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Bevacizumab in Patients with Non-Squamous Non-Small-Cell Lung
Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): a
Non-Randomised, Phase II Study
Benjamin Besse1, Sylvestre Le Moulec2, Julien Mazières3, Hélène Senellart4, Fabrice
Barlesi5, Christos Chouaid6, Eric Dansin7, Henri Bérard8, Lionel Falchero9, Radj
Gervais10, Gilles Robinet11, Anne-Marie Ruppert12, Roland Schott13, Hervé Léna14,
Christelle Clément-Duchêne15, Xavier Quantin16, Pierre Jean Souquet17, Jean
Trédaniel18, Denis Moro-Sibilot19, Maurice Pérol20, Anne-Catherine Madroszyk21, and
Jean-Charles Soria1
1Institut Gustave Roussy, Villjuif, France; 2Hôpital d'Instruction des Armées du Val-de-
Grâce, Paris, France; 3CHU Toulouse - Hôpital De Larrey, Toulouse, France; 4Institut
De Cancérologie De l'Ouest, Site René Gauducheau, France; 5Aix-Marseille University,
Assistance Publique Hôpitaux de Marseille, Marseille, France; 6CHI Crétiel, Crétreil,
France; 7CLCC Oscar Lambret, Lille, France; 8Hôpital d’Instruction des Armées Sainte
Anne, France; 9L'Hôpital Nord Ouest, Villefranche Sur Saone, France); 10Centre
François Baclesse, Caen, France; 11CHU Morvan, Brest, France; 12Hôpital Tenon,
APHP, Paris, France; 13Centre Paul Strauss, Strasbourg, France; 14CHU Rennes,
Hôpital Pontchaillou, Rennes, France; 15Hôpital de Brabois, Vandoeuvre-lès-Nancy,
France; 16CHU Montpellier and ICM Val d’Aurelle, Montpellier, France; 17Centre
Hospitalier de Lyon Sud, Lyon, France; 18Hôpital Saint-Joseph, Paris, France; 19CHU
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De Grenoble, Hôpital A. Michalon, La Tronche, France; 20Centre Leon Bérard, Lyon,
France; and 21Institut Paoli Calmettes, Marseille, France
Running title: Bevacizumab in NSCLC patients with asymptomatic brain metastases
Keywords: Bevacizumab, NSCLC, brain metastases, asymptomatic, erlotinib
Corresponding author:
Dr Benjamin Besse
Mailing address:Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805,
France
Phone number: +33 142114322
Fax number: +33 142115219
E-mail address: [email protected]
Disclosure of Potential Conflicts of Interest: BB has received research funding from
Roche Genentech. HS received honoraria from Roche and Novartis. FB has consulted
for Roche and received honoraria and research funding from Roche. CC has received
research funding from Roche, Lilly, and Amgen. ED has received honoraria from Roche,
AstraZeneca, and Boehringer Ingelheim. RS has received honoraria from Roche. HL
has consulted for Roche and Lilly and received honoraria from Roche. XQ has received
honoraria from Roche. PJS has consulted for Roche, received honoraria from Roche,
Amgen, Pfizer, Boehringer Ingelheim, and Lilly, and received research funding from
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Roche. DMS has consulted for Roche and received honoraria from Roche. MP has
consulted for Roche-Genentech and Lilly and received honoraria from Roche and Lilly.
J-CS has consulted for Roche. SLM, JM, HB, LF, RG, GR, A-MR, CCD, JT, and A-CM
declare that they have no competing interests.
Word count (excluding references): 4,031
Total number of figures and tables: 6
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Statement of Translational Relevance
The development of brain metastases is common in patients with advanced non-small-
cell lung cancer (NSCLC). Systemic treatments have often not been considered for
brain metastases due to the complexities of crossing the blood–brain barrier. To our
knowledge, BRAIN is the first prospective study to investigate bevacizumab-based
regimens in both a first-line and second-line setting in patients with NSCLC and
asymptomatic brain metastases. The results suggested that a bevacizumab-based
regimen is capable of eliciting an intracranial response and might offer an alternative
treatment option for patients with NSCLC and asymptomatic brain metastases, instead
of the current option of whole brain radiotherapy. Further prospective research is
needed in this subgroup to validate the initial findings presented in this exploratory
phase II trial.
