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A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors
original article
Annals of Oncology 21: 1990–1998, 2010 doi:10.1093/annonc/mdq076 Published online 27 May 2010
A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors P. Scho¨ffski1*, P. Reichardt2, J.-Y. Blay3, H. Dumez1, J. A. Morgan4, I. Ray-Coquard3, N. Hollaender5, A. Jappe5 & G. D. Demetri4 1
Received 23 October 2009; revised 11 February 2010; accepted 16 February 2010
original article
Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST. Patients and methods: In phase I, patients received imatinib (600/800 mg/day) combined with weekly (20 mg) or daily (2.5/5.0 mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5 mg plus imatinib 600 mg/day. Primary end point was 4-month progression-free survival (PFS). Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD. Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST. Key words: everolimus (RAD001), gastrointestinal stromal tumors, GIST, imatinib
introduction Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, although they account for <1% of all digestive tract tumors, with an estimated yearly incidence of 10–20 cases per million [1, 2]. Because GIST are generally resistant to conventional chemotherapy, the standard treatment of localized GIST is surgical resection. Unfortunately, in many patients, tumors recur postoperatively, resulting in progressive metastatic disease with a median survival of 19 months [3, 4]. Until the introduction of imatinib [5, 6], treatment options for metastatic disease after surgical resection were limited. Imatinib mesylate (Glivec; Novartis Pharmaceuticals, Basel, Switzerland), an oral tyrosine kinase inhibitor (TKI), selectively targets several kinases, including the KIT receptor tyrosine kinase, which is active in 85%–90% of patients with GIST [6–9]. Additionally, later studies reported the presence of *Correspondence to: Dr P. Scho¨ffski, Laboratory of Experimental Oncology, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32-16-346900; Fax: +32-16-346901; E-mail: [email protected]
activating mutations in the PDGFRA oncogene in wild-type KIT-bearing GIST [10, 11]. Imatinib dramatically improved outcomes for patients with metastatic GIST and is now standard first-line therapy in the metastatic setting [5]. In advanced-phase GIST, primary imatinib resistance [progressive disease (PD) <3 months] occurs in <10% of patients, but most patients acquire secondary resistance after a median of 2 years [5, 12–15]. This resistance may occur because of the development of additional KIT mutations, genomic amplification of KIT, or activation of alternative oncogenic signaling mechanisms, including the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway [16, 17]. For patients who develop imatinib resistance, treatment with sunitinib malate (Sutent; Pfizer, New York, NY), an oral TKI, has shown therapeutic benefit; however, the median progressionfree survival (PFS) with sunitinib is close to 6 months and most patients develop resistance within 1 year. New therapies are needed to treat patients with advanced imatinib-resistant GIST [18, 19]. mTOR, an intracellular protein kinase, regulates cellular responses to growth factors and responds to cellular stress and available nutrient and energy resources. Dysregulation of the
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; 2Department of Hematology and Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany; 3Department of Oncology, Centre Leon Berard, Lyon, France; 4Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 5Department of Oncology, Novartis Pharma AG, Basel, Switzerland
original article
Annals of Oncology
patients and methods patients Eligible patients were aged ‡18 years, had a histologically proven diagnosis of GIST with one or more measurable lesions, were resistant to imatinib, had a World Health Organization (WHO) performance status of two or less, and adequate bone marrow, liver, and renal function [leukocytes ‡ 3 · 109/l, neutrophils ‡ 1.5 · 109/l, hemoglobin ‡ 9 g/dl, platelets ‡ 100 · 109/l, total bilirubin and creatinine < 1.5 · upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase activity < 2.5 · ULN]. Patients previously treated with rapamycin analogues in combination with imatinib with central nervous system metastases or a concurrent severe medical condition (e.g. human immunodeficiency virus infection, uncontrolled diabetes, cardiac dysrhythmia, or acute renal or liver disease) were excluded. All patients provided informed consent. The study was approved by the institutional review board at each
participating center and conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines.
study design Phase I assessed the safety and tolerability of the combination of everolimus with imatinib to determine the optimal dose for both agents. As detailed in Table 1, patients initially received a weekly dose of 20 mg everolimus in combination with 600 mg daily imatinib. However, on the basis of favorable safety data, the protocol was amended and patients were enrolled to receive daily everolimus (2.5 and 5 mg) along with daily imatinib (600 and 800 mg). A classical 4 + 2 scheme was applied; daily everolimus doses (with 600 mg daily imatinib) were to be escalated from 2.5 to 5 mg in case of one or less dose-limiting toxic effects (DLTs) in four patients or two or less DLTs in six patients, respectively. In the 2.5-mg cohort, imatinib was escalated to 800 mg later. Phase II patients were enrolled into two strata to evaluate the efficacy of coadministering 2.5 mg everolimus with 600 mg imatinib daily (Table 1). Stratum 1 represented second-line therapy after progression on imatinib, and stratum 2 represented third-line therapy after treatment with second-line drug therapies (e.g. TKIs) given after prior progression on imatinib. Before entering the study, patients in stratum 1 continued to receive imatinib for 4 weeks while baseline assessments [computed tomography (CT) or magnetic resonance imaging (MRI)] was carried out. In stratum 2, patients discontinued their second-line drug regimen for at least 14 days or five half-lives of the used agent before entering the study while continuing to receive imatinib. All patients self-administered everolimus as a single dose, followed by imatinib taken twice daily. The primary efficacy end point (phase II) was 4-month PFS rate in the per-protocol (PP) population. A Simon two-stage design [26] was used to differentiate between a 4-month PFS rate of 5% and 20% in each stratum: two or more of 21 and five or more of 41 patients with PFS at month 4 were required at the end of stage 1 and stage 2, respectively. The PP population included all patients who received one or more doses of everolimus and imatinib and had an efficacy evaluation after 4 months. Patients with no evaluable tumor assessment at month 4 or thereafter were excluded from the PP population. However, patients who discontinued due to disease progression or died before 4 months were included in this population.
safety and response evaluations DLT, defined as any ‡ grade 3 treatment-related adverse event (AE) occurring within the first 4 weeks, was assessed using National Cancer Institute—Common Toxicity Criteria version 2.0 [27]. Safety evaluations for both phases were conducted over the whole period of treatment with everolimus and imatinib and included standard laboratory tests, physical examinations, and WHO performance status. Treatment continued until disease progression, unacceptable toxicity, or discontinuation at the patient’s request or the investigator’s decision. In both phases, tumor responses were evaluated according to investigator-assessed RECIST with radiologic scans (CT or MRI) at baseline and every 2 months [28]. Primary efficacy analyses of phase II were on the basis of the 4-month PFS rate, which was defined as the portion of patients who have not progressed or died within 4 months of treatment in the PP population. Secondary efficacy analyses were carried out in the intent-totreat (ITT) population and consisted of best overall tumor response, PFS (phase II only), and overall survival (OS; phase I and II). PFS was censored at last adequate tumor assessment if a patient did not progress or die, and for patients without observed death OS was censored at the last contact before the cut-off date for the analysis. The ITT population included all patients administered at least one dose of everolimus or imatinib. Figure 1. Everolimus complements imatinib by inhibiting PI3K/Akt/ mTOR signaling downstream of KIT and PDGFRA, resulting in decreased cell proliferation, survival, and angiogenesis. mTOR, mammalian target of rapamycin; PDGFRA, platelet-derived growth factor receptor A.
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statistics Results were summarized by dose cohort (phase I) and stratum (phase II) using the appropriate descriptive statistics. The 4-month PFS rate is given
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mTOR pathway promotes cancer cell growth and survival and contributes to the pathogenesis of a variety of malignancies [20–22]. Everolimus (RAD001; Afinitor; Novartis Pharmaceuticals), an oral mTOR inhibitor, specifically targets mTOR and pathways involved in cell growth, survival, and angiogenesis [23, 24]. Preclinical studies combining everolimus and imatinib resulted in a synergistic antiproliferative effect and the induction of apoptosis in imatinib-resistant GIST cell lines [25]. Everolimus complements imatinib by inhibiting Akt/ mTOR signaling downstream of KIT and platelet-derived growth factor receptor A (Figure 1), providing a rationale for coadministering both drugs to patients with metastatic imatinib-resistant GIST. We conducted this nonrandomized, phase I–II, open-label multicenter study to assess the safety, tolerability, and efficacy of the combined administration of everolimus with imatinib in patients with advanced imatinibresistant GIST.
