Clin Transl Oncol (2015) 17:743–750 DOI 10.1007/s12094-015-1304-0
RESEARCH ARTICLE
A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma J. M. Sepu´lveda1 • C. Belda-Iniesta2 • M. Gil-Gil3 • P. Pe´rez-Segura4 • A. Berrocal5 • G. Reyne´s6 • O. Gallego7 • J. Capellades8 • J. M. Ordon˜ez9 • B. La Orden9 • C. Balan˜a´10
Received: 2 April 2015 / Accepted: 16 May 2015 / Published online: 2 June 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Purpose The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. Patients and methods Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m2 days 1–7 and 15–21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. Results Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44 %) had gross total resection. O6-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9 % (95 % CI 9.3–40.0 %). The median PFS and The results exposed in this manuscript are originals and have been presented in part as poster communication at the 2013 American Society of Clinical Oncology Annual Meeting (abstract 2087). & C. Balan˜a´ [email protected] 1
Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
2
Medical Oncology Department, Hospital Madrid Norte Sanchinarro, Madrid, Spain
3
Neuro-Oncology Unit, Institut Catala` d’Oncologia, Bellvitge, L’Hospitalet, Spain
4
Medical Oncology Department, Hospital Clı´nico San Carlos, Madrid, Spain
5
Medical Oncology Department, Consorcio Hospital General Universitario, Valencia, Spain
6
Medical Oncology Department, Hospital Universitari i Polite`cnic La Fe, Valencia, Spain
overall survival (OS) were 4.2 months (95 % CI 3.6–5.4 months) and 7.3 months (95 % CI 5.8–8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19 %; 95 % CI 7.2–36.4) were long-term survivors, with a median PFS and OS (50 % events) of 9.5 months (95 % CI 7.9–23.6) and 15.4 (95 % CI 8.9–NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. Conclusions This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy. Keywords Bevacizumab Glioblastoma Recurrent Temozolomide
7
Medical Oncology Department, Hospital De Sant Pau, Barcelona, Spain
8
Radiology Department, Hospital del Mar, Barcelona, Spain
9
Roche Farma SA, Madrid, Spain
10
Medical Oncology Department, Hospital Germans Trias i Pujol, Institut Catala d’Oncologia (ICO), Carretera Canyet sn, 08916 Badalona, Barcelona, Spain
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Introduction Glioblastoma (GB) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. The current standard of care for newly diagnosed GB is surgical resection followed by adjuvant radiotherapy (RT) with temozolomide (TMZ) [1, 2]. Median survival in newly diagnosed patients with best available treatments is 14.6 months. Hegi et al. identified a distinct survival advantage in patients with methylated O6methylguanine-DNA methyltransferase (MGMT) status receiving TMZ compared to those who received radiation alone, with a median survival of 21.7 versus 15.3 months, respectively [3, 4]. MGMT methylation has been established to be a prognostic factor, regardless of treatment modality. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy (CT), and RT, GB still has a dismal prognosis and nearly all patients will experience relapse of this aggressive cancer following first-line treatment. There are no widely accepted systemic therapies (approved or unapproved) for previously treated GB. Historically, the response rates for patients with recurrent GBs have been in the range of 5–10 %, with progression free survival (PFS) at 6 months (PFS6) seen in only 10–25 % of these patients [5]. Currently, many patients are offered no further therapeutic intervention after first-line treatment; others may be offered experimental treatments or marginally effective therapies. Many studies aim to overcome several determinants of resistance to conventional therapy by various approaches to improve the dismal prognosis of GB such as modifying TMZ administration and combining TMZ with other molecular-targeting agents. GB is characterized by sustained angiogenesis, the key regulator of which is vascular endothelial growth factor (VEGF). Bevacizumab (BV) (AvastinÒ; Genentech, Inc, San Francisco, CA, USA), a monoclonal antibody against VEGF, was granted accelerated approval on May 5, 2009 by the US Food and Drug Administration as a single agent for the treatment of patients with recurrent GBs that have failed initial therapy. That approval was based on the results of two studies, a randomized, non-comparative phase II trial (BRAIN study; AVF3708g) in GB patients who experienced first or second recurrence following standard of care with TMZ [6] and another phase II trial conducted by the National Cancer Institute (NCI) [7]. In the BRAIN study, patients received BV alone or in combination with irinotecan. In both, the BV (n = 85) and BV plus irinotecan (n = 82) cohorts, objective response rate (28.2 and 37.8 %) and PFS6 (42.6 and 50.3 %) were significantly higher than those of the external historical controls [6]. In other phase II trial, the 48 pretreated recurrent GB patients
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received BV in monotherapy, reaching a median PFS of 16 weeks, PFS6 of 29 % and a median overall survival (OS) of 31 weeks [7]. Recently, data of two phase III trials of BV for newly diagnosed GB have been presented [8, 9]. In both the studies, the addition of BV prolonged PFS but did not improve survival. On the basis of the promising results of prior studies of BV [6, 7, 10, 11], we conducted a prospective phase II, multicenter trial to evaluate the efficacy and safety of TMZ in combination with BV in patients with recurrent GB at first relapse, previously treated with chemoradiotherapy and TMZ. The 10 mg/kg/every 2-week schedule of BV was chosen based on the efficacy and safety observed in the same context when treating patients with recurrent GB [11]; the TMZ schedule ‘‘Week on/Week off’’ was selected based on the high rate of PFS6 reported with this scheme by Wick et al. [12, 13]. Additionally, we explored the possible association between the response reached with that regimen and the methylation status of MGMT gene.