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Abstract
Background: The phase II prospective, non-comparative BRAIN study (NCT00800202)
investigated efficacy and safety of bevacizumab in chemotherapy-naive or pretreated
patients with non-small-cell lung cancer (NSCLC) and asymptomatic untreated brain
metastases, to provide data in this previously unexplored subgroup.
Methods: Patients with stage IV non-squamous NSCLC, Eastern Cooperative
Oncology Group performance status 0–1, and untreated, asymptomatic brain
metastases received first-line bevacizumab (15 mg/kg) plus carboplatin [area under the
curve ×6] and paclitaxel (200 mg/m2) every 3 weeks (B+CP), or second-line
bevacizumab plus erlotinib (150 mg/day) (B+E) until unacceptable toxicity or disease
progression. Primary endpoint: 6-month progression-free survival (PFS). The trial could
be stopped if there were more than three (B+CP) or more than two (B+E) intracranial
hemorrhages.
Findings: In first-line B+CP cohort (n = 67), 6-month PFS rate was 56.5% with a
median PFS of 6.7 months (95% CI, 5.7–7.1) and median overall survival (OS) of
16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in
intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n =
24), efficacy results for the second-line B+E cohort were exploratory only; 6-month PFS
rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0–8.4), median OS was
12.0 months, and ORR was 12.5%. Adverse events were comparable with previous
trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved
without sequelae.
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Conclusion: The BRAIN study demonstrates encouraging efficacy and acceptable
safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC
and asymptomatic, untreated brain metastases.
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Introduction
The development of brain metastases is common in patients with advanced non-
small-cell lung cancer (NSCLC), occurring in 24 to 44% of patients (1–3), more
frequently in patients with adenocarcinoma histology. Brain metastases often lead to
deterioration in neurological and neurocognitive function (1) and are associated with
significant morbidity (4), including a risk of spontaneous hemorrhage at a rate of 1.4 to
10% (average of 2 to 3%) (5). The primary score used to predict prognosis of patients
with brain metastases remains the recursive partitioning analysis (RPA) score, which
splits patients into three classes (class 1: patients with Karnofsky performance status
≥70% and age <65 years with controlled primary and no extracranial metastases; class
3: KPS <70%; class 2: all others) (6–9). Most patients are RPA class 3 with a prognosis
of 2 months, or RPA class 2 with a prognosis of 6 months (10). Recently, a new
prognostic index was reported – the graded prognostic assessment – which takes into
account the number of metastases to give a score from 0 to 4 (4 representing the best
prognosis) (11).
Whole-brain radiotherapy (WBRT) represents the standard treatment for NSCLC
brain metastases (12), based on improvements in survival (13). Because the blood–
brain barrier is disrupted in the presence of brain metastases (14, 15), systemic
treatments could potentially offer an alternative to WBRT. In a phase II study, the
response rate of brain metastases to pemetrexed–cisplatin before WBRT was
numerically superior to that of extracranial metastases: 41.9% versus 34.9%,
respectively (16). It has been demonstrated that WBRT can be delayed until the end of
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initial cisplatin-based chemotherapy without impacting overall survival (OS) (17).
Furthermore, a retrospective analysis of a phase III study of 175 patients with NSCLC
and brain metastases suggested that use of multiple systemic treatments allows the
delay of WBRT and its associated morbidity until the appearance of neurological
symptoms, without decreasing OS (18).
