to that previously reported in the large trials of imatinib in GIST.^16,17 Actually, this group includes patients achieving CR under imatinib only and those who had had resection of metastatic disease up front, before imatinib introduction, and who were in CR at the time of evaluation. In the latter group, CR is clearly not due to imatinib only but to the combination of surgery followed by imatinib. Random assignment was not possible in 40 patients for reasons described in Figure 1. Therefore, 58 patients were randomly assigned. On March 16, 2004, the data monitoring committee decided to withhold the random assignment because of an excess number of progressions in the INT arm. All patients in the INT arm were proposed by their physician to restart imatinib. All patients in progression restarted imatinib. However, only two (10%) of the 21 nonprogressing patients at that date, restarted immediately. As of October 2005, 26 progressions (81%) have occurred in the 32 patients of the INT arm, as compared with eight of the 26 patients in the CONT arm (31%; Fig 2A). Twenty-eight of the 32 patients of the INT arm (87.5%) have therefore restarted imatinib, whereas four patients remain progression free without imatinib. Overall survival is similar in the two groups (log-rank P = .61; Fig 2B).

View larger version (33K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Description of randomly and nonrandomly assigned GI stromal tumor (GIST) patients. STOP, imatinib treatment stopped; CONT, continuous.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Progression-free survival (PFS) in randomly assigned patients, (B) overall survival (OS) in the continuous (CONT) and interrupted (INT) arms, and (C) imatinib-resistant PFS in the CONT and INT arms.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Progression-free survival (PFS) depending on residual disease on computed tomography (CT) scan at the date of random assignment (interrupted [INT] group only) and (B) PFS depending on residual disease on CT scan at the date of random assignment (continuous [CONT] group only).

	DISCUSSION

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First, a minority of patients experience important adverse effects that may affect quality of life or may even require treatment interruption. Second, even though the incidence and magnitude of adverse effects are very limited in most patients, these chronic adverse effects prompt some patients to request "treatment holidays" or treatment interruption. Third, it has been shown in large series that resistance to imatinib in GIST occurs at a median time of 24 months, and happens in a substantial proportion of patients at 4 years.^11,12 Resistance to imatinib is related to several factors, including (1) alteration of pharmacokinetics on prolonged exposure²⁰ and (2) acquisition of additional mutations in the KIT gene, yielding imatinib-resistant kit proteins.^11-13,19 This latter phenomenon may happen through an imatinib-dependent selection of pre-existing imatinib-resistant tumor cells harboring these additional mutations in vivo. Whether treatment interruption may limit or favor this selection process is not known. However, treatment interruption may enable tumor progression, which may then be less efficiently treated with reinitiation of imatinib. The potential value of imatinib treatment interruption in GIST cannot be evaluated on only retrospective analysis of patients who stopped treatment, for obvious selection biases. The present study was thus performed to address the issue of treatment interruption in a prospective randomized trial.

The primary objective of this trial was to evaluate the impact of treatment interruption on PFS in patients with advanced GIST whose tumor is controlled by imatinib treatment. We chose the date of 1 year because, at this date, patients are less likely to improve their therapeutic response. The data obtained indicate that imatinib interruption is associated with a major risk of progression: median time to progression after imatinib interruption was 6 months, and most patients had relapsed 1 year after treatment interruption. Even though four patients have not still relapsed more than 1 year after interruption, this rapid progression rate led us to interrupt the clinical trial according to the second predefined stopping rule. The progressions observed in patients of the INT group were diagnosed on the basis of RECIST; typical images of "nodule within a mass" associated with progression under imatinib treatment³⁰ were not observed in this setting (not shown). Importantly, 92% of patients in whom imatinib was restarted during progression again experienced tumor control. With a longer follow-up, the risk of developing progression while receiving imatinib 400 mg/d was similar in both groups, and overall survival was not significantly different in both arms. However, this analysis is not powered to demonstrate equivalence in survival in the two arms. We, therefore, cannot exclude an increased risk of resistance after imatinib reintroduction, given the limited number of patients who were randomly assigned, although the vast majority of patients will again experience tumor control on imatinib reintroduction. Of note, an analysis of the mutations of KIT and PDGFR is currently being performed; the impact of mutation on relapse rate in the INT group will be investigated.