Patients and methods Eligibility criteria Patients with confirmed GB at first relapse, having received prior chemoradiotherapy based on TMZ followed by at least three cycles of 5-day TMZ [1], were enrolled. Other inclusion criteria included Word Health Organization (WHO) performance status (PS) B2; adequate hepatic, renal, and bone marrow function; at least 4 weeks from completion of CT; and at least 3 months from last RT dose. Contraceptive measures were required for sexually active patients. Patients were excluded from participation if they had signs of recent brain hemorrhage on magnetic resonance imaging (MRI); history of bleeding diathesis or coagulopathy; previous treatment with BV; and other comorbidity conditions including uncontrolled hypertension and clinically significant cardiac disease (New York Heart Association, Class CII). Treatment schedule Patients received BV 10 mg/kg intravenously every 14 days, combined with TMZ 150 mg/m2 days 1–7 and 15–21 orally every 28 days (1 cycle = 28 days). Treatment was suspended in instances of attributably grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity. Treatment was restarted when toxicity was resolved. Patients continued on treatment until disease progression, unacceptable toxicity or withdrawal of the informed consent form.
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Study assessments Before study entry, a routine blood analysis (hematology, coagulation, and biochemistry) was obtained, as well as urinalysis, an assessment of the WHO PS, and a complete physical exam (including comprehensive neurologic examination). In addition, patients underwent baseline MRI within 28 days before starting therapy and after every 2 cycles (8 weeks) on trial. PS, vital signs assessments, physical and neurologic examination, and urinalysis were repeated before each treatment cycle until final follow-up visit: blood counts were obtained every 2 weeks. Formalinfixed, paraffin-embedded tumor samples of initial biopsy were sent to a central laboratory for analysis of MGMT by methylation specific multiple ligation-dependent probe amplification (MS-MLPA) [14, 15]: tumors were classified as methylated or unmethylated. Tumor evaluation was indicated every two cycles by MRI obtained for each patient on study and measured the postcontrast enhancing lesions using the modified criteria described by Macdonald et al. [16]. MRI was done with a study-specific brain tumor protocol that included axial T1, T2, fluid attenuation inversion recovery (FLAIR), diffusion weighted imaging, apparent diffusion coefficient, sagittal T1, and postcontrast axial and coronal images [10]. Patients were followed until disease progression was documented. Toxicity was evaluated at the initiation of each cycle and until 90 days after the last study drug dose administration, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Statistical considerations The primary end point was PFS6, defined as the percentage of patients who were alive and progression free at that time. Using Kaplan–Meier methodology, we estimated PFS6 and associated 95 % confidence intervals (CIs). Target accrual was 32 patients with GB to distinguish between a 15 and 35 % PFS6, with \0.10 probability of concluding the combination is effective if PFS6 is \15 % and ineffective if PFS6 is more than 35 % [5], i.e., if C5 patients are alive and progression free at 6 months, the study combination warrants further research. Secondary end points were global PFS and OS, as well as overall response (OR): in addition to the response evaluation made by each investigator, a centralized imaging review was performed by an independent radiologist. Moreover, we undertook an exploratory analysis of how those responses are correlated with the methylation status of MGMT gen. All efficacy analyses were performed on the intention to treat (ITT) population, defined as all included patients. OS
745
was calculated from the inclusion in the study until time of death or the date of last follow-up if censored, and PFS was defined as the time between inclusion in the study and disease progression, death without progression, or last follow-up. Kaplan–Meier methods were used to estimate PFS6, median PFS, and median OS; the corresponding 95 % CIs were calculated. Frequency and percentage of response rate, together with the 95 % CIs, are presented. The statistical analyses were run using the SAS software package version 9.2.