Bevacizumab is a recombinant monoclonal antibody targeting VEGF. First-line
treatment of non-squamous NSCLC in the phase III Eastern Cooperative Oncology
Group (ECOG) 4599 trial reported a longer median OS for bevacizumab plus paclitaxel
and carboplatin compared with paclitaxel and carboplatin alone (19). Bevacizumab in
combination with erlotinib [an epidermal growth factor receptor (EGFR) tyrosine-kinase
inhibitor (TKI)] as a second-line treatment in unselected patients with non-squamous
NSCLC (20) significantly prolonged progression-free survival (PFS) but not OS
compared with erlotinib alone (21). Patients with central nervous system (CNS)
metastases were initially excluded from bevacizumab clinical trials after the occurrence
of a fatal cerebral hemorrhage in the phase I study (22). However, the brain metastasis
contraindication was removed from the EU Summary of Product Characteristics in 2009
after the submission of comprehensive safety data (23). Retrospective analysis of
clinical trial data demonstrated that three (3.3%) of 91 bevacizumab-treated patients
with brain metastases experienced CNS bleeding (grade 4), compared with one (1%,
grade 5) of 96 patients who were not exposed to bevacizumab (24).
Although brain metastases are a very common and clinically challenging
progression of NSCLC, there are few prospective studies addressing the management
of asymptomatic patients with NSCLC brain metastases. In the BRAIN study (ML21823,
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NCT00800202) the BRAIN investigators sought to prospectively explore the safety and
efficacy of bevacizumab either in combination with chemotherapy or with erlotinib in
chemotherapy-naive or pretreated patients with NSCLC, respectively.
Materials and Methods
Study design and patients
BRAIN was an open-label, non-comparative, non-randomized, multicenter, phase
II study assessing bevacizumab in two separate arms of patients with metastatic non-
squamous NSCLC and asymptomatic brain metastases. In one arm, bevacizumab was
assessed in combination with chemotherapy in the first-line setting, and in the other
non-comparative arm (all efficacy and safety data are detailed in the Appendix)
bevacizumab plus erlotinib was assessed in the second-line setting after failure of
platinum-based chemotherapy. The two arms were assessed independently of one
another and were not compared. Having two independent arms approved in one
protocol allowed investigators the freedom to enroll patients into either arm depending
on the line of therapy required by their patient.
The main inclusion criteria were: patients ≥18 years of age with an ECOG
performance status (PS) of 0 to 1, with asymptomatic, untreated brain metastases, at
least one measurable lesion (not exclusively applying to brain metastases) according to
Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematological,
hepatic, and renal function. Exclusion criteria included symptomatic, treated, or
hemorrhagic brain metastases, brain metastases only amenable to surgical treatment or
radiosurgery (according to the investigators’ institutional guidelines), previous anti-
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angiogenic treatment or neoadjuvant or adjuvant chemotherapy ≤6 months before
enrollment to the first-line arm, or a history of hemoptysis or poorly controlled arterial
hypertension. No maximum number of lesions was specified and steroid treatment was
not allowed.
Patients were not selected based on EGFR mutation status in either arm
because EGFR testing was not widely performed at the time of study initiation. EGFR
mutation analysis was optional and was performed at the discretion of the investigator, if
part of their routine practice. EGFR mutation status was retrospectively collected from
patient notes where available. All EGFR assays were performed at investigational sites
by either high-resolution melting or sequencing. All patients were required to provide
written informed consent. The trial was approved by local independent ethics
committees, including an independent review board, and complied with the Declaration
of Helsinki and Good Clinical Practice principles.
Study treatment
Patients received paclitaxel 200 mg/m2 and carboplatin AUC ×6 every 3 weeks
for a maximum of six cycles, plus concomitant then maintenance bevacizumab (15
mg/kg every 3 weeks) until disease progression or unacceptable toxicity (B+CP first-line
arm). Second-line bevacizumab plus erlotinib (B+E) treatment is detailed in the
appendix.
