Bevacizumab in Patients with Non-Squamous Non-Small-Cell … · 2015. 2. 5. · FB has consulted...

1

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

on May 2, 2021. © 2015 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on January 22, 2015; DOI: 10.1158/1078-0432.CCR-14-2082

http://clincancerres.aacrjournals.org/

2

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




3

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




4

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.




5

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.




6

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.




7

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




8

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,




9

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-




10

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.




11

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.




12

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.




13

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




14

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




15

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




16

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




17

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




18

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




19

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




20

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.




21

Grant Support: This study was supported by F. Hoffmann-La Roche Ltd. Medical

writing support was funded by F. Hoffmann-La Roche Ltd.




22

References

1. Langer CJ, Mehta MP. Current management of brain metastases, with a focus on

systemic options. J Clin Oncol 2005;23:6207–19.

2. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep

2012;14:48–54.

3. Ding X, Dai HH, Hui ZG, Ji W, Liang J, Lv J, et al. Risk factors of brain metastases

in completely resected pathological stage IIIA-N2 non-small cell lung cancer.

Radiat Oncol 2012;7:119.

4. Tsao MN, Lloyd N, Wong RKS, Chow E, Rakavitch E, Laperriere N.Whole brain

radiotherapy for the treatment of newly diagnosed multiple brain metastases.

Cochrane Database Syst Rev 2012;4:CD003869.

5. Yoo H, Jung E, Gwak HS, Shin SH, Lee SH. Surgical outcomes of hemorrhagic

metastatic brain tumors. Cancer Res Treat 2011;43:102–7.

6. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-

specific prognostic factors, indexes, and treatment outcomes for patients with

newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.

Int J Radiat Oncol Biol Phys 2010;77:655–61.

7. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive

partitioning analysis (RPA) of prognostic factors in three radiation therapy

oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys

1997;37:745–51.

8. Nieder C, Nestle U, Motaref B, Walter K, Niewald M, Schnabel K. Prognostic

factors in brain metastases: should patients be selected for aggressive treatment




23

according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol

Phys 2000;46:297–302.

9. Chaubet-Houdu M, Besse B, Le Pechoux C, Le Chevalier T. Management of brain

metastases in non-small cell lung cancer. Cancer Chemother Rev 2012;7(1).

10. Videtic GM, Reddy CA, Chao ST, Rice TW, Adelstein DJ, Barnett GH, et al.

Gender, race, and survival: a study in non-small-cell lung cancer brain metastases

patients utilizing the radiation therapy oncology group recursive partitioning

analysis classification. Int J Radiat Oncol Biol Phys 2009;75:1141–47.

11. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index

and comparison to three other indices for patients with brain metastases: an

analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys

2008;70:510–4.

12. Ricciardi S, de Marinis F. Multimodality management of non-small cell lung cancer

patients with brain metastases. Curr Opin Oncol 2010;22:86–93.

13. Tsao MN, Rades D, Wirth A, Lo SS, Danielson BL, Gaspar LE, et al.

Radiotherapeutic and surgical management for newly diagnosed brain

metastasis(es): an American Society for Radiation Oncology evidence-based

guideline. Pract Radiat Oncol 2012;2:210–25.

14. Zhang RD, Price JE, Fujimaki T, Bucana CD, Fidler IJ. Differential permeability of

the blood-brain barrier in experimental brain metastases produced by human

neoplasms implanted into nude mice. Am J Pathol 1992;141:1115–24.

15. Fortin D. The blood-brain barrier: its influence in the treatment of brain tumors

metastases. Curr Cancer Drug Targets 2012;12:247–59.




24

16. Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, Paillotin D, et al. Pemetrexed

and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer

(NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II

trial (GFPC 07-01). Ann Oncol 2011;22:2466–70.

17. Robinet G, Thomas P, Breton JL, et al. Results of a phase III study of early versus

delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine

combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe

Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol 2001;12:59–

67.

18. Chaubet-Houdu M, Le Pechoux C, Lanoy E, Bouda D, Besse B. Multimodal

strategy may improve survival in non-small cell lung cancer (NSCLC) patients (pt)

with brain metastases (BM). Ann Oncol 2012;23(Suppl 9):Abstr 1284P.

19. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-

carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J

Med 2006;355:2542–50.

20. Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, et al.

Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal

antibody bevacizumab in combination with the HER-1/epidermal growth factor

receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell

lung cancer. J Clin Oncol 2005;23:2544–55.

21. Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of

bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung




25

cancer after failure of standard first-line chemotherapy (BeTa): a double-blind,

placebo-controlled, phase 3 trial. Lancet 2011;377:1846–54.

22. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, et al.