Results Patient characteristics A total of thirty-two patients from eight Spanish centers were enrolled from June 2010 to July 2011. Table 1 Table 1 Patient characteristics No. of patients
%
Age (years) Median
57
Range
29–74
Sex Male
17
53
Female
15
47
0
8
25
1
16
50
2
8
25
22
69
10
31
Normal
11
34
Without clinic relevance
6
19
With clinic relevance
12
38
No data
3
9
Gross total
14
44
Subtotal
18
56
Curative
21
66
Palliative
11
34
Methylated
12
38
Unmethylated Missing
6 14
19 43
WHO performance status
Signs and/or symptoms present Yes No Neurologic examination
Initial tumor resection
Surgery intention
MGMT promoter methylation status
WHO World Health Organization, RT radiotherapy, CT chemotherapy, MGMT methylated O6-methylguanine-DNA methyltransferase
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Table 2 Adverse events related to treatment (C10 %) per patient (%) according to NCI-CTC criteria v3.0 (n = 32) Grade 1/2
Grade 1/2 (%)
Grade 3/4
Grade 3/4 (%)
Hematological toxicity Lymphocytopenia
6
19
10
31
Thrombocytopenia Neutropenia
12 3
38 9
2 2
6 6 6
Non-hematological toxicity Fatigue
10
31
2
Nausea
9
28
–
–
Hypertension
5
15
–
–
Hemorrhage
4
13
1a
3
Vomiting
3
9
1
3
An adverse event was considered attributable to bevacizumab, capecitabine or radiation if it was deemed remotely, possibly or probably related a
Intracranial hemorrhage
presents the basal characteristics of the patients. Eight patients (25 %) had a WHO PS of 2, and 22 (69 %) presented neurological symptoms. Treatment compliance All patients received at least one cycle of BV ? TMZ. Twenty-two patients died during the treatment due to disease progression and 8 patients prematurely discontinued the treatment (3 lost of follow-up, 2 adverse events, 1 consent withdrawal, 1 investigator criteria, and 1 disease progression). The median number of cycles completed was four for both drugs. Twelve patients (16 cycles) had at least one BV cycle interrupted, 8 of them due to hematological toxicity. One patient had to halt 2 cycles of BV and 5 patients 1 cycle each one, mainly due to non-hematological toxicity. TMZ dose was reduced in 5 cycles (3 cases of thrombocytopenia). Ten patients had to halt 1 TMZ cycle, one patient 2 cycles and another one 13 cycles, mainly due to thrombocytopenia and/or neutropenia. Safety All patients were evaluable for safety. Treatment-related toxicity occurring at a frequency [10 % of patients is summarized in Table 2. Eighteen (56 %) and twenty-seven (84 %) patients suffered any adverse event considered related to BV or TMZ, respectively. Grade 3–4 most frequent related toxicities were lymphopenia and fatigue. Five patients had grade 1–2 hypertension that was managed by oral medications, and 2 patients had grade 3–4 thrombosis. Cardiac dysfunction with heart failure symptoms was not observed. No patient died from treatment toxicity.
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Efficacy Seven patients were alive and progression free at 6 months, representing a PFS6 rate of 21.9 % (95 % CI 9.3–40.0 %). The median PFS and OS were 4.2 months (95 % CI 3.6–5.4 months) and 7.3 months (95 % CI 5.8–8.8 months), respectively (Fig. 1). Six of 32 pts (19 %; 95 % CI 7.2–36.4) were long-term survivors (defined as those patients with a PFS C30 weeks), with a median PFS and OS of 9.5 months (95 % CI 7.9–23.6) and 15.4 months (95 % CI 8.9–NA), respectively: no differences in baseline characteristics were identified in comparison with total population. Following investigator assessments, thirteen patients (40 %; 95 % CI 24–59 %) had an OR and 25 patients (78 %; 95 % CI 60–91 %) reached a disease control (OR ? stable disease): in Table 3, data are shown from the evaluations made by each investigator as well as those made centrally. The majority of patients experienced tumor shrinkage during the treatment period (Fig. 2). Eighteen patients underwent methylation status testing: in 12 (67 %) of them, methylation of the MGMT promoter was observed. No significant association with MGMT status was found in terms of OR (33 % methylated vs 50 % non-methylated), PFS (4.2 months methylated vs 3.9 months non-methylated) or OS (7.6 months methylated vs 7.3 months non-methylated).