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Assessments
Assessments were performed every two cycles, including chest–abdomen scans
and mandatory MRI scans for assessment of brain metastases. The occurrence of brain
hemorrhage was monitored by the sponsor and the independent Data Safety Monitoring
Board. If more than three patients in the first line had a clinically significant intracranial
hemorrhage [symptomatic, with National Cancer Institute Common Terminology Criteria
for Adverse Events (AEs) grading ≥2] occurring between first administration of
bevacizumab and up to 60 days after bevacizumab discontinuation, the study arm
would be stopped.
Study endpoints
The primary endpoint was investigator-assessed 6-month PFS rate, a frequently
used and clinically meaningful endpoint in trials of brain tumors, as it gives an early
window of opportunity to assess efficacy and reduces time-dependent assessment bias
introduced by visit or image frequency (25, 26). Secondary endpoints were investigator-
assessed overall response rate (ORR) according to RECIST, median PFS, median OS,
and safety. Exploratory endpoints included response rates of brain metastases
assessed by the investigator and by independent radiological review, investigator-
assessed response rates of extracranial lesions, duration of response of brain
metastases in patients with measurable brain disease, and benefit of treatment in
patients with known EGFR mutation-positive NSCLC. Further exploratory biomarker
data will be presented in a separate publication.
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Statistical methods
A single-step Fleming method was used to calculate the sample size, using an
alpha risk of 2.5% and a beta risk of 10%. The predefined criteria for first-line B+CP 6-
month PFS rate was ≤30% (H0) and ≥50% (H1). This required 66 patients to
demonstrate the efficacy of first-line B+CP. Treatment efficacy would be proven if the
lower limit of the confidence interval (CI) was above the predefined minimum threshold
of efficacy, with the point estimate above the predefined threshold of interest. The
statistical assumptions were based on previous trial data (19, 21). PFS at 6 months and
median PFS and OS were analyzed using Kaplan–Meier methodology with 95% CIs; for
response rates, 95% CIs were estimated using the Pearson–Clopper method.
The intention-to-treat (ITT) population included all patients enrolled; patients who
did not undergo any post-enrollment evaluations were not included in the ITT
population. The safety population included all patients who received at least one dose of
study treatment.
Results
Between April 2009 and April 2011, a total of 91 patients (all RPA class 2) were
enrolled into the BRAIN trial in 22 centers in France. All 91 patients enrolled and treated
in this study were included in the ITT and safety populations: 67 patients in B+CP and
24 patients in B+E. The data cut-off date was December 13, 2012. Results of the B+CP
cohort only are given here. For results from the second-line B+E cohort see the
Appendix.
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Patient characteristics
A total of 67 patients were enrolled into the first-line B+CP cohort. Patient
disposition is shown in Fig. 1 and baseline characteristics are given in Table 1. A total of
24 patients prematurely withdrew or discontinued any study treatment (16 due to AEs,
one due to death, seven due to patient or investigator decision). EGFR mutation status
testing was optional and was collected from 42 patients; six patients were positive for
EGFR mutations (four exon 19 deletions, two exon 21 mutations). Median follow-up was
16.3 months. Median duration of exposure to bevacizumab was eight cycles.
Efficacy outcomes
Investigator-assessed ORR in the ITT population was 62.7% (95% CI, 50.0–
74.2) (Fig. 2 and Supplementary Table S1); the response rate of brain metastases by
independent radiological review was 61.2% (48.5–72.9; n = 41) (individual patient
responses are shown in Fig. 2). The response rate of extracranial lesions was 64.2%
(95% CI, 51.5–75.5). The median duration of brain metastases response in patients with
measurable brain disease (n = 29) was 8.1 months (95% CI, 5.5–11.3). Progression
was the most frequent cause for bevacizumab withdrawal (89.6%): intracranial
progression in 20.9%, extracranial progression in 50.7% of patients, and progression at
both sites in 9% of patients.