Another interesting observation is the high rate of recurrence after interruption in patients with no residual tumor left visible on CT scan; this strongly suggests that most patients have still widespread, disseminated, residual viable disease after imatinib treatment. Until more accurate tools to evaluate residual tumor cells are available in GIST, these data indicate that it is not safe to interrupt imatinib treatment on the basis of a complete remission, as defined using standard morphologic criteria. Conversely, in the CONT group, none of the patients with unassessable disease progressed while receiving imatinib. Of note, the role of debulking surgery in patients who are accessible to complete removal has been questioned in recent reports.^21,22,31 This question needs, however, to be addressed in a prospective randomized trial. Importantly, only a minority of these patients (7%) were considered possible candidates for complete resection of metastatic sites by the local multidisciplinary board (not shown).

Finally, the inclusion of patients with completely removed metastasis, along with patients with strictly localized tumors, into clinical trials testing imatinib in the adjuvant setting should be carefully considered. In trials in which PFS is the primary end point, imatinib may yield different outcome in metastatic patients in surgical CR compared with patients with localized tumors. In view of the present results, a 6-month PFS would be expected after imatinib interruption in the former group, whereas in the latter, even in high-risk patients, 30% are at least expected to experience long-term disease-free survival.

One of the objectives of treatment discontinuation strategy tested in this trial was to enable patients to experience drug holidays without the mild, yet chronic, adverse effects of prolonged imatinib treatment. Of note, the reported adverse effects of imatinib were mainly grade 1 and 2 in this series, and their incidence was lower than that reported in the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) 62005 trial for the 400 mg/d arm,¹⁷ possibly because patients who initiated imatinib treatment from 2002 to 2004 were in better clinical condition (ie, lower performance status, higher hemoglobin levels) than were those included in initial trials.³²

In the present study, the general EORTC QLQC30 questionnaire was used to evaluate the quality of life. Fifty percent of patients with more than 1 year of follow-up completed the questionnaire, as frequently reported for quality-of-life studies.³³ Even though the number of patients is limited, no significant improvement in global health status, functional scores, and symptom scores was observed in the INT arm. It can be concluded, however, that imatinib discontinuation is not associated with a major improvement or worsening of the quality of life of these patients. These data do not support the hypothesis that imatinib discontinuation is associated with a major improvement in quality of life in GIST patients.

Because imatinib treatment of advanced GIST is the model of a targeted therapy of a solid tumor, the observations presented in this specific model may, therefore, have a broader significance, and indicate that such targeted treatment may not be interrupted, even in patients in apparent complete remission.^34,35 Whether longer duration of imatinib treatment will enable treatment interruption, however, is not known; the BFR14 protocol has now been amended to randomly assign imatinib interruption at 3 years in the population of patients not previously randomly assigned.

In conclusion, this randomized trial of imatinib discontinuation in advanced GIST patients was interrupted prematurely because of a significantly higher rate of progression in the discontinuation arm, even in patients without residual disease on standard imaging. Imatinib reintroduction re-established tumor control in most, but not all patients; no differences in the incidence of secondary resistance to imatinib, nor in overall survival, have been observed so far. Imatinib discontinuation has not been found to be associated with a significant improvement in quality of life. We conclude that imatinib discontinuation, although feasible, cannot be recommended in routine practice.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Patrice Berthaud, Novartis Leadership: N/A Consultant: Jean-Yves Blay, Novartis Pfizer; Axel Le Cesne, Novartis; Isabelle Ray-Coquard, Novartis; Florence Duffaud, Novartis Stock: N/A Honoraria: Jean-Yves Blay, Novartis Pfizer; Axel Le Cesne, Novartis; Isabelle Ray-Coquard, Novartis; Binh Bui, Novartis; Florence Duffaud, Novartis; Antoine Adenis, Novartis Research Funds: Jean-Yves Blay, Novartis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Patrice Berthaud, David Perol