Discussion This prospective phase II study confirms the feasibility of a combination of BV and TMZ in patients with recurrent GB at first relapse, previously treated with CT and TMZ. Most of patients experienced tumor shrinkage during the treatment period, and the observed PFS6 rate claim the regimen worth for further study. Nevertheless, the 6-month PFS appeared to be inferior to that of other prospective studies where BV was used alone or in combination with CT [6, 7, 10, 11, 17–20]. The primary endpoint of this study was PFS6 rate. Although comparisons over time and studies may be problematic, the PFS6 rate of 22 % seen in this study with the addition of BV to TMZ, albeit relatively not too high, is within the range 19–50 % reported across a number of phase II studies evaluating BV plus chemoradiotherapy (Table 4). One possible explanation for the inferiority of our study outcome compared with others using BV alone or in combination with CT (mainly with irinotecan), may be that our study population had worse prognostic factors. Prognosis is better for patients who undergo gross total resection than for patients who undergo subtotal resection or who cannot undergo surgery due to tumor location [21–
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Fig. 1 a Progression free survival (ITT population). b Overall survival (ITT population)
23]. Fifty-six percent of the patients in our study have had a partial resection, and 75 % of the patients had a WHO performance status of C1. Moreover, inclusion criteria mandated disease progression after TMZ therapy, and efficacy was rigorously evaluated by an independent radiology facility using the Macdonald modified criteria. Indeed, our data are similar to those published by other authors with the same combination (BV ? TMZ) and
where all patients were progressive after TMZ therapy [10, 24]. Kreisl et al. [7] treated 48 patients with recurrent GB with BV in monotherapy. They suggest that a BV-mediated antitumor effect occurs in a subpopulation of patients: patients who did not have PR on early MRI scans had a significantly shorter PFS. If no change in vascular permeability is seen on an early MRI scan, one may suppose that
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Table 3 Antitumor efficacy (intention to treat analysis: 32 patients)
Investigators reported response
Centralized reported imaging response
n
%
95 % CI
n
CR
2
6
1–21
1
3
PR
11
34
19–53
12
38
21–56
SD
12
38
21–56
9
28
14–47
PD
6
19
7–36
5
16
5–33
3
–
a
3
–
–
–
4
12
–
NE
1
NA
–
a
%
1
95 % CI 0–16
CR complete response, PR partial response, SD stable disease, PD progressive disease, NE non-evaluable, NA non-available a
Magnetic resonance imaging could not be done due to clinical deterioration: patient died 1 month later
Fig. 2 Maximum decrease from baseline sum of the products of diameters (SPD). The maximum percent decrease from baseline SPD was defined as the percent change in SPD from baseline to the minimum postbaseline SPD. Patients who had determined measurable disease at baseline and at least one postbaseline tumor assessment were included (n = 30). PD progression disease, SD stable disease, PR ? CR partial ? Complete response
VEGF inhibition is not being achieved with this regimen, conferring a low probability of long-term tumor control with BV. We found 6 patients who reached a PFS longer than 30 weeks: 5 of them presented an early response, at first evaluation (after 2 cycles of therapy). In our study, there was no evidence of a difference in OR, PFS, nor OS regarding the methylated status of MGMT gene: probably, that is due to the small number of patients for which MGMT methylated status was known. Also, as commented by Desjardins et al. [10], the use of archival tumor material to assess MGMT, which was derived from tumor samples obtained from original, pretreatment, surgical specimens, may not have reflected tumor MGMT status at study enrollment. However, Wick
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et al. [12] and Kong et al. [25] also described the absence of significant PFS and OS differences with regard to the methylation status of the MGMT promoter in their respective studies. Toxicities were expected and manageable. The incidence of BV-related adverse events in patients with GB was similar to that observed in previous BV ? CT trials [6, 7, 10, 11, 17–20, 24], and no patient died from treatment toxicity. In conclusion, the combination of BV and TMZ seems to be useful and safe in patients with recurrent GB. Randomized trials should be focused in determining whether TMZ adds any clinical benefit to treatment with BV, even in patients previously treated with TMZ
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Table 4 Prospective clinical trials of bevacizumab in recurrent glioblastoma Author and regimen
No. of patients
RR (%)
PFS-6 (%)
PFS-median (monthsa)
OS-median (monthsa)
48
35
29
3.7
7.2
50
25
25
2.7
6.4
85
28
43
4.2
9.2
82
38
50
5.6
8.7
35
57
46
5.5
9.7
23
61
30
4.6
9.2
20b
–
25
4.2
7.0
61c
74
44
5.0
9.0
15
–
6.7
2.4
3.6
32
28
19
3.6
8.5
32
40
22
4.2
7.3
Kreisl [7] BV (BV ? IR after tumor progression) Raizer [19] BV Friedman [6] BV BV ? IR Vredenburgh [11] BV ? IR Vredenburgh [20] BV ? IR Bokstein [17] BV ? IR Narayana [18] BV ? IR or Carboplatin Verhoeff [24] BV ? TMZ Desjardins [10] BV ? TMZ Sepu´lveda (current study) BV ? TMZ
RR response rate, PFS-6 progression free survival at 6 months, OS overall survival, BV bevacizumab, CT chemotherapy, IR irinotecan, TMZ temozolomide a
Median PFS and median OS that were reported in weeks were standardized to months using the following formula: weeks/52 9 12
b
Three patients had anaplastic glioma
c
Twenty-four patients had anaplastic glioma
(standard adjuvant treatment). Moreover, the identification of accurate radiographic (i.e., early response) and biologic markers for predicting long-term benefit from BV therapy is awaited to identify subpopulations that are more likely to benefit from addition of BV, and that may in fact have an improved PFS and OS compared with other specific subpopulations. Acknowledgments Financial support for this research was provided by Roche Farma, S.A. Jesu´s Gonza´lez, MD (Pivotal CRO) provided advice for writing and submitting this paper. Conflict of interest Carmen Balan˜a´ has received honoraria from Roche, Merck Serono, and Novartis for lectures and advisory boards. Gaspar Reyne´s has received honoraria from Roche and Merck (previously Schering Plough) for lectures and advisory boards. Ethical standards The study was performed after approval by the Independent Ethics Committee of each site and in accordance with the Declaration of Helsinki, the Good Clinical Practices, and local ethical and legal requirements (Spanish laws). Before study entry, all patients provided written informed consent according to local ethical committee regulations.