original article
Annals of Oncology
Table 1. Phase I–II study design overview Prior treatment
Imatinib for ‡4 months with 2 months ‡600 mg/day Imatinib with uninterrupted treatment ‡800 mg/day for the last 2 months Prior treatment
Everolimus
No. of patients enrolled (ITT population)
600 600 600 800
20 mg/week 2.5 mg/day 5 mg/day 2.5 mg/day
13 13 5 11
mg/day mg/day mg/day mg/day
Phase II Imatinib
Everolimus
No. of patients enrolled (ITT population)
No. of patients in PP population
600 mg/dayb
2.5 mg/day
28
23
600 mg/dayb
2.5 mg/day
47
35
ITT, intent to treat; PP, per protocol. a Stratum 1 was stopped at the end of stage 1 due to the availability of new treatment options (sunitinib). b Three patients (one in stratum 1 and two in stratum 2) received 800 mg/day (protocol deviation).
with 95% confidence interval (CI). The time-to-event variables PFS (phase II only) and OS (phase I and II) were estimated using the Kaplan– Meier method. The derived median survival times and survival probabilities are given with 95% CI.
results Phase I patients were enrolled from November 2002 to September 2006 and phase II patients entered the study from April 2005 to January 2007. The database was locked in April 2008.
phase I everolimus weekly administration. Thirteen patients were treated on the 20/600 (everolimus/imatinib) schedule for a median of 3.4 months (range 1.2–13.8), with 1 patient (8%) discontinuing due to an AE and 12 (92%) due to PD. Patient characteristics are shown in Table 2. No DLTs were observed within the predefined 4-week period. Four patients (31%) experienced serious AEs, with only one (grade 4 anemia) suspected to be related to the study drug. Nausea, diarrhea, fatigue, and anemia were the most frequently reported AEs that were suspected of being related to the study drug. As shown in Table 3, 39% of patients had either a grade 3 or a grade 4 AE, regardless of causality. As shown in Table 4, seven (54%) patients had stable disease (SD) and four (31%) patients had PD, while the median OS was 9.4 months (95% CI 5.6–13.8). After 12 months, eight (62%) patients had died and four (31%) patients survived, with an estimated survival rate of 39%. everolimus daily administration. Twenty-nine patients were administered daily everolimus in combination with imatinib:
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13 (45%) in the 2.5/600 cohort, 5 (17%) in the 5.0/600 cohort, and 11 (38%) in the 2.5/800 cohort. Patient characteristics are shown in Table 2. Compared with the 5.0/600 cohort, the 2.5/ 600 cohort had a higher percentage of males (77% versus 20%). In the 2.5/600 cohort, no DLTs were observed in the first four patients. In the 5.0/600 cohort, there were two (15%) DLTs among the first five patients; therefore, accrual to the 5.0/ 600 cohort was stopped, and 2.5 mg/day was declared the maximum tolerated dose of everolimus with a 600 mg/day dose of imatinib, with this cohort expanded to 13 patients. Two DLTs occurred among the next nine patients in the 2.5/600 cohort. In the 2.5/600 cohort, seven (54%) patients experienced serious AEs, with three patients having a serious AE suspected to be related to the study drug. In the 2.5/800 cohort, five DLTs were observed. In the 2.5/800 cohort, seven (64%) patients experienced serious AEs. Overall, nausea, diarrhea, fatigue, and anemia were the most frequently reported AEs that were suspected of being related to the study drug. Grade 3 or 4 AEs regardless of causality are shown for all cohorts in Table 3. Among the 2.5/600, 5.0/600, and 2.5/800 cohorts, the median/mean duration of treatment was 2.7/5.7 (range 0.7–35.5), 2.4/4.4 (range 1.1–9.5), and 2.1/2.9 months (range 0.4–6.7), respectively. In the 2.5/600 cohort, four (31%) patients discontinued due to AEs, eight (62%) due to PD, and one (8%) patient died due to underlying disease. In the 5.0/600 cohort, two (40%) patients discontinued due to AEs, two (40%) due to PD, and one (20%) due to an abnormal laboratory value (grade 3 thrombocytopenia). In the 2.5/800 cohort, three (27%) patients discontinued due to AEs, one (9%) due to an abnormal laboratory value (grade 3
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Stratum 1a: imatinib for ‡4 months with 2 months ‡600 mg/day Stratum 2: imatinib until progressive disease and postimatinib second-line treatment
Phase I Imatinib
original article
Annals of Oncology
Table 2. Baseline characteristics of phase I and II patients receiving everolimus in combination with imatinib Patient characteristics
Phase I Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13) (25–71)
All Patients (n = 75)
All Patients (n = 42)
Everolimus 5.0 mg/day (n = 5) 53 (37–70)
59 (42–82)
55 (25–82)
55 (29–80)
61 (26–83)
58 (26–83)
(77) (23)
1 (20) 4 (80)
9 (82) 2 (18)
31 (74) 11 (26)
21 (75) 7 (25)
31 (66) 16 (34)
52 (69) 23 (31)
(92) (8)
5 (100) 0
11 (100) 0
41 (98) 1 (2)
27 (96) 1 (4)
47 (100) 0
74 (99) 1 (1)
(23) (69) (8)
1 (20) 2 (40) 2 (40)
7 (64) 4 (36) 0
21 (50) 16 (38) 5 (12)
11 (39) 16 (57) 1 (4)
21 (45) 23 (49) 3 (6)
32 (43) 39 (52) 4 (5)
(8)
0 0 0 0 4 (80) 0 1 (20)
1 1 2 1 13 3 9 – 12
(29)
2 1 1 1 10 –b 9 1 3
(32) (4) (11)
0 4 2 1 22 – 13 0 5
(11)
2 5 3 2 32 – 22 1 8
(29) (1) (11) (1) (13) (13) (72)
(8) (31) (8) (23) –
0 1 1 1 2 0 3 – 3
(9) (9) (9) (18) (27)
(7) (4) (4) (4) (36)
(9) (4) (2) (47) (28)
(23)
0
(8) (23) (69)
0 0 0 5 (100)
0 3 (27) 3 (27) 5 (46)
0 5 (12) 9 (21) 28 (67)
1 6 2 19
(4) (21) (7) (68)
0 4 (9) 8 (17) 35 (75)
1 10 10 54
0 0 4 (80) 1 (20) 0
2 (18) 0 9 (82) 0 0
3 14 21 1 3
2 14 11 0 1
(7) (50) (39)
– – – – –
– – – – –
(8) (39) (46) (8)
(27)
(2) (2) (5) (2) (31) (7) (21)
(7) (33) (50) (2) (7)
(4)
– – –
– – –
– – –
– – –
35 (75) 11 (23) 1 (2)
– – –
– – – –
– – – –
– – – –
– – – –
3 26 16 2
– – – –
(6) (55) (34) (4)
(3) (7) (4) (3) (43)
WHO PS, World Health Organization performance status; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. a Stratum 1 represents second-line therapy, and stratum 2 represents third-line therapy. b ‘–’ indicates that the patient characteristic was not measured.