Median PFS was 6.7 months (95% CI, 5.7–7.1) (Fig. 3A) and the median OS was
16.0 months (12.0–21.0) (Fig. 3B). The 6-month PFS and 12-month OS rates were
56.5% (95% Cl, 43.8–67.4) and 64.2% (51.5–74.4), respectively. As the lower 95% CI
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for 6-month PFS was above the predefined threshold (30% for this arm), the primary
endpoint was met.
Efficacy results according to EGFR mutation status are shown in Table 2. The 6-
month PFS rate for patients with EGFR mutation-positive disease was 50.0%, with
those testing as EGFR wild-type having a 6-month PFS rate of 58.5%.
Post-study therapy
Among the B+CP patients, 85.1% received post-study therapy: 82.1% received
at least one systemic cancer treatment (most common treatments were pemetrexed
64.2% and erlotinib 47.8%); 13.4% received radiotherapy for NSCLC; and 3.0%
underwent surgery. All six patients with confirmed EGFR mutation-positive NSCLC went
on to receive EGFR TKI therapy after disease progression. A total of 33 patients
received WBRT for their metastases, and the median time to WBRT was 12.7 months
(range: 2.8 to 34.7 months).
Safety
One intracranial hemorrhage (ICH) event (grade 1) occurred, which resolved.
This patient received their last dose of bevacizumab 21 days before that event, and
disease progression was determined to have occurred simultaneously with the event.
The investigator considered this event related to progression and bevacizumab. A total
of 27 (40.3%) patients experienced serious AEs, the most common being neutropenia
(23.9%). There was one serious AE, a case of epilepsy not considered to be related to
treatment, that led to death in this group. Grade ≥3 AEs occurred in 83.6% of patients
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in the first-line cohort, and grade ≥3 AEs of special interest occurred in 19.4% of
patients (Table 3). The most common grade ≥3 AEs (>10%) were neutropenia (43.3%)
and thrombocytopenia (11.8%).
Discussion
To our knowledge, the exploratory phase II BRAIN study represents the first
prospective study of bevacizumab in patients with non-squamous NSCLC and untreated
brain metastases.
The primary endpoint of 6-month PFS rate met the protocol-defined criteria for
first-line treatment (B+CP). The overall safety profile was consistent with that of patients
with NSCLC without brain metastases (19–21). In the ECOG 4599 study, the treatment
scheme was similar (first-line bevacizumab plus paclitaxel and carboplatin) and resulted
in a median OS of 12.3 months and a median PFS of 6.2 months (19) compared with
16.0 and 6.7 months, respectively, in the BRAIN B+CP arm. The favourable outcomes
in BRAIN compared with E4599, may be due to differences in baseline characteristics,
including the increased number of patients with ECOG PS 0, as these patients could be
more likely to respond well to treatment.
In patients with brain metastases, the current standard of care, WBRT, results in
a median survival of 4.0 months from diagnosis of brain metastases (12). In patients
with multiple brain metastases in the phase III RTOG 9508 trial of WBRT with or without
radiosurgery boost, first-line WBRT without radiosurgery boost resulted in median OS of
6.7 months (27). In a first-line phase III study of early versus delayed WBRT plus
chemotherapy in patients with NSCLC and inoperable brain metastasis, OS was 23
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weeks (5.3 months) (17). The difference in discontinuation due to intracranial
progression compared with extracranial progression seen in BRAIN (20.9 vs 50.7% in
B+CP, 16.7 vs 54.2% in B+E) may suggest that bevacizumab-based regimens provide
a better control of intracranial metastases. In BRAIN, a total of 33 patients received
WBRT post-study. A retrospective analysis of a NSCLC cohort treated with
bevacizumab followed by WBRT, showed no increased toxicity with this treatment
regimen, with median survival from WBRT of 3.2 months (28). Furthermore the
REBECA trial has confirmed that combined bevacizumab and WBRT appears tolerable
for brain metastases treatment (29).