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RESEARCH ARTICLE
A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma J. M. Sepu´lveda1 • C. Belda-Iniesta2 • M. Gil-Gil3 • P. Pe´rez-Segura4 • A. Berrocal5 • G. Reyne´s6 • O. Gallego7 • J. Capellades8 • J. M. Ordon˜ez9 • B. La Orden9 • C. Balan˜a´10
Received: 2 April 2015 / Accepted: 16 May 2015 / Published online: 2 June 2015 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2015
Abstract Purpose The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. Patients and methods Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m2 days 1–7 and 15–21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. Results Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44 %) had gross total resection. O6-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9 % (95 % CI 9.3–40.0 %). The median PFS and The results exposed in this manuscript are originals and have been presented in part as poster communication at the 2013 American Society of Clinical Oncology Annual Meeting (abstract 2087). & C. Balan˜a´ [email protected] 1
Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
2
Medical Oncology Department, Hospital Madrid Norte Sanchinarro, Madrid, Spain
3
Neuro-Oncology Unit, Institut Catala` d’Oncologia, Bellvitge, L’Hospitalet, Spain
4
Medical Oncology Department, Hospital Clı´nico San Carlos, Madrid, Spain
5
Medical Oncology Department, Consorcio Hospital General Universitario, Valencia, Spain
6
Medical Oncology Department, Hospital Universitari i Polite`cnic La Fe, Valencia, Spain
overall survival (OS) were 4.2 months (95 % CI 3.6–5.4 months) and 7.3 months (95 % CI 5.8–8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19 %; 95 % CI 7.2–36.4) were long-term survivors, with a median PFS and OS (50 % events) of 9.5 months (95 % CI 7.9–23.6) and 15.4 (95 % CI 8.9–NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. Conclusions This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy. Keywords Bevacizumab Glioblastoma Recurrent Temozolomide
7
Medical Oncology Department, Hospital De Sant Pau, Barcelona, Spain
8
Radiology Department, Hospital del Mar, Barcelona, Spain
9
Roche Farma SA, Madrid, Spain
10
Medical Oncology Department, Hospital Germans Trias i Pujol, Institut Catala d’Oncologia (ICO), Carretera Canyet sn, 08916 Badalona, Barcelona, Spain
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Introduction Glioblastoma (GB) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. The current standard of care for newly diagnosed GB is surgical resection followed by adjuvant radiotherapy (RT) with temozolomide (TMZ) [1, 2]. Median survival in newly diagnosed patients with best available treatments is 14.6 months. Hegi et al. identified a distinct survival advantage in patients with methylated O6methylguanine-DNA methyltransferase (MGMT) status receiving TMZ compared to those who received radiation alone, with a median survival of 21.7 versus 15.3 months, respectively [3, 4]. MGMT methylation has been established to be a prognostic factor, regardless of treatment modality. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy (CT), and RT, GB still has a dismal prognosis and nearly all patients will experience relapse of this aggressive cancer following first-line treatment. There are no widely accepted systemic therapies (approved or unapproved) for previously treated GB. Historically, the response rates for patients with recurrent GBs have been in the range of 5–10 %, with progression free survival (PFS) at 6 months (PFS6) seen in only 10–25 % of these patients [5]. Currently, many patients are offered no further therapeutic intervention after first-line treatment; others may be offered experimental treatments or marginally effective therapies. Many studies aim to overcome several determinants of resistance to conventional therapy by various approaches to improve the dismal prognosis of GB such as modifying TMZ administration and combining TMZ with other molecular-targeting agents. GB is characterized by sustained angiogenesis, the key regulator of which is vascular endothelial growth factor (VEGF). Bevacizumab (BV) (AvastinÒ; Genentech, Inc, San Francisco, CA, USA), a monoclonal antibody against VEGF, was granted accelerated approval on May 5, 2009 by the US Food and Drug Administration as a single agent for the treatment of patients with recurrent GBs that have failed initial therapy. That approval was based on the results of two studies, a randomized, non-comparative phase II trial (BRAIN study; AVF3708g) in GB patients who experienced first or second recurrence following standard of care with TMZ [6] and another phase II trial conducted by the National Cancer Institute (NCI) [7]. In the BRAIN study, patients received BV alone or in combination with irinotecan. In both, the BV (n = 85) and BV plus irinotecan (n = 82) cohorts, objective response rate (28.2 and 37.8 %) and PFS6 (42.6 and 50.3 %) were significantly higher than those of the external historical controls [6]. In other phase II trial, the 48 pretreated recurrent GB patients
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received BV in monotherapy, reaching a median PFS of 16 weeks, PFS6 of 29 % and a median overall survival (OS) of 31 weeks [7]. Recently, data of two phase III trials of BV for newly diagnosed GB have been presented [8, 9]. In both the studies, the addition of BV prolonged PFS but did not improve survival. On the basis of the promising results of prior studies of BV [6, 7, 10, 11], we conducted a prospective phase II, multicenter trial to evaluate the efficacy and safety of TMZ in combination with BV in patients with recurrent GB at first relapse, previously treated with chemoradiotherapy and TMZ. The 10 mg/kg/every 2-week schedule of BV was chosen based on the efficacy and safety observed in the same context when treating patients with recurrent GB [11]; the TMZ schedule ‘‘Week on/Week off’’ was selected based on the high rate of PFS6 reported with this scheme by Wick et al. [12, 13]. Additionally, we explored the possible association between the response reached with that regimen and the methylation status of MGMT gene.