lymphopenia), five (46%) due to PD, one (9%) due to consent withdrawal, and one (9%) patient died due to intra-abdominal hemorrhage after liver biopsy. As shown in Table 4, tumor response included one (8%) partial response (PR) and six (46%) SD in the 2.5/600 cohort,
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four (80%) SD in the 5.0/600 cohort, and six (55%) SD in the 2.5/800 cohort. Among the 2.5/600, 5.0/600, and 2.5/800 cohorts, the median OS was 10.9 months [3.3 to not available (NA)], 18.7 months (3.8 to NA), and not reached (12.0 to NA), respectively. After 12 months, the estimated survival rates were
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Median age, years (range) 53 (46–66) 47 Sex, n (%) Male 11 (85) 10 Female 2 (15) 3 Race, n (%) Caucasian 13 (100) 12 Black 0 1 WHO PS, n (%) 0 10 (77) 3 1 1 (8) 9 2 2 (15) 1 Primary tumor site, n (%) Colon 0 1 Liver 0 0 Peritoneum 0 1 Rectum 0 0 Small intestine 3 (23) 4 Soft tissue sarcoma 2 (15) 1 Stomach 2 (15) 3 Pancreas – – Other 6 (46) 3 Time since diagnosis, years, n (%) <1 0 0 1 to <2 1 (8) 1 2 to <3 3 (23) 3 ‡3 9 (69) 9 Best overall response to prior imatinib therapy CR 0 1 PR 9 (69) 5 SD 2 (15) 6 PD 0 0 Unknown 2 (15) 1 Post-imatinib therapies Sunitinib – – Tyrosine kinase inhibitora – – – – Cyclin-dependent kinase inhibitora Best overall response to the most recent therapy PR – – SD – – PD – – Unknown – –
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum 1 Stratum 2 (n = 28) (n = 47)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
original article
Annals of Oncology
Table 3. Phase I and II grade 3 or 4 AEs seen in more than one patient receiving everolimus in combination with imatinib regardless of causality Grade 3–4 AEs, n (%)
All patients (n = 75)
Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13)
Everolimus 5.0 mg/day (n = 5)
5 (39) 2 (15) 1 (8)
8 (62) 0 0
5 (100) 1 (20) 3 (60)
9 (82) 3 (27) 0
27 (64) 6 (14) 4 (10)
15 (54) 1 (4) 1 (4)
35 (75) 1 (2) 1 (2)
50 (67) 2 (3) 2 (3)
0 1 2 1 0 0 0 1 0 1 0 – – – – – – – – – – – –
0 1 (8) 0 0 0 0 1 (8) 0 0 0 1 (8) – – – – – – – – – – – –
3 1 0 0 3 0 0 0 0 0 1 – – – – – – – – – – – –
1 0 1 2 0 2 1 1 2 1 0 – – – – – – – – – – – –
4 3 3 3 3 2 2 2 2 2 2 – – – – – – – – – – – –
(10) (7) (7) (7) (7) (5) (5) (5) (5) (5) (5)
–b – – – 0 – 0 0 – – – 2 1 0 2 1 1 1 1 1 1 1 2
(7) (4) (4) (4) (4) (4) (4) (4) (7)
– – – – 5 (11) – 3 (6) 6 (13) – – – 2 (4) 3 (6) 3 (6) 0 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 0
– – – – 5 – 3 6 – – – 4 4 3 2 2 2 2 2 2 2 2 2
(5) (5) (4) (3) (3) (3) (3) (3) (2) (3) (3) (3)
3 (23) 3 (23) 1 (8) 0 0
6 6 0 1 1
1 1 0 1 1
(46) (18) (18) (9) (9)
15 12 3 3 3
(36) (29) (7) (7) (7)
3 4 3 1 2
(11) (14) (11) (4) (7)
8 8 4 1 3
(17) (17) (9) (2) (6)
11 12 7 2 5
(15) (16) (9) (3) (7)
2 (15) 1 (8) 0 1 (8) – – –
2 (15) 2 (15) 0 1 (8) – – –
4 (36) 1 (9) 2 (18) 0 – – –
11 4 2 2 – – –
(26) (10) (5) (5)
7 1 1 1 1 2 0
(25) (4) (4) (4) (4) (7)
12 2 1 2 4 3 2
(26) (4) (2) (4) (9) (6) (4)
19 3 2 3 5 5 2
(25) (4) (3) (4) (7) (7) (3)
(8) (15) (8)
(8) (8)
(46) (46) (8) (8)
(60) (20)
(60)
(20)
(20) (20) (20) (20)
3 (60) 0 0 0 – – –
5 2 2 1 1
(9) (9) (18) (18) (9) (9) (18) (9)
All patients (n = 42)
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum 1 Stratum 2 (n = 28) (n = 47)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
(7) (4)
(7) (4) (8)
AE, adverse event; LDH, lactate dehydrogenase; WBC, white blood cell; AST, aspartate aminotransferase. Stratum 1 represents second-line therapy, and stratum 2 represents third-line therapy. b ‘–’ indicates that the AE was not measured. c Newly occurring or worsened National Cancer Institute—Common Toxicity Criteria version 2 grade. a
43% in the 2.5/600 cohort, 60% in the 5.0/600 cohort, and 82% in the 2.5/800 cohort. The 2.5/600 schedule was selected for the phase II study.
phase II Phase II enrolled 75 patients treated on the 2.5/600 schedule, and they were divided into 28 (37%) in stratum 1 and 47 (63%)
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in stratum 2 (Figure 2). All patients in stratum 2 were previously treated with sunitinib [n = 35 (75%)], other TKIs [n = 11 (23%)], or cyclin-dependent kinase inhibitors [n = 1 (2%)] in addition to imatinib. Patient baseline characteristics are listed in Table 2. No appreciable differences were noted. Serious AEs were reported in 11 (39%) and 25 (53%) patients in strata 1 and 2, respectively. Serious AEs suspected to
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Any grade 3–4 AE Diarrhea General physical health deterioration Nausea Dehydration Pyrexia Sepsis Vomiting Angioedema Dyspnea Fatigue Pneumonia Postprocedural hemorrhage Stomatitis Abdominal pain Asthenia Melena Increased LDH Gastroenteritis Gastrointestinal hemorrhage Hemorrhagic anemia Peripheral edema Pulmonary embolism Renal failure Tumor hemorrhage Tumor pain Hematologic abnormalitiesc Absolute lymphocytes Hemoglobin Absolute neutrophils Platelet count WBC count (total) Biochemistry abnormalitiesc Hypokalemia Hyponatremia AST Creatinine Bilirubin Hypocalcemia Hypoglycemia
Phase I
original article
Annals of Oncology
Table 4. Efficacy measures for phases I and II Efficacy
Phase I Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13)
Everolimus 5 mg/day (n = 5)
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum Stratum 1 (n = 28) 2 (n = 47)
4/23 (17) [5.0–38.8]
13/35 (37) [21.5–55.1]
–
–
–
1.9 [1.8–3.7]
3.5 [1.9–5.2]
–
–
–
21 [4.7–37.6]
40 [24.6–55.9]
–
–
–
13 [0–26.1]
20 [7.0–33.3]
10.9 [3.3 to NA]
18.7 [3.8 to NA]
NR [12.0 to NA]
14.9 [14.9 to NA]
10.7 [6.3–16.8]
1 (8) [0.2–36.0] 6 (46) 6 (46) 0
0 4 (80) 0 1 (20)
0 6 (55) 1 (9) 4 (36)
0 10 (36) 15 (54) 3 (11)
1 20 15 11
(2) [0.1–11.3] (43) (32) (23)
PFS, progression-free survival; PP, per protocol; CI, confidence interval; ITT, intent to treat; OS, overall survival; NA, not available; NR, not reached; PR, partial response; SD, stable disease; PD, progressive disease. a PP population: stratum 1 (n = 23, 15/1 patients had PD/died <4 months) and stratum 2 (n = 35, 15/1 patients had PD/died <4 months); phase II dose was everolimus 2.5 mg/day + imatinib 600 mg/day, with stratum 1 representing second-line therapy and stratum 2 representing third-line therapy. b If a patient did not progress or die, PFS was censored at last adequate tumor assessment. c ‘–’ indicates that the efficacy end point was not measured.
be related to the study drug were reported for 4 (14%) patients in stratum 1 and 11 (26%) patients in stratum 2. Gastrointestinal disorders were the most common drug-related AEs reported, with diarrhea, nausea, fatigue, and anemia being the most frequent. The most common grade 3–4 AEs, regardless of causality, were hypokalemia, anemia, lymphopenia, fatigue, and vomiting (Table 3). In stratum 1, 27 (96%) patients had AEs, including 15 (54%) patients with grade 3–4 AEs, whereas in stratum 2, all patients experienced AEs, including 35 (75%) patients with grade 3–4 AEs. Table 4 presents all the efficacy data for the phase II study. In stratum 1, 4 of 23 assessable patients (17%; 95% CI 5.0–38.8) were progression free at 4 months. Despite meeting the criterion to enter stage 2, the stratum was discontinued due to the availability of alternative treatments in second line (sunitinib), which was not yet the case when this study was designed. In stratum 2, 13 of 35 assessable patients (37%; 95% CI 21.5–55.1) were progression free at 4 months, meeting the predefined conditions for stage 2. In the ITT population, stratum 1 (n = 28) had a median PFS of 1.9 months (95% CI 1.8–3.7), while stratum 2 (n = 47) had a median PFS of 3.5 months (95% CI 1.9–5.2) (Figure 3A). On the basis of Kaplan–
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Meier analysis, the estimated 4-month PFS probability was 21% (95% CI 4.7–37.6) in stratum 1 and 40% (95% CI 24.6–55.9) in stratum 2, respectively, corresponding well with the results obtained in the PP population. The 6-month PFS probability was 13% (95% CI 0–26.1) and 20% (95% CI 7.0–33.3) for strata 1 and 2, respectively. Median OS was 14.9 months (95% CI 14.9 to NA) in stratum 1, compared with 10.7 months (95% CI 6.3–16.8) in stratum 2 (Figure 3B). A total of 61 (81%) patients in both strata were assessable for best overall tumor response. Stratum 1 had 10 (36%) SD and 15 (54%) PD, while stratum 2 had 1 (2%) PR, 20 (43%) SD, and 15 (32%) PD. The median/mean duration of treatment was 1.9/2.9 (range 0.2–9.7) and 2.4/4.2 months (range 0.2–21.9) for strata 1 and 2, respectively. In stratum 1, all patients discontinued therapy: 23 (82%) due to PD, 2 (7%) due to AEs, 2 (7%) withdrew consent, and 1 (4%) patient died due to underlying disease. In stratum 2, 46 (98%) patients discontinued: 31 (66%) due to PD, 10 (21%) due to AEs, 1 (2%) due to abnormal laboratory value(s), 3 (6%) withdrew consent, and 1 (2%) patient died due to acute coronary syndrome. One (2%) patient was still receiving treatment at the time of data cut-off (25 April 2008).