The B+E efficacy results were also encouraging in second-line therapy (see
Appendix); however, owing to the small number of patients, the efficacy analysis in this
arm was of a descriptive nature only. The lack of mandatory epidermal growth factor
receptor mutation analysis further limits the value of the B+E analysis. The phase III
BeTa study of bevacizumab plus erlotinib in patients with NSCLC who failed first-line
treatment, reported a median OS of 9.3 months, a median PFS of 3.4 months, and an
ORR of 13%, compared with 12.0 months, 6.3 months, and 12.5%, respectively, in this
study (21).
All measures of efficacy were promising compared with historical data for both
cohorts as demonstrated above. It is acknowledged that these historical comparisons
are with patients who were not known to have brain metastases at baseline. Overall
survival of 16.0 and 12.0 months for the first and second line arms, respectively, are
favorable outcomes for patients with asymptomatic brain metastases, a poorly
investigated group to date. As a comparison, the expected median OS would have been
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6 months since all patients included in the current study cohorts were RPA class 2. The
historical dataset however included patients regardless of neurological symptoms (9). It
is important to note that the BRAIN study enrolled only patients with asymptomatic brain
metastases, therefore comparisons of this selected population with outcomes and data
derived from patients presenting with symptomatic brain metastases cannot be reliably
made. However, the most appropriate historical controls available have been discussed.
With regard to ORR, tumor burden was assessed on a 6-weekly scanning schedule in
both study cohorts. It is unlikely that we over-estimated the response assessments
because the independent radiological review, which was done only on the brain MRI,
resulted in a similar assessment of ORR (Table 2 and Appendix Table 2).
Response rates were similar for brain metastases compared with other
metastatic sites. Optimising the intracranial control with systemic treatment could have
delayed the neurological symptoms indicative of recurrence, theoretically leading to the
safe postponement of WBRT to the time of central nervous system (CNS) disease
progression.
Although there were previous safety concerns regarding the use of bevacizumab
in patients with brain metastases, the incidence of ICH in this study was low and similar
to historical controls in NSCLC without brain metastases, although direct cross-trial
comparisons should be viewed with caution (30–32). One could hypothesise that the
small lesions described in the study (mean size 13 mm) might be less likely to bleed, or
perhaps have less intracranial edema. In this study, one ICH event (grade 1) was
reported in the B+CP arm, whereas no ICH events were reported in the B+E cohort. A
retrospective analysis identified three patients with grade 4 cerebral hemorrhage out of
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91 bevacizumab-treated patients with NSCLC and brain metastases in randomized
controlled trials (24). Retrospective analyses of patients with NSCLC and treated brain
metastases in the ATLAS and PASSPORT studies reported no grade >2 hemorrhages
(n = 85) (32). A recent evidence-based review was carried out on the risk of CNS
hemorrhage in NSCLC patients receiving anti-VEGF therapy, which concluded that
there was no significantly increased risk of CNS hemorrhage associated with anti-VEGF
therapy (33). The most common grade ≥3 AEs reported in BRAIN (neutropenia and
thrombocytopenia) were as expected for a B+CP regimen.