Patients and methods Eligibility criteria Patients with confirmed GB at first relapse, having received prior chemoradiotherapy based on TMZ followed by at least three cycles of 5-day TMZ [1], were enrolled. Other inclusion criteria included Word Health Organization (WHO) performance status (PS) B2; adequate hepatic, renal, and bone marrow function; at least 4 weeks from completion of CT; and at least 3 months from last RT dose. Contraceptive measures were required for sexually active patients. Patients were excluded from participation if they had signs of recent brain hemorrhage on magnetic resonance imaging (MRI); history of bleeding diathesis or coagulopathy; previous treatment with BV; and other comorbidity conditions including uncontrolled hypertension and clinically significant cardiac disease (New York Heart Association, Class CII). Treatment schedule Patients received BV 10 mg/kg intravenously every 14 days, combined with TMZ 150 mg/m2 days 1–7 and 15–21 orally every 28 days (1 cycle = 28 days). Treatment was suspended in instances of attributably grade 3 or greater non-hematologic toxicity or grade 4 hematologic toxicity. Treatment was restarted when toxicity was resolved. Patients continued on treatment until disease progression, unacceptable toxicity or withdrawal of the informed consent form.
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Study assessments Before study entry, a routine blood analysis (hematology, coagulation, and biochemistry) was obtained, as well as urinalysis, an assessment of the WHO PS, and a complete physical exam (including comprehensive neurologic examination). In addition, patients underwent baseline MRI within 28 days before starting therapy and after every 2 cycles (8 weeks) on trial. PS, vital signs assessments, physical and neurologic examination, and urinalysis were repeated before each treatment cycle until final follow-up visit: blood counts were obtained every 2 weeks. Formalinfixed, paraffin-embedded tumor samples of initial biopsy were sent to a central laboratory for analysis of MGMT by methylation specific multiple ligation-dependent probe amplification (MS-MLPA) [14, 15]: tumors were classified as methylated or unmethylated. Tumor evaluation was indicated every two cycles by MRI obtained for each patient on study and measured the postcontrast enhancing lesions using the modified criteria described by Macdonald et al. [16]. MRI was done with a study-specific brain tumor protocol that included axial T1, T2, fluid attenuation inversion recovery (FLAIR), diffusion weighted imaging, apparent diffusion coefficient, sagittal T1, and postcontrast axial and coronal images [10]. Patients were followed until disease progression was documented. Toxicity was evaluated at the initiation of each cycle and until 90 days after the last study drug dose administration, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Statistical considerations The primary end point was PFS6, defined as the percentage of patients who were alive and progression free at that time. Using Kaplan–Meier methodology, we estimated PFS6 and associated 95 % confidence intervals (CIs). Target accrual was 32 patients with GB to distinguish between a 15 and 35 % PFS6, with \0.10 probability of concluding the combination is effective if PFS6 is \15 % and ineffective if PFS6 is more than 35 % [5], i.e., if C5 patients are alive and progression free at 6 months, the study combination warrants further research. Secondary end points were global PFS and OS, as well as overall response (OR): in addition to the response evaluation made by each investigator, a centralized imaging review was performed by an independent radiologist. Moreover, we undertook an exploratory analysis of how those responses are correlated with the methylation status of MGMT gen. All efficacy analyses were performed on the intention to treat (ITT) population, defined as all included patients. OS
745
was calculated from the inclusion in the study until time of death or the date of last follow-up if censored, and PFS was defined as the time between inclusion in the study and disease progression, death without progression, or last follow-up. Kaplan–Meier methods were used to estimate PFS6, median PFS, and median OS; the corresponding 95 % CIs were calculated. Frequency and percentage of response rate, together with the 95 % CIs, are presented. The statistical analyses were run using the SAS software package version 9.2.