doi:10.1093/annonc/mdq076 | 1995
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4-month PFS rate —PP populationa n/N (%) [CI] Survival (Kaplan–Meier method)—ITT population Median PFS, –c b months [CI] – 4-month PFS rate, % [CI]b – 6-month PFS |rate, % [CI]b Median OS, 9.4 [5.6–13.8] months [CI] Activity/response, n (%)—ITT population PR [CI] 0 SD 7 (54) PD 4 (31) Unknown 2 (15)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
original article
Annals of Oncology
Assessed for eligibility (N = 80) Not meeting inclusion criteria (n = 5)
Patients nonrandomly assigned to 2nd- or 3rd- line therapy (n = 75)
Allocated to 3rd-line therapy (stratum 2) and received everolimus 2.5 mg/d + imatinib 600 mg/d (n = 47)
Discontinued treatment due to
Discontinued treatment due to
Disease progression (n = 23)
Disease progression (n = 31)
Adverse event (n = 2)
Adverse event (n = 10)
Consent withdrawal (n = 2)
Consent withdrawal (n = 3)
Death (n = 1)
Abnormal laboratory value (n = 1) Death (n = 1) Ongoing at data cutoff (n = 1)
Analyzed (n = 28)
Analyzed (n = 47)
Excluded from PP analysis (n = 5)
Excluded from PP analysis (n = 12)
PP population (n = 23)
PP population (n = 35)
Figure 2. Consolidated Standards of Reporting Trials diagram of phase II study. PP, per protocol.
discussion Phase I of this phase I–II nonrandomized study established the optimal doses for coadministering both agents. Everolimus and imatinib are both metabolized by the cytochrome P-450 enzyme CYP3A4; thus, it was important to establish that the doses of the two agents would not result in excessive toxicity [24, 29]. Because previously obtained data indicate that daily administration of everolimus would exert a greater pharmacodynamic effect than weekly administration at higher doses, patients were administered daily everolimus in combination with imatinib to identify optimal dosing for the combination [30–32]. The 2.5- and 5.0-mg daily everolimus doses were selected on the basis of prior knowledge of the efficacy of 5 and 10 mg/day everolimus and the possibility of an increase in exposure to everolimus when given in combination with imatinib [32]. DLTs were observed in each daily dosing cohort, but only the everolimus 5.0/600 dosing regimen was not well tolerated. Phase II data indicate a potential therapeutic benefit in coadministering everolimus 2.5 mg/day with imatinib 600 mg/ day to patients with advanced imatinib-resistant GIST. Overall, patients in both strata appeared to benefit from the combined administration of everolimus and imatinib. A trend toward a longer median PFS and 4-month PFS was observed in stratum 2 compared with stratum 1; however, this was reversed
1996 | Scho¨ffski et al.
for median OS, possibly reflecting the longer time since diagnosis in stratum 2, as well as the fact that patients in stratum 2 have a much worse prognosis, with second-line therapy having failed as well. The study was not designed to make formal comparisons between the two strata. Coadministering everolimus with imatinib was adequately tolerated, and only 16% of patients in either stratum discontinued due to AEs. While this study was in progress, the oral TKI sunitinib gained approval in the United States, Europe, and Japan for the treatment of imatinib-resistant GIST and has since become standard therapy for patients in whom imatinib fails or who cannot tolerate imatinib [33]. In the Demetri et al. [19] randomized trial investigating the efficacy of sunitinib in patients with advanced imatinib-resistant GIST, 312 patients received sunitinib or placebo. Median time to progression for sunitinib-treated patients was 27.3 weeks (95% CI 16.0–32.1) compared with 6.4 weeks (95% CI 4.4–10.0) for those who received placebo, and 16% of patients receiving sunitinib were progression free at 6 months compared with 1% receiving placebo. Sunitinib also significantly improved OS (hazard ratio 0.49; 95% CI 0.29–0.83; P = 0.007). Despite the significant benefit of sunitinib treatment, 19% of patients did not respond, and most patients eventually progressed and died of their disease, indicating the continued need for additional treatment options. After failure or in case of
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Allocated to 2nd-line therapy (stratum 1) and received everolimus 2.5 mg/d + imatinib 600 mg/d (n = 28)
original article A
Probability of Stable Disease, Partial Response and Complete Response (%)
Annals of Oncology
100 90
Stratum 1 (# events/N=24/28) (Median: 1.9; CI: 1.8-3.7)
80
Stratum 2 (# events/N=35/47) (Median: 3.5; CI: 1.9-5.2)
70 60 50 40 30 20 10 0 0
B
2
3
28 47
4
5
5 14
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Since Start of Treatment
3 7
100
Survival Probability (%)
90 80 70 60 50 40 30 20 Stratum 1 (# events/N=9/28) (Median: 14.9; CI: 14.9- )
10
Stratum 2 (# events/N=22/47) (Median: 10.7; CI: 6.3-16.8)
0 0 Number at Risk Stratum 1 Stratum 2
1
2
28 47
3
4
5
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Since Start of Treatment
18 23
13 15
10 8
Figure 3. Kaplan–Meier estimates of PFS (A) and OS (B) by phase II stratum (intent-to-treat population). PFS, progression-free survival; OS, overall survival.
intolerance to sunitinib, no other drugs are routinely available for the patients outside of clinical trials or medical need/ compassionate use programs. The scientific community has explored a number of other agents including TKIs in this clinical setting. While drugs such as sorafenib [34] and nilotinib [35] have shown some promise in individual patients (in most cases, disease stabilization according to conventional imaging criteria), none of these drugs have yet been filed for approval by Food and Drug Administration or European Medicines Agency for the refractory GIST population. The results of this study indicate that the combination of everolimus and imatinib in patients with PD after progressing on imatinib and sunitinib therapy merits further investigation, as the predefined criteria for PFS in this protocol were met in all strata.
funding Novartis Pharmaceuticals, Basel, Switzerland.
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acknowledgements Allan T. Van Oosterom, University Hospitals Leuven, was involved in the design and early conduct of this trial. The authors wish to thank Scott S. Case of SciStrategy Communications for his medical writing assistance on behalf of Novartis Pharmaceuticals. Prior presentation—presented in part at the 41st American Society of Clinical Oncology (ASCO) Congress, 13–17 May 2005, Orlando, FL, and the 44th ASCO Congress, 30 May to 3 June 2008, Chicago, IL.
disclosure Dr Scho¨fski is a member of the speakers’ bureau of Novartis and has received research funding from them. Dr Demetri has reported consultancy work and/or honoraria for Novartis, Pfizer, Ariad, Johnson and Johnson, Genentech, Infinity Pharmaceuticals, ZioPharm, Alnylam, Idera, Bayer, EMDSerono, Amgen, Millenium/Takeda, PamGene, Plexxikon,
doi:10.1093/annonc/mdq076 | 1997
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Number at Risk Stratum 1 Stratum 2
1
original article N-of-One, and Kolltan Pharmaceuticals; his institute has received research support from Daiichi-Sankyo, Infinity Pharmaceuticals, Bristol-Myers Squibb, Johnson & Johnson, Ariad, Pfizer, and Novartis; he reports equity in Plexxikon, N-of-One, and Kolltan Pharmaceuticals. Drs Hollaender and Jappe are employees of Novartis. The other authors have not reported any conflicts of interest.
references
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17. Antonescu CR, Besmer P, Guo T et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005; 11: 4182–4190. 18. Reichardt P. Novel approaches to imatinib- and sunitinib-resistant GIST. Curr Oncol Rep 2008; 10: 344–349. 19. Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329–1338. 20. Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist 2007; 12: 1007–1018. 21. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005; 17: 158–166. 22. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471–484. 23. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671–688. 24. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 2005; 14: 313–328. 25. Bauer S, Duensing A, Demetri GD et al. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 2007; 26: 7560–7568. 26. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 27. National Cancer Institute. Common Toxicity Criteria version 2 (CTC v2.0). 1999 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 28. 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. 29. Dagher R, Cohen M, Williams G et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002; 8: 3034–3038. 30. O’Donnell A, Faivre S, Burris HA III et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1588–1595. 31. Tanaka C, O’Reilly T, Kovarik JM et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26: 1596–1602. 32. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1603–1610. 33. Rock EP, Goodman V, Jiang JX et al. Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007; 12: 107–113. 34. Wiebe L, Kasza KE, Maki RG et al. Activity of sorafenib in patients with imatinib and sunitinib-resistant gastrointestinal stromal tumors: a phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol 2008; 26 (Suppl): (Abstr 10502). 35. Montemurro M, Scho¨ffski P, Reichardt P et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer 2009; 45: 2293–2297.