Administrative support: Jean-Yves Blay, Axel Le Cesne, Patrice Berthaud, David Perol

Provision of study materials or patients: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Florence Duffaud, Catherine Delbado, Antoine Adenis, Patrice Viens, Maria Rios, Emmanuelle Bompas, Didier Cupissol, Cecile Guillemet, Pierre Kerbrat, Jérome Fayette

Collection and assembly of data: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, David Perol

Data analysis and interpretation: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Florence Duffaud, Antoine Adenis, Sylvie Chabaud, David Perol

Manuscript writing: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Sylvie Chabaud

Final approval of manuscript: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Florence Duffaud, Catherine Delbado, Antoine Adenis, Patrice Viens, Maria Rios, Emmanuelle Bompas, Didier Cupissol, Cecile Guillemet, Pierre Kerbrat, Jérome Fayette, David Perol

	ACKNOWLEDGMENTS

 
We thank Jean Geneve, MD, and Marta Jimenez for the support of the Bureau d'Etude Clinique et Thérapeutique of the FNCLCC, Severine Guillemaut for the monitoring, Francoise Ducimetière, Sylvain Tanguy and Valérie Bourne-Branchu for the management of the study; Marie-Dominique Reynaud for the reviewing and editing of the manuscript; and Novartis for imatinib free of charge to the sponsor of the study until its registration.

Contribution of all centers for the BFR14 trial (Hospital, City, investigator(s), number of patients included):

Institut Gustave Roussy (Villejuif): A. Le Cesne, C. Delbaldo (n = 58); Centre Léon Bérard (Lyon): I. Ray-Coquard, J.-Y. Blay (n = 25); Hôpital Edouard Herriot (Lyon): J.-Y. Blay, E. Bompas, J. Fayette, C. Lombard-Bohas (n = 20); Institut Bergonié (Bordeaux): B.N. Bui, N. Tchen, N. Trufflandier (n = 14); Hôpital de la Timone (Marseille): F. Duffaud (n = 11); Centre Oscar Lambret (Lille): A. Adenis, N. Penel, S. Dominguez (n = 8); Institut Paoli Calmettes (Marseille): P. Viens, A.C. Braud (deceased), F. Bertucci, A. Madroszyk-Flandin, F. Viret (n = 8); Centre Alexis Vautrin (Vandoeuvre Les Nancy): M. Rios (n = 7); Centre René Gauducheau (Saint Herblain): F. Rolland, E. Bompas, J. Bennouna, G. Dabouis, S. Bordenave-Caffre, H. Senellart (n = 5); Centre Val d'Aurelle Paul Lamarque (Montpellier): D. Cupissol (n = 5); Centre Henri Becquerel (Rouen): C. Guillemet, C. Veyret (n = 4); Centre Eugène Marquis (Rennes): P. Kerbrat, J.-L. Raoul, E. Boucher (n = 3); Centre Georges François Leclerc (Dijon): P. Fargeot (n = 3); Institut Claudius Régaud (Toulouse); C. Chevreau, J.-P. Delord (n = 3); Institut Jean Godinot (Reims): J.-C. Eymard (n = 2): Hôpital Tenon (AP-HP, Paris): J.-P. Lotz, T. Andre (n = 2); Centre Antoine Lacassagne (Nice): A. Thyss (n = 1); Centre Jean Perrin (Clermont Ferrand): J. O. Bay (n = 1); Centre René Huguenin (Saint-Cloud): F. Bertheault-Cvitkovic, A. Goupil (n = 1); and Clinique du Mail (Grenoble): D. Coeffic, D. Assouline, C. Leyronnas (n = 1).

	NOTES

 
Supported by grant from the 2003 Emergence Fund of the French Institut National du Cancer (INCa) through the Canceropole CLARA, an unrestricted grant of the Comité de l’Ain de la Ligue Contre Le Cancer, a Grant from the Comité du Rhône de la Ligue Contre Le Cancer, the CONTICANET Network of Excellence of the sixth Framework Program of the European Commission.

J.-Y.B. and A.L.C. contributed equally to this work.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 31, 2006; accepted December 13, 2006.

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