Results Patient characteristics A total of thirty-two patients from eight Spanish centers were enrolled from June 2010 to July 2011. Table 1 Table 1 Patient characteristics No. of patients
%
Age (years) Median
57
Range
29–74
Sex Male
17
53
Female
15
47
0
8
25
1
16
50
2
8
25
22
69
10
31
Normal
11
34
Without clinic relevance
6
19
With clinic relevance
12
38
No data
3
9
Gross total
14
44
Subtotal
18
56
Curative
21
66
Palliative
11
34
Methylated
12
38
Unmethylated Missing
6 14
19 43
WHO performance status
Signs and/or symptoms present Yes No Neurologic examination
Initial tumor resection
Surgery intention
MGMT promoter methylation status
WHO World Health Organization, RT radiotherapy, CT chemotherapy, MGMT methylated O6-methylguanine-DNA methyltransferase
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Table 2 Adverse events related to treatment (C10 %) per patient (%) according to NCI-CTC criteria v3.0 (n = 32) Grade 1/2
Grade 1/2 (%)
Grade 3/4
Grade 3/4 (%)
Hematological toxicity Lymphocytopenia
6
19
10
31
Thrombocytopenia Neutropenia
12 3
38 9
2 2
6 6 6
Non-hematological toxicity Fatigue
10
31
2
Nausea
9
28
–
–
Hypertension
5
15
–
–
Hemorrhage
4
13
1a
3
Vomiting
3
9
1
3
An adverse event was considered attributable to bevacizumab, capecitabine or radiation if it was deemed remotely, possibly or probably related a
Intracranial hemorrhage
presents the basal characteristics of the patients. Eight patients (25 %) had a WHO PS of 2, and 22 (69 %) presented neurological symptoms. Treatment compliance All patients received at least one cycle of BV ? TMZ. Twenty-two patients died during the treatment due to disease progression and 8 patients prematurely discontinued the treatment (3 lost of follow-up, 2 adverse events, 1 consent withdrawal, 1 investigator criteria, and 1 disease progression). The median number of cycles completed was four for both drugs. Twelve patients (16 cycles) had at least one BV cycle interrupted, 8 of them due to hematological toxicity. One patient had to halt 2 cycles of BV and 5 patients 1 cycle each one, mainly due to non-hematological toxicity. TMZ dose was reduced in 5 cycles (3 cases of thrombocytopenia). Ten patients had to halt 1 TMZ cycle, one patient 2 cycles and another one 13 cycles, mainly due to thrombocytopenia and/or neutropenia. Safety All patients were evaluable for safety. Treatment-related toxicity occurring at a frequency [10 % of patients is summarized in Table 2. Eighteen (56 %) and twenty-seven (84 %) patients suffered any adverse event considered related to BV or TMZ, respectively. Grade 3–4 most frequent related toxicities were lymphopenia and fatigue. Five patients had grade 1–2 hypertension that was managed by oral medications, and 2 patients had grade 3–4 thrombosis. Cardiac dysfunction with heart failure symptoms was not observed. No patient died from treatment toxicity.
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Efficacy Seven patients were alive and progression free at 6 months, representing a PFS6 rate of 21.9 % (95 % CI 9.3–40.0 %). The median PFS and OS were 4.2 months (95 % CI 3.6–5.4 months) and 7.3 months (95 % CI 5.8–8.8 months), respectively (Fig. 1). Six of 32 pts (19 %; 95 % CI 7.2–36.4) were long-term survivors (defined as those patients with a PFS C30 weeks), with a median PFS and OS of 9.5 months (95 % CI 7.9–23.6) and 15.4 months (95 % CI 8.9–NA), respectively: no differences in baseline characteristics were identified in comparison with total population. Following investigator assessments, thirteen patients (40 %; 95 % CI 24–59 %) had an OR and 25 patients (78 %; 95 % CI 60–91 %) reached a disease control (OR ? stable disease): in Table 3, data are shown from the evaluations made by each investigator as well as those made centrally. The majority of patients experienced tumor shrinkage during the treatment period (Fig. 2). Eighteen patients underwent methylation status testing: in 12 (67 %) of them, methylation of the MGMT promoter was observed. No significant association with MGMT status was found in terms of OR (33 % methylated vs 50 % non-methylated), PFS (4.2 months methylated vs 3.9 months non-methylated) or OS (7.6 months methylated vs 7.3 months non-methylated).