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1. Cichoz-Lach H, Kasztelan-Szczerbinska B, Slomka M. Gastrointestinal stromal tumors: epidemiology, clinical picture, diagnosis, prognosis and treatment. Pol Arch Med Wewn 2008; 118: 216–221. 2. Joensuu H. Gastrointestinal stromal tumor (GIST). Ann Oncol 2006 17 (Suppl 10): x280–x286. 3. von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am 2005; 19: 547–564, vii. 4. Dematteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: 51–58. 5. Demetri GD, von MM, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–480. 6. Dematteo RP, Heinrich MC, El-Rifai WM et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002; 33: 466–477. 7. 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. 8. Tuveson DA, Willis NA, Jacks T et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001; 20: 5054–5058. 9. Rubin BP, Singer S, Tsao C et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001; 61: 8118–8121. 10. Heinrich MC, Corless CL, Duensing A et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299: 708–710. 11. Corless CL, Schroeder A, Griffith D et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005; 23: 5357–5364. 12. van Oosterom AT, Judson I, Verweij J et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001; 358: 1421–1423. 13. Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364: 1127–1134. 14. Van Glabbeke M, Verweij J, Casali PG et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 2005; 23: 5795–5804. 15. Heinrich MC, Corless CL, Blanke CD et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006; 24: 4764–4774. 16. Debiec-Rychter M, Cools J, Dumez H et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005; 128: 270–279.
Annals of Oncology
Annals of Oncology 21: 1990–1998, 2010 doi:10.1093/annonc/mdq076 Published online 27 May 2010
A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors P. Scho¨ffski1*, P. Reichardt2, J.-Y. Blay3, H. Dumez1, J. A. Morgan4, I. Ray-Coquard3, N. Hollaender5, A. Jappe5 & G. D. Demetri4 1
Received 23 October 2009; revised 11 February 2010; accepted 16 February 2010
original article
Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST. Patients and methods: In phase I, patients received imatinib (600/800 mg/day) combined with weekly (20 mg) or daily (2.5/5.0 mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5 mg plus imatinib 600 mg/day. Primary end point was 4-month progression-free survival (PFS). Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD. Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST. Key words: everolimus (RAD001), gastrointestinal stromal tumors, GIST, imatinib
introduction Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, although they account for <1% of all digestive tract tumors, with an estimated yearly incidence of 10–20 cases per million [1, 2]. Because GIST are generally resistant to conventional chemotherapy, the standard treatment of localized GIST is surgical resection. Unfortunately, in many patients, tumors recur postoperatively, resulting in progressive metastatic disease with a median survival of 19 months [3, 4]. Until the introduction of imatinib [5, 6], treatment options for metastatic disease after surgical resection were limited. Imatinib mesylate (Glivec; Novartis Pharmaceuticals, Basel, Switzerland), an oral tyrosine kinase inhibitor (TKI), selectively targets several kinases, including the KIT receptor tyrosine kinase, which is active in 85%–90% of patients with GIST [6–9]. Additionally, later studies reported the presence of *Correspondence to: Dr P. Scho¨ffski, Laboratory of Experimental Oncology, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32-16-346900; Fax: +32-16-346901; E-mail: [email protected]
activating mutations in the PDGFRA oncogene in wild-type KIT-bearing GIST [10, 11]. Imatinib dramatically improved outcomes for patients with metastatic GIST and is now standard first-line therapy in the metastatic setting [5]. In advanced-phase GIST, primary imatinib resistance [progressive disease (PD) <3 months] occurs in <10% of patients, but most patients acquire secondary resistance after a median of 2 years [5, 12–15]. This resistance may occur because of the development of additional KIT mutations, genomic amplification of KIT, or activation of alternative oncogenic signaling mechanisms, including the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway [16, 17]. For patients who develop imatinib resistance, treatment with sunitinib malate (Sutent; Pfizer, New York, NY), an oral TKI, has shown therapeutic benefit; however, the median progressionfree survival (PFS) with sunitinib is close to 6 months and most patients develop resistance within 1 year. New therapies are needed to treat patients with advanced imatinib-resistant GIST [18, 19]. mTOR, an intracellular protein kinase, regulates cellular responses to growth factors and responds to cellular stress and available nutrient and energy resources. Dysregulation of the
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; 2Department of Hematology and Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany; 3Department of Oncology, Centre Leon Berard, Lyon, France; 4Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 5Department of Oncology, Novartis Pharma AG, Basel, Switzerland
original article
Annals of Oncology
patients and methods patients Eligible patients were aged ‡18 years, had a histologically proven diagnosis of GIST with one or more measurable lesions, were resistant to imatinib, had a World Health Organization (WHO) performance status of two or less, and adequate bone marrow, liver, and renal function [leukocytes ‡ 3 · 109/l, neutrophils ‡ 1.5 · 109/l, hemoglobin ‡ 9 g/dl, platelets ‡ 100 · 109/l, total bilirubin and creatinine < 1.5 · upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase activity < 2.5 · ULN]. Patients previously treated with rapamycin analogues in combination with imatinib with central nervous system metastases or a concurrent severe medical condition (e.g. human immunodeficiency virus infection, uncontrolled diabetes, cardiac dysrhythmia, or acute renal or liver disease) were excluded. All patients provided informed consent. The study was approved by the institutional review board at each
participating center and conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines.
study design Phase I assessed the safety and tolerability of the combination of everolimus with imatinib to determine the optimal dose for both agents. As detailed in Table 1, patients initially received a weekly dose of 20 mg everolimus in combination with 600 mg daily imatinib. However, on the basis of favorable safety data, the protocol was amended and patients were enrolled to receive daily everolimus (2.5 and 5 mg) along with daily imatinib (600 and 800 mg). A classical 4 + 2 scheme was applied; daily everolimus doses (with 600 mg daily imatinib) were to be escalated from 2.5 to 5 mg in case of one or less dose-limiting toxic effects (DLTs) in four patients or two or less DLTs in six patients, respectively. In the 2.5-mg cohort, imatinib was escalated to 800 mg later. Phase II patients were enrolled into two strata to evaluate the efficacy of coadministering 2.5 mg everolimus with 600 mg imatinib daily (Table 1). Stratum 1 represented second-line therapy after progression on imatinib, and stratum 2 represented third-line therapy after treatment with second-line drug therapies (e.g. TKIs) given after prior progression on imatinib. Before entering the study, patients in stratum 1 continued to receive imatinib for 4 weeks while baseline assessments [computed tomography (CT) or magnetic resonance imaging (MRI)] was carried out. In stratum 2, patients discontinued their second-line drug regimen for at least 14 days or five half-lives of the used agent before entering the study while continuing to receive imatinib. All patients self-administered everolimus as a single dose, followed by imatinib taken twice daily. The primary efficacy end point (phase II) was 4-month PFS rate in the per-protocol (PP) population. A Simon two-stage design [26] was used to differentiate between a 4-month PFS rate of 5% and 20% in each stratum: two or more of 21 and five or more of 41 patients with PFS at month 4 were required at the end of stage 1 and stage 2, respectively. The PP population included all patients who received one or more doses of everolimus and imatinib and had an efficacy evaluation after 4 months. Patients with no evaluable tumor assessment at month 4 or thereafter were excluded from the PP population. However, patients who discontinued due to disease progression or died before 4 months were included in this population.
safety and response evaluations DLT, defined as any ‡ grade 3 treatment-related adverse event (AE) occurring within the first 4 weeks, was assessed using National Cancer Institute—Common Toxicity Criteria version 2.0 [27]. Safety evaluations for both phases were conducted over the whole period of treatment with everolimus and imatinib and included standard laboratory tests, physical examinations, and WHO performance status. Treatment continued until disease progression, unacceptable toxicity, or discontinuation at the patient’s request or the investigator’s decision. In both phases, tumor responses were evaluated according to investigator-assessed RECIST with radiologic scans (CT or MRI) at baseline and every 2 months [28]. Primary efficacy analyses of phase II were on the basis of the 4-month PFS rate, which was defined as the portion of patients who have not progressed or died within 4 months of treatment in the PP population. Secondary efficacy analyses were carried out in the intent-totreat (ITT) population and consisted of best overall tumor response, PFS (phase II only), and overall survival (OS; phase I and II). PFS was censored at last adequate tumor assessment if a patient did not progress or die, and for patients without observed death OS was censored at the last contact before the cut-off date for the analysis. The ITT population included all patients administered at least one dose of everolimus or imatinib. Figure 1. Everolimus complements imatinib by inhibiting PI3K/Akt/ mTOR signaling downstream of KIT and PDGFRA, resulting in decreased cell proliferation, survival, and angiogenesis. mTOR, mammalian target of rapamycin; PDGFRA, platelet-derived growth factor receptor A.