These findings are interesting when considered in the light of expected outcomes
for patients with brain metastases secondary to primary NSCLC where the median
prognoses are poor. The favorable outcomes in BRAIN for both treatment groups might
be explained by numerous factors, such as the highly selected population, and the
absence of patients with ECOG PS 2. Of note, patients were screened and enrolled in
this study and treated before they became symptomatic and required steroids. In a real-
life setting, while brain computed tomography scans may be included in initial diagnosis
and subsequent follow-up visits, some patients may present with neurological
symptoms before screening and therefore before treatment for intracranial disease can
begin. Therefore, it is possible that the BRAIN results may indicate a degree of lead-
time bias. Additionally the use of frequent brain MRIs may have resulted in inclusion of
patients with very small brain metastases that would prove more responsive than larger
metastases. It must be noted, however, that although these practices are a real-life
issue in the authors’ institutions, this may not be consistent in a global setting. The high
proportion of patients with adenocarcinoma histology (88.1% of the B+CP group) might
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also help to explain the results, because this subgroup has been observed to derive a
greater benefit from bevacizumab-based therapy (34). High post-study treatment rates
(85.1%) might also have influenced OS. Activating mutations of the EGFR are also
known to influence patient outcomes, especially when such patients receive EGFR TKIs
as part of their treatment regimen. EGFR mutation testing was not mandated by this
study; however, the protocol was amended to allow the collection of pre-existing test
results from the patients’ records where available. Definitive results were not available
for all patients. Six patients in the B+CP arm were found to have EGFR mutation-
positive disease, all of whom received EGFR TKIs as part of their post-progression
therapy. None of the ten samples evaluated for EGFR mutations out of the 24 patients
who received B+E was positive, and efficacy was not better in patients with unknown or
unevaluable EGFR mutation status. This could argue against an enrichment of EGFR
mutated tumors; however, it is difficult to draw firm conclusions from this small patient
group.
Overall, the BRAIN data appear to be favorable and consistent with the E4599
and BeTa Lung results. However, this interpretation should be placed in the context of
small cohort sizes and the absence of control arms. There are also potential issues with
cross-trial comparisons, where patients with brain metastases were previously excluded
from trial treatment. To date, no clinical trials are planned or ongoing in this particular
patient population; however, further investigation to confirm these phase II findings
would be helpful.
Conclusion
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The BRAIN study indicated that B+CP demonstrated promising activity in the
first-line treatment of patients with NSCLC and asymptomatic, untreated brain
metastases according to prespecified criteria. The B+E combination showed a potential
efficacy signal in second-line therapy; however, owing to the low number of patients
enrolled, analysis of the B+E cohort was of a descriptive nature only. The incidence and
intensity of ICH was low and comparable with that expected in bevacizumab-treated
historical controls without brain metastases, as was the overall safety profile. BRAIN is
the first study in patients with NSCLC and asymptomatic, untreated brain metastases.
Although the data have not yet been validated in a larger trial, they suggest that
bevacizumab-based systemic treatment may be an alternative approach to WBRT
followed by chemotherapy in this highly selected population.
Contributors
All authors contributed to manuscript writing or revising and had final approval of the
manuscript. BB, FB, and J-CS designed the study and collected, assembled, analysed,
and interpreted the data. DMS and GR designed the study. JM, AMR, CC, MP, and
SLM collected, assembled, analysed, and interpreted the data. HB, LF, ED, JT, HS, HL,
ACM, XQ, RS, JPS, and RG collected and assembled the data. CCD analysed and
interpreted the data.
Acknowledgments: We would like to acknowledge the participating clinicians and
patients and the BRAIN study team past and present.
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Grant Support: This study was supported by F. Hoffmann-La Roche Ltd. Medical
writing support was funded by F. Hoffmann-La Roche Ltd.
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Tables
Table 1: Characteristics of patients at baseline (data are
NSCLC patients with
asymptomatic brain metastases,
treated with
bevacizumab+paclitaxel+carbopl
atin (n = 67)a
Sex
Male 46 (69%)
Female 21 (31%)
Age, years 61 (40–79)
ECOG performance status
0 37 (55%)
1 30 (45%)
Histology
Adenocarcinoma 59 (88%)
Large cell carcinoma 8 (12%)
Recurrence of previous lung cancer
No 61 (91%)
Yes 6 (9%)
Additional metastatic sites
Lymph nodes 36 (54%)
Liver 17 (25%)
Adrenal 14 (21%)
Pleura 4 (6%)
Bone 34 (51%)
Other 16 (24%)
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Median diameter per lesion, mm 13.5
Median number of target brain lesions at baselineb
0 26 (39%)
1 30 (45%)
2 11 (16%)
Smoking status
Past smoker 33 (49%)
Current smoker 20 (30%)
Never smoker 14 (21%)
Recursive partitioning analysis class
2 67 (100%)
EGFR mutation status
Tested 42 (63%)
Positive 6 (14%)
Exon 19 mutations 4
Exon 21 mutations 2
Negative 34 (81%)
Sample not evaluable 2 (5%)
No data available 0
aData are n (%) or median (range). bAll patients in the study had brain lesions [target (i.e., measurable) or
non-target].