Discussion This prospective phase II study confirms the feasibility of a combination of BV and TMZ in patients with recurrent GB at first relapse, previously treated with CT and TMZ. Most of patients experienced tumor shrinkage during the treatment period, and the observed PFS6 rate claim the regimen worth for further study. Nevertheless, the 6-month PFS appeared to be inferior to that of other prospective studies where BV was used alone or in combination with CT [6, 7, 10, 11, 17–20]. The primary endpoint of this study was PFS6 rate. Although comparisons over time and studies may be problematic, the PFS6 rate of 22 % seen in this study with the addition of BV to TMZ, albeit relatively not too high, is within the range 19–50 % reported across a number of phase II studies evaluating BV plus chemoradiotherapy (Table 4). One possible explanation for the inferiority of our study outcome compared with others using BV alone or in combination with CT (mainly with irinotecan), may be that our study population had worse prognostic factors. Prognosis is better for patients who undergo gross total resection than for patients who undergo subtotal resection or who cannot undergo surgery due to tumor location [21–
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Fig. 1 a Progression free survival (ITT population). b Overall survival (ITT population)
23]. Fifty-six percent of the patients in our study have had a partial resection, and 75 % of the patients had a WHO performance status of C1. Moreover, inclusion criteria mandated disease progression after TMZ therapy, and efficacy was rigorously evaluated by an independent radiology facility using the Macdonald modified criteria. Indeed, our data are similar to those published by other authors with the same combination (BV ? TMZ) and
where all patients were progressive after TMZ therapy [10, 24]. Kreisl et al. [7] treated 48 patients with recurrent GB with BV in monotherapy. They suggest that a BV-mediated antitumor effect occurs in a subpopulation of patients: patients who did not have PR on early MRI scans had a significantly shorter PFS. If no change in vascular permeability is seen on an early MRI scan, one may suppose that
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Table 3 Antitumor efficacy (intention to treat analysis: 32 patients)
Investigators reported response
Centralized reported imaging response
n
%
95 % CI
n
CR
2
6
1–21
1
3
PR
11
34
19–53
12
38
21–56
SD
12
38
21–56
9
28
14–47
PD
6
19
7–36
5
16
5–33
3
–
a
3
–
–
–
4
12
–
NE
1
NA
–
a
%
1
95 % CI 0–16
CR complete response, PR partial response, SD stable disease, PD progressive disease, NE non-evaluable, NA non-available a
Magnetic resonance imaging could not be done due to clinical deterioration: patient died 1 month later
Fig. 2 Maximum decrease from baseline sum of the products of diameters (SPD). The maximum percent decrease from baseline SPD was defined as the percent change in SPD from baseline to the minimum postbaseline SPD. Patients who had determined measurable disease at baseline and at least one postbaseline tumor assessment were included (n = 30). PD progression disease, SD stable disease, PR ? CR partial ? Complete response
VEGF inhibition is not being achieved with this regimen, conferring a low probability of long-term tumor control with BV. We found 6 patients who reached a PFS longer than 30 weeks: 5 of them presented an early response, at first evaluation (after 2 cycles of therapy). In our study, there was no evidence of a difference in OR, PFS, nor OS regarding the methylated status of MGMT gene: probably, that is due to the small number of patients for which MGMT methylated status was known. Also, as commented by Desjardins et al. [10], the use of archival tumor material to assess MGMT, which was derived from tumor samples obtained from original, pretreatment, surgical specimens, may not have reflected tumor MGMT status at study enrollment. However, Wick
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et al. [12] and Kong et al. [25] also described the absence of significant PFS and OS differences with regard to the methylation status of the MGMT promoter in their respective studies. Toxicities were expected and manageable. The incidence of BV-related adverse events in patients with GB was similar to that observed in previous BV ? CT trials [6, 7, 10, 11, 17–20, 24], and no patient died from treatment toxicity. In conclusion, the combination of BV and TMZ seems to be useful and safe in patients with recurrent GB. Randomized trials should be focused in determining whether TMZ adds any clinical benefit to treatment with BV, even in patients previously treated with TMZ
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Table 4 Prospective clinical trials of bevacizumab in recurrent glioblastoma Author and regimen
No. of patients
RR (%)
PFS-6 (%)
PFS-median (monthsa)
OS-median (monthsa)
48
35
29
3.7
7.2
50
25
25
2.7
6.4
85
28
43
4.2
9.2
82
38
50
5.6
8.7
35
57
46
5.5
9.7
23
61
30
4.6
9.2
20b
–
25
4.2
7.0
61c
74
44
5.0
9.0
15
–
6.7
2.4
3.6
32
28
19
3.6
8.5
32
40
22
4.2
7.3
Kreisl [7] BV (BV ? IR after tumor progression) Raizer [19] BV Friedman [6] BV BV ? IR Vredenburgh [11] BV ? IR Vredenburgh [20] BV ? IR Bokstein [17] BV ? IR Narayana [18] BV ? IR or Carboplatin Verhoeff [24] BV ? TMZ Desjardins [10] BV ? TMZ Sepu´lveda (current study) BV ? TMZ
RR response rate, PFS-6 progression free survival at 6 months, OS overall survival, BV bevacizumab, CT chemotherapy, IR irinotecan, TMZ temozolomide a
Median PFS and median OS that were reported in weeks were standardized to months using the following formula: weeks/52 9 12
b
Three patients had anaplastic glioma
c
Twenty-four patients had anaplastic glioma
(standard adjuvant treatment). Moreover, the identification of accurate radiographic (i.e., early response) and biologic markers for predicting long-term benefit from BV therapy is awaited to identify subpopulations that are more likely to benefit from addition of BV, and that may in fact have an improved PFS and OS compared with other specific subpopulations. Acknowledgments Financial support for this research was provided by Roche Farma, S.A. Jesu´s Gonza´lez, MD (Pivotal CRO) provided advice for writing and submitting this paper. Conflict of interest Carmen Balan˜a´ has received honoraria from Roche, Merck Serono, and Novartis for lectures and advisory boards. Gaspar Reyne´s has received honoraria from Roche and Merck (previously Schering Plough) for lectures and advisory boards. Ethical standards The study was performed after approval by the Independent Ethics Committee of each site and in accordance with the Declaration of Helsinki, the Good Clinical Practices, and local ethical and legal requirements (Spanish laws). Before study entry, all patients provided written informed consent according to local ethical committee regulations.
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