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statistics Results were summarized by dose cohort (phase I) and stratum (phase II) using the appropriate descriptive statistics. The 4-month PFS rate is given
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mTOR pathway promotes cancer cell growth and survival and contributes to the pathogenesis of a variety of malignancies [20–22]. Everolimus (RAD001; Afinitor; Novartis Pharmaceuticals), an oral mTOR inhibitor, specifically targets mTOR and pathways involved in cell growth, survival, and angiogenesis [23, 24]. Preclinical studies combining everolimus and imatinib resulted in a synergistic antiproliferative effect and the induction of apoptosis in imatinib-resistant GIST cell lines [25]. Everolimus complements imatinib by inhibiting Akt/ mTOR signaling downstream of KIT and platelet-derived growth factor receptor A (Figure 1), providing a rationale for coadministering both drugs to patients with metastatic imatinib-resistant GIST. We conducted this nonrandomized, phase I–II, open-label multicenter study to assess the safety, tolerability, and efficacy of the combined administration of everolimus with imatinib in patients with advanced imatinibresistant GIST.
original article
Annals of Oncology
Table 1. Phase I–II study design overview Prior treatment
Imatinib for ‡4 months with 2 months ‡600 mg/day Imatinib with uninterrupted treatment ‡800 mg/day for the last 2 months Prior treatment
Everolimus
No. of patients enrolled (ITT population)
600 600 600 800
20 mg/week 2.5 mg/day 5 mg/day 2.5 mg/day
13 13 5 11
mg/day mg/day mg/day mg/day
Phase II Imatinib
Everolimus
No. of patients enrolled (ITT population)
No. of patients in PP population
600 mg/dayb
2.5 mg/day
28
23
600 mg/dayb
2.5 mg/day
47
35
ITT, intent to treat; PP, per protocol. a Stratum 1 was stopped at the end of stage 1 due to the availability of new treatment options (sunitinib). b Three patients (one in stratum 1 and two in stratum 2) received 800 mg/day (protocol deviation).
with 95% confidence interval (CI). The time-to-event variables PFS (phase II only) and OS (phase I and II) were estimated using the Kaplan– Meier method. The derived median survival times and survival probabilities are given with 95% CI.
results Phase I patients were enrolled from November 2002 to September 2006 and phase II patients entered the study from April 2005 to January 2007. The database was locked in April 2008.
phase I everolimus weekly administration. Thirteen patients were treated on the 20/600 (everolimus/imatinib) schedule for a median of 3.4 months (range 1.2–13.8), with 1 patient (8%) discontinuing due to an AE and 12 (92%) due to PD. Patient characteristics are shown in Table 2. No DLTs were observed within the predefined 4-week period. Four patients (31%) experienced serious AEs, with only one (grade 4 anemia) suspected to be related to the study drug. Nausea, diarrhea, fatigue, and anemia were the most frequently reported AEs that were suspected of being related to the study drug. As shown in Table 3, 39% of patients had either a grade 3 or a grade 4 AE, regardless of causality. As shown in Table 4, seven (54%) patients had stable disease (SD) and four (31%) patients had PD, while the median OS was 9.4 months (95% CI 5.6–13.8). After 12 months, eight (62%) patients had died and four (31%) patients survived, with an estimated survival rate of 39%. everolimus daily administration. Twenty-nine patients were administered daily everolimus in combination with imatinib:
1992 | Scho¨ffski et al.
13 (45%) in the 2.5/600 cohort, 5 (17%) in the 5.0/600 cohort, and 11 (38%) in the 2.5/800 cohort. Patient characteristics are shown in Table 2. Compared with the 5.0/600 cohort, the 2.5/ 600 cohort had a higher percentage of males (77% versus 20%). In the 2.5/600 cohort, no DLTs were observed in the first four patients. In the 5.0/600 cohort, there were two (15%) DLTs among the first five patients; therefore, accrual to the 5.0/ 600 cohort was stopped, and 2.5 mg/day was declared the maximum tolerated dose of everolimus with a 600 mg/day dose of imatinib, with this cohort expanded to 13 patients. Two DLTs occurred among the next nine patients in the 2.5/600 cohort. In the 2.5/600 cohort, seven (54%) patients experienced serious AEs, with three patients having a serious AE suspected to be related to the study drug. In the 2.5/800 cohort, five DLTs were observed. In the 2.5/800 cohort, seven (64%) patients experienced serious AEs. Overall, nausea, diarrhea, fatigue, and anemia were the most frequently reported AEs that were suspected of being related to the study drug. Grade 3 or 4 AEs regardless of causality are shown for all cohorts in Table 3. Among the 2.5/600, 5.0/600, and 2.5/800 cohorts, the median/mean duration of treatment was 2.7/5.7 (range 0.7–35.5), 2.4/4.4 (range 1.1–9.5), and 2.1/2.9 months (range 0.4–6.7), respectively. In the 2.5/600 cohort, four (31%) patients discontinued due to AEs, eight (62%) due to PD, and one (8%) patient died due to underlying disease. In the 5.0/600 cohort, two (40%) patients discontinued due to AEs, two (40%) due to PD, and one (20%) due to an abnormal laboratory value (grade 3 thrombocytopenia). In the 2.5/800 cohort, three (27%) patients discontinued due to AEs, one (9%) due to an abnormal laboratory value (grade 3
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Stratum 1a: imatinib for ‡4 months with 2 months ‡600 mg/day Stratum 2: imatinib until progressive disease and postimatinib second-line treatment
Phase I Imatinib
original article
Annals of Oncology
Table 2. Baseline characteristics of phase I and II patients receiving everolimus in combination with imatinib Patient characteristics
Phase I Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13) (25–71)
All Patients (n = 75)
All Patients (n = 42)
Everolimus 5.0 mg/day (n = 5) 53 (37–70)
59 (42–82)
55 (25–82)
55 (29–80)
61 (26–83)
58 (26–83)
(77) (23)
1 (20) 4 (80)
9 (82) 2 (18)
31 (74) 11 (26)
21 (75) 7 (25)
31 (66) 16 (34)
52 (69) 23 (31)
(92) (8)
5 (100) 0
11 (100) 0
41 (98) 1 (2)
27 (96) 1 (4)
47 (100) 0
74 (99) 1 (1)
(23) (69) (8)
1 (20) 2 (40) 2 (40)
7 (64) 4 (36) 0
21 (50) 16 (38) 5 (12)
11 (39) 16 (57) 1 (4)
21 (45) 23 (49) 3 (6)
32 (43) 39 (52) 4 (5)
(8)
0 0 0 0 4 (80) 0 1 (20)
1 1 2 1 13 3 9 – 12
(29)
2 1 1 1 10 –b 9 1 3
(32) (4) (11)
0 4 2 1 22 – 13 0 5
(11)
2 5 3 2 32 – 22 1 8
(29) (1) (11) (1) (13) (13) (72)
(8) (31) (8) (23) –
0 1 1 1 2 0 3 – 3
(9) (9) (9) (18) (27)
(7) (4) (4) (4) (36)
(9) (4) (2) (47) (28)
(23)
0
(8) (23) (69)
0 0 0 5 (100)
0 3 (27) 3 (27) 5 (46)
0 5 (12) 9 (21) 28 (67)
1 6 2 19
(4) (21) (7) (68)
0 4 (9) 8 (17) 35 (75)
1 10 10 54
0 0 4 (80) 1 (20) 0
2 (18) 0 9 (82) 0 0
3 14 21 1 3
2 14 11 0 1
(7) (50) (39)
– – – – –
– – – – –
(8) (39) (46) (8)
(27)
(2) (2) (5) (2) (31) (7) (21)
(7) (33) (50) (2) (7)
(4)
– – –
– – –
– – –
– – –
35 (75) 11 (23) 1 (2)
– – –
– – – –
– – – –
– – – –
– – – –
3 26 16 2
– – – –
(6) (55) (34) (4)
(3) (7) (4) (3) (43)
WHO PS, World Health Organization performance status; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. a Stratum 1 represents second-line therapy, and stratum 2 represents third-line therapy. b ‘–’ indicates that the patient characteristic was not measured.