Phase I safety and pharmacokinetic study of recombinant human anti-vascular

endothelial growth factor in patients with advanced cancer. J Clin Oncol

2001;19:843–50.

23. Avastin® Summary of Product Characteristics. 2014.

http://www.medicines.org.uk/emc/medicine/15748/SPC/ (Accessed on April 08,

2014).

24. Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab

safety in patients with central nervous system metastases. Clin Cancer Res

2010;16:269–78.

25. Polley MY, Lamborn KR, Chang SM, Butowski N, Clarke J, Prados M. Six-month

progression-free survival as an alternative primary efficacy endpoint to overall

survival in newly diagnosed glioblastoma patients receiving temozolomine. Neuro

Oncol 2010;12:274–82.

26. Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, et al.

Progression-free survival: an important end point in evaluating therapy for

recurrent high-grade gliomas. Neuro Oncol 2008;10:162–70.

27. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al.

Whole brain radiation therapy with and without stereotactic radiosurgery boost for

patients with one to three brain metastases: phase III results of the RTOG 9508

trial. Lancet 2004;363:1665–72.




26

28. Arroundeau J, Le Pecheoux C, Le Moulec S, Barlesi F, Lesueur P, Besse B.

Bevacizumab safety when combined with whole-brain radiotherapy (WBRT). J

Thorac Oncol 2014;9 (suppl 1):S49–50.

29. Levy C, Allouache D, Lacroix J, Dugue A, Supiot S, Campone M, et al. REBECA: a

phase I study of bevacizumab and whole-brain radiation therapy for treatment of

brain metastasis from solid tumours. Ann Oncol 2014; Epub ahead of print.

30. Dansin E, Cinieri S, Garrido P, Griesinger F, Isla D, Koehler M, et al. MO19390

(SAiL): bleeding events in a phase IV study of first-line bevacizumab with

chemotherapy in patients with advanced non-squamous NSCLC. Lung Cancer

2012;76:373–9.

31. Archer V, Reck M, Sandler AB, et al. Risk of symptomatic central nervous system

(CNS) progression and secondary hemorrhage in patients with non-squamous

non-small cell lung cancer (NSCLC) receiving bevacizumab (BV)-based first-line

therapy. J Clin Oncol 2008;26(Suppl):Abstr 8114.

32. Akerley WL, Langer CJ, Oh Y, Strickland DK, Joo Royer S, Xia Q, et al.

Acceptable safety of bevacizumab therapy in patients with brain metastases due to

non-small cell lung cancer. J Clin Oncol 2008;26(Suppl 20):Abstr 8043.

33. Sandler A, Hirsh V, Reck M, von Pawel J, Akerley W, Johnson DH. An evidence-

based review of the incidence of CNS bleeding with anti-VEGF therapy in non-

small cell lung cancer patients with brain metastases. Lung Cancer 2012;78:1–7.

34. Sandler A, Yi J, Dahlberg S, et al. Treatment outcomes by tumor histology in

Eastern Cooperative Group Study E4599 of bevacizumab with




27

paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol

2010;5:1416–23.




28

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%)




29

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].




30

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

on May 2, 2021. ©

2015 Am

erican Association for C

ancer Research.

clincancerres.aacrjournals.org D

ownloaded from

Author m

anuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Author M

anuscript Published O

nlineFirst on January 22, 2015; D

OI: 10.1158/1078-0432.C

CR

-14-2082


31

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.




32

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.




Published OnlineFirst January 22, 2015.Clin Cancer Res Benjamin Besse, Sylvestre Le Moulec, Julien Mazieres, et al. (BRAIN): a Non-Randomised, Phase II StudyLung Cancer and Asymptomatic, Untreated Brain Metastases Bevacizumab in Patients with Non-Squamous Non-Small-Cell

Updated version

10.1158/1078-0432.CCR-14-2082doi:

Access the most recent version of this article at:

Material

Supplementary

http://clincancerres.aacrjournals.org/content/suppl/2015/01/23/1078-0432.CCR-14-2082.DC1

Access the most recent supplemental material at:

Manuscript

Authoredited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://clincancerres.aacrjournals.org/content/early/2015/02/05/1078-0432.CCR-14-2082To request permission to re-use all or part of this article, use this link



http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-14-2082

http://clincancerres.aacrjournals.org/content/suppl/2015/01/23/1078-0432.CCR-14-2082.DC1

http://clincancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://clincancerres.aacrjournals.org/content/early/2015/02/05/1078-0432.CCR-14-2082


Bevacizumab in Patients with Non-Squamous Non-Small-Cell … · 2015. 2. 5. · FB has consulted...

Documents

Transcript of Bevacizumab in Patients with Non-Squamous Non-Small-Cell … · 2015. 2. 5. · FB has consulted...