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Table 2. PFS, OS, and response rates according to EGFR mutation status in 67 patients treated with bevacizumab plus
paclitaxel and carboplatin
EGFR mutation positive (n = 6)a EGFR wild type (n = 34)a Non-evaluable (n = 27)a
6-month PFS (95% CI) 50% (11.1–80.4) 58% (40.2–73.0) 56% (35.2–71.8)
Median PFS (95% CI), months 6·0 (3.9–10.2) 6·7 (5.4–7.5) 6·6 (5.4–7.1)
Median OS (95% CI), months 29·5 (16.0–33.7) 13·1 (8.1–21.3) 15·2 (8.3–21.0)
12-month survival rate (95% CI) 100% (100) 59% (40.6–73.2) 63% (42.1–78.1)
18-month survival rate (95% CI) 83% (27.3–97.5) 41% (24.8–56.9) 37% (19.6–54.6)
Responders 6 (100%) 21 (62%) 15 (56%)
Complete response 0 0 0
Partial response 6 (100%) 21 (62%) 15 (56%)
Stable disease 0 7 (21%) 11 (41%)
Progressive disease, n (%) 0 5 (15%) 1 (4%)
Missing, n (%) 0 1 (3%) 0
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Table 3: Overview of AEs in 67 patients treated with bevacizumab plus paclitaxel and
carboplatin
Bevacizumab plus
paclitaxel and
carboplatin (n = 67)a
Any AE 67 (100%)
Serious AEs 27 (40%)
Grade 3–5 AEs 56 (84%)
Grade 5 AEs (leading to death) 1 (2%)b
Patients who discontinued bevacizumab treatment due to AE 8 (12%)
Grade 3–5 AESIs
Total patients with at least one grade 3–5 AESIc 13 (19%)
Bevacizumab-related AESIs
Thromboembolic events (venous) 7 (10%)
Hypertension 2 (3%)
Proteinuria 3 (4%)
Thromboembolic events (arterial) 1 (2%)
Bleeding event (post-procedural hematoma) 0
Erlotinib-related AESIs 0
Diarrhoea 0
Rash 0
AESI = adverse events of special interest.
aAll data are n (%).
bEpilepsy.
cPatients may have had more than one AESI.
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Figure Legends
Figure 1. Trial profile. B+CP = bevacizumab plus carboplatin and paclitaxel, B+E =
bevacizumab plus erlotinib.
Figure 2. Response rates for patients treated with first-line bevacizumab plus
carboplatin and paclitaxel and waterfall plots for best overall response. (A)
Response rates for primary tumours and metastases, (B) best overall response for
primary tumours in individual patients, (C) best overall response for brain lesions, (D)
best overall response for extracranial lesions. *These patients had new lesions
despite having a reduction in the primary lesion so were classed as having a best
overall response of progressive disease.
Figure 3. Kaplan–Meier curves for first-line treatment with bevacizumab plus
carboplatin and paclitaxel. (A) Progression-free survival, (B) overall survival.
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Published OnlineFirst January 22, 2015.Clin Cancer Res Benjamin Besse, Sylvestre Le Moulec, Julien Maazieres, et al. (BRAIN): a Non-Randomised, Phase II StudyLung Cancer and Asymptomatic, Untreated Brain Metastases Bevacizumab in Patients with Non-Squamous Non-Small-Cell
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