lymphopenia), five (46%) due to PD, one (9%) due to consent withdrawal, and one (9%) patient died due to intra-abdominal hemorrhage after liver biopsy. As shown in Table 4, tumor response included one (8%) partial response (PR) and six (46%) SD in the 2.5/600 cohort,
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four (80%) SD in the 5.0/600 cohort, and six (55%) SD in the 2.5/800 cohort. Among the 2.5/600, 5.0/600, and 2.5/800 cohorts, the median OS was 10.9 months [3.3 to not available (NA)], 18.7 months (3.8 to NA), and not reached (12.0 to NA), respectively. After 12 months, the estimated survival rates were
doi:10.1093/annonc/mdq076 | 1993
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Median age, years (range) 53 (46–66) 47 Sex, n (%) Male 11 (85) 10 Female 2 (15) 3 Race, n (%) Caucasian 13 (100) 12 Black 0 1 WHO PS, n (%) 0 10 (77) 3 1 1 (8) 9 2 2 (15) 1 Primary tumor site, n (%) Colon 0 1 Liver 0 0 Peritoneum 0 1 Rectum 0 0 Small intestine 3 (23) 4 Soft tissue sarcoma 2 (15) 1 Stomach 2 (15) 3 Pancreas – – Other 6 (46) 3 Time since diagnosis, years, n (%) <1 0 0 1 to <2 1 (8) 1 2 to <3 3 (23) 3 ‡3 9 (69) 9 Best overall response to prior imatinib therapy CR 0 1 PR 9 (69) 5 SD 2 (15) 6 PD 0 0 Unknown 2 (15) 1 Post-imatinib therapies Sunitinib – – Tyrosine kinase inhibitora – – – – Cyclin-dependent kinase inhibitora Best overall response to the most recent therapy PR – – SD – – PD – – Unknown – –
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum 1 Stratum 2 (n = 28) (n = 47)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
original article
Annals of Oncology
Table 3. Phase I and II grade 3 or 4 AEs seen in more than one patient receiving everolimus in combination with imatinib regardless of causality Grade 3–4 AEs, n (%)
All patients (n = 75)
Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13)
Everolimus 5.0 mg/day (n = 5)
5 (39) 2 (15) 1 (8)
8 (62) 0 0
5 (100) 1 (20) 3 (60)
9 (82) 3 (27) 0
27 (64) 6 (14) 4 (10)
15 (54) 1 (4) 1 (4)
35 (75) 1 (2) 1 (2)
50 (67) 2 (3) 2 (3)
0 1 2 1 0 0 0 1 0 1 0 – – – – – – – – – – – –
0 1 (8) 0 0 0 0 1 (8) 0 0 0 1 (8) – – – – – – – – – – – –
3 1 0 0 3 0 0 0 0 0 1 – – – – – – – – – – – –
1 0 1 2 0 2 1 1 2 1 0 – – – – – – – – – – – –
4 3 3 3 3 2 2 2 2 2 2 – – – – – – – – – – – –
(10) (7) (7) (7) (7) (5) (5) (5) (5) (5) (5)
–b – – – 0 – 0 0 – – – 2 1 0 2 1 1 1 1 1 1 1 2
(7) (4) (4) (4) (4) (4) (4) (4) (7)
– – – – 5 (11) – 3 (6) 6 (13) – – – 2 (4) 3 (6) 3 (6) 0 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 0
– – – – 5 – 3 6 – – – 4 4 3 2 2 2 2 2 2 2 2 2
(5) (5) (4) (3) (3) (3) (3) (3) (2) (3) (3) (3)
3 (23) 3 (23) 1 (8) 0 0
6 6 0 1 1
1 1 0 1 1
(46) (18) (18) (9) (9)
15 12 3 3 3
(36) (29) (7) (7) (7)
3 4 3 1 2
(11) (14) (11) (4) (7)
8 8 4 1 3
(17) (17) (9) (2) (6)
11 12 7 2 5
(15) (16) (9) (3) (7)
2 (15) 1 (8) 0 1 (8) – – –
2 (15) 2 (15) 0 1 (8) – – –
4 (36) 1 (9) 2 (18) 0 – – –
11 4 2 2 – – –
(26) (10) (5) (5)
7 1 1 1 1 2 0
(25) (4) (4) (4) (4) (7)
12 2 1 2 4 3 2
(26) (4) (2) (4) (9) (6) (4)
19 3 2 3 5 5 2
(25) (4) (3) (4) (7) (7) (3)
(8) (15) (8)
(8) (8)
(46) (46) (8) (8)
(60) (20)
(60)
(20)
(20) (20) (20) (20)
3 (60) 0 0 0 – – –
5 2 2 1 1
(9) (9) (18) (18) (9) (9) (18) (9)
All patients (n = 42)
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum 1 Stratum 2 (n = 28) (n = 47)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
(7) (4)
(7) (4) (8)
AE, adverse event; LDH, lactate dehydrogenase; WBC, white blood cell; AST, aspartate aminotransferase. Stratum 1 represents second-line therapy, and stratum 2 represents third-line therapy. b ‘–’ indicates that the AE was not measured. c Newly occurring or worsened National Cancer Institute—Common Toxicity Criteria version 2 grade. a
43% in the 2.5/600 cohort, 60% in the 5.0/600 cohort, and 82% in the 2.5/800 cohort. The 2.5/600 schedule was selected for the phase II study.
phase II Phase II enrolled 75 patients treated on the 2.5/600 schedule, and they were divided into 28 (37%) in stratum 1 and 47 (63%)
1994 | Scho¨ffski et al.
in stratum 2 (Figure 2). All patients in stratum 2 were previously treated with sunitinib [n = 35 (75%)], other TKIs [n = 11 (23%)], or cyclin-dependent kinase inhibitors [n = 1 (2%)] in addition to imatinib. Patient baseline characteristics are listed in Table 2. No appreciable differences were noted. Serious AEs were reported in 11 (39%) and 25 (53%) patients in strata 1 and 2, respectively. Serious AEs suspected to
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Any grade 3–4 AE Diarrhea General physical health deterioration Nausea Dehydration Pyrexia Sepsis Vomiting Angioedema Dyspnea Fatigue Pneumonia Postprocedural hemorrhage Stomatitis Abdominal pain Asthenia Melena Increased LDH Gastroenteritis Gastrointestinal hemorrhage Hemorrhagic anemia Peripheral edema Pulmonary embolism Renal failure Tumor hemorrhage Tumor pain Hematologic abnormalitiesc Absolute lymphocytes Hemoglobin Absolute neutrophils Platelet count WBC count (total) Biochemistry abnormalitiesc Hypokalemia Hyponatremia AST Creatinine Bilirubin Hypocalcemia Hypoglycemia
Phase I
original article
Annals of Oncology
Table 4. Efficacy measures for phases I and II Efficacy
Phase I Imatinib 600 mg/day Everolimus Everolimus 2.5 mg/day 20 mg/week (n = 13) (n = 13)
Everolimus 5 mg/day (n = 5)
Phase II Imatinib 600 mg/day + everolimus 2.5 mg/daya Stratum Stratum 1 (n = 28) 2 (n = 47)
4/23 (17) [5.0–38.8]
13/35 (37) [21.5–55.1]
–
–
–
1.9 [1.8–3.7]
3.5 [1.9–5.2]
–
–
–
21 [4.7–37.6]
40 [24.6–55.9]
–
–
–
13 [0–26.1]
20 [7.0–33.3]
10.9 [3.3 to NA]
18.7 [3.8 to NA]
NR [12.0 to NA]
14.9 [14.9 to NA]
10.7 [6.3–16.8]
1 (8) [0.2–36.0] 6 (46) 6 (46) 0
0 4 (80) 0 1 (20)
0 6 (55) 1 (9) 4 (36)
0 10 (36) 15 (54) 3 (11)
1 20 15 11
(2) [0.1–11.3] (43) (32) (23)
PFS, progression-free survival; PP, per protocol; CI, confidence interval; ITT, intent to treat; OS, overall survival; NA, not available; NR, not reached; PR, partial response; SD, stable disease; PD, progressive disease. a PP population: stratum 1 (n = 23, 15/1 patients had PD/died <4 months) and stratum 2 (n = 35, 15/1 patients had PD/died <4 months); phase II dose was everolimus 2.5 mg/day + imatinib 600 mg/day, with stratum 1 representing second-line therapy and stratum 2 representing third-line therapy. b If a patient did not progress or die, PFS was censored at last adequate tumor assessment. c ‘–’ indicates that the efficacy end point was not measured.
be related to the study drug were reported for 4 (14%) patients in stratum 1 and 11 (26%) patients in stratum 2. Gastrointestinal disorders were the most common drug-related AEs reported, with diarrhea, nausea, fatigue, and anemia being the most frequent. The most common grade 3–4 AEs, regardless of causality, were hypokalemia, anemia, lymphopenia, fatigue, and vomiting (Table 3). In stratum 1, 27 (96%) patients had AEs, including 15 (54%) patients with grade 3–4 AEs, whereas in stratum 2, all patients experienced AEs, including 35 (75%) patients with grade 3–4 AEs. Table 4 presents all the efficacy data for the phase II study. In stratum 1, 4 of 23 assessable patients (17%; 95% CI 5.0–38.8) were progression free at 4 months. Despite meeting the criterion to enter stage 2, the stratum was discontinued due to the availability of alternative treatments in second line (sunitinib), which was not yet the case when this study was designed. In stratum 2, 13 of 35 assessable patients (37%; 95% CI 21.5–55.1) were progression free at 4 months, meeting the predefined conditions for stage 2. In the ITT population, stratum 1 (n = 28) had a median PFS of 1.9 months (95% CI 1.8–3.7), while stratum 2 (n = 47) had a median PFS of 3.5 months (95% CI 1.9–5.2) (Figure 3A). On the basis of Kaplan–
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Meier analysis, the estimated 4-month PFS probability was 21% (95% CI 4.7–37.6) in stratum 1 and 40% (95% CI 24.6–55.9) in stratum 2, respectively, corresponding well with the results obtained in the PP population. The 6-month PFS probability was 13% (95% CI 0–26.1) and 20% (95% CI 7.0–33.3) for strata 1 and 2, respectively. Median OS was 14.9 months (95% CI 14.9 to NA) in stratum 1, compared with 10.7 months (95% CI 6.3–16.8) in stratum 2 (Figure 3B). A total of 61 (81%) patients in both strata were assessable for best overall tumor response. Stratum 1 had 10 (36%) SD and 15 (54%) PD, while stratum 2 had 1 (2%) PR, 20 (43%) SD, and 15 (32%) PD. The median/mean duration of treatment was 1.9/2.9 (range 0.2–9.7) and 2.4/4.2 months (range 0.2–21.9) for strata 1 and 2, respectively. In stratum 1, all patients discontinued therapy: 23 (82%) due to PD, 2 (7%) due to AEs, 2 (7%) withdrew consent, and 1 (4%) patient died due to underlying disease. In stratum 2, 46 (98%) patients discontinued: 31 (66%) due to PD, 10 (21%) due to AEs, 1 (2%) due to abnormal laboratory value(s), 3 (6%) withdrew consent, and 1 (2%) patient died due to acute coronary syndrome. One (2%) patient was still receiving treatment at the time of data cut-off (25 April 2008).
doi:10.1093/annonc/mdq076 | 1995
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4-month PFS rate —PP populationa n/N (%) [CI] Survival (Kaplan–Meier method)—ITT population Median PFS, –c b months [CI] – 4-month PFS rate, % [CI]b – 6-month PFS |rate, % [CI]b Median OS, 9.4 [5.6–13.8] months [CI] Activity/response, n (%)—ITT population PR [CI] 0 SD 7 (54) PD 4 (31) Unknown 2 (15)
Imatinib 800 mg/day Everolimus 2.5 mg/day (n = 11)
original article
Annals of Oncology
Assessed for eligibility (N = 80) Not meeting inclusion criteria (n = 5)
Patients nonrandomly assigned to 2nd- or 3rd- line therapy (n = 75)
Allocated to 3rd-line therapy (stratum 2) and received everolimus 2.5 mg/d + imatinib 600 mg/d (n = 47)
Discontinued treatment due to
Discontinued treatment due to
Disease progression (n = 23)
Disease progression (n = 31)
Adverse event (n = 2)
Adverse event (n = 10)
Consent withdrawal (n = 2)
Consent withdrawal (n = 3)
Death (n = 1)
Abnormal laboratory value (n = 1) Death (n = 1) Ongoing at data cutoff (n = 1)
Analyzed (n = 28)
Analyzed (n = 47)
Excluded from PP analysis (n = 5)
Excluded from PP analysis (n = 12)
PP population (n = 23)
PP population (n = 35)
Figure 2. Consolidated Standards of Reporting Trials diagram of phase II study. PP, per protocol.
discussion Phase I of this phase I–II nonrandomized study established the optimal doses for coadministering both agents. Everolimus and imatinib are both metabolized by the cytochrome P-450 enzyme CYP3A4; thus, it was important to establish that the doses of the two agents would not result in excessive toxicity [24, 29]. Because previously obtained data indicate that daily administration of everolimus would exert a greater pharmacodynamic effect than weekly administration at higher doses, patients were administered daily everolimus in combination with imatinib to identify optimal dosing for the combination [30–32]. The 2.5- and 5.0-mg daily everolimus doses were selected on the basis of prior knowledge of the efficacy of 5 and 10 mg/day everolimus and the possibility of an increase in exposure to everolimus when given in combination with imatinib [32]. DLTs were observed in each daily dosing cohort, but only the everolimus 5.0/600 dosing regimen was not well tolerated. Phase II data indicate a potential therapeutic benefit in coadministering everolimus 2.5 mg/day with imatinib 600 mg/ day to patients with advanced imatinib-resistant GIST. Overall, patients in both strata appeared to benefit from the combined administration of everolimus and imatinib. A trend toward a longer median PFS and 4-month PFS was observed in stratum 2 compared with stratum 1; however, this was reversed
1996 | Scho¨ffski et al.
for median OS, possibly reflecting the longer time since diagnosis in stratum 2, as well as the fact that patients in stratum 2 have a much worse prognosis, with second-line therapy having failed as well. The study was not designed to make formal comparisons between the two strata. Coadministering everolimus with imatinib was adequately tolerated, and only 16% of patients in either stratum discontinued due to AEs. While this study was in progress, the oral TKI sunitinib gained approval in the United States, Europe, and Japan for the treatment of imatinib-resistant GIST and has since become standard therapy for patients in whom imatinib fails or who cannot tolerate imatinib [33]. In the Demetri et al. [19] randomized trial investigating the efficacy of sunitinib in patients with advanced imatinib-resistant GIST, 312 patients received sunitinib or placebo. Median time to progression for sunitinib-treated patients was 27.3 weeks (95% CI 16.0–32.1) compared with 6.4 weeks (95% CI 4.4–10.0) for those who received placebo, and 16% of patients receiving sunitinib were progression free at 6 months compared with 1% receiving placebo. Sunitinib also significantly improved OS (hazard ratio 0.49; 95% CI 0.29–0.83; P = 0.007). Despite the significant benefit of sunitinib treatment, 19% of patients did not respond, and most patients eventually progressed and died of their disease, indicating the continued need for additional treatment options. After failure or in case of
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Allocated to 2nd-line therapy (stratum 1) and received everolimus 2.5 mg/d + imatinib 600 mg/d (n = 28)
original article A
Probability of Stable Disease, Partial Response and Complete Response (%)
Annals of Oncology
100 90
Stratum 1 (# events/N=24/28) (Median: 1.9; CI: 1.8-3.7)
80
Stratum 2 (# events/N=35/47) (Median: 3.5; CI: 1.9-5.2)
70 60 50 40 30 20 10 0 0
B
2
3
28 47
4
5
5 14
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Since Start of Treatment
3 7
100
Survival Probability (%)
90 80 70 60 50 40 30 20 Stratum 1 (# events/N=9/28) (Median: 14.9; CI: 14.9- )
10
Stratum 2 (# events/N=22/47) (Median: 10.7; CI: 6.3-16.8)
0 0 Number at Risk Stratum 1 Stratum 2
1
2
28 47
3
4
5
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months Since Start of Treatment
18 23
13 15
10 8
Figure 3. Kaplan–Meier estimates of PFS (A) and OS (B) by phase II stratum (intent-to-treat population). PFS, progression-free survival; OS, overall survival.
intolerance to sunitinib, no other drugs are routinely available for the patients outside of clinical trials or medical need/ compassionate use programs. The scientific community has explored a number of other agents including TKIs in this clinical setting. While drugs such as sorafenib [34] and nilotinib [35] have shown some promise in individual patients (in most cases, disease stabilization according to conventional imaging criteria), none of these drugs have yet been filed for approval by Food and Drug Administration or European Medicines Agency for the refractory GIST population. The results of this study indicate that the combination of everolimus and imatinib in patients with PD after progressing on imatinib and sunitinib therapy merits further investigation, as the predefined criteria for PFS in this protocol were met in all strata.
funding Novartis Pharmaceuticals, Basel, Switzerland.
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acknowledgements Allan T. Van Oosterom, University Hospitals Leuven, was involved in the design and early conduct of this trial. The authors wish to thank Scott S. Case of SciStrategy Communications for his medical writing assistance on behalf of Novartis Pharmaceuticals. Prior presentation—presented in part at the 41st American Society of Clinical Oncology (ASCO) Congress, 13–17 May 2005, Orlando, FL, and the 44th ASCO Congress, 30 May to 3 June 2008, Chicago, IL.
disclosure Dr Scho¨fski is a member of the speakers’ bureau of Novartis and has received research funding from them. Dr Demetri has reported consultancy work and/or honoraria for Novartis, Pfizer, Ariad, Johnson and Johnson, Genentech, Infinity Pharmaceuticals, ZioPharm, Alnylam, Idera, Bayer, EMDSerono, Amgen, Millenium/Takeda, PamGene, Plexxikon,
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Number at Risk Stratum 1 Stratum 2
1
original article N-of-One, and Kolltan Pharmaceuticals; his institute has received research support from Daiichi-Sankyo, Infinity Pharmaceuticals, Bristol-Myers Squibb, Johnson & Johnson, Ariad, Pfizer, and Novartis; he reports equity in Plexxikon, N-of-One, and Kolltan Pharmaceuticals. Drs Hollaender and Jappe are employees of Novartis. The other authors have not reported any conflicts of interest.
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