Published OnlineFirst January 22, 2015; DOI: 10.1158/1078-0432.CCR-14-2082
Clinical Cancer Research
Cancer Therapy: Clinical
Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study res3, He le ne Senellart4, Benjamin Besse1, Sylvestre Le Moulec2, Julien Mazie 5 6 7 rard8, Lionel Falchero9, Fabrice Barlesi , Christos Chouaid , Eric Dansin , Henri Be 10 11 12 Le na14, Radj Gervais , Gilles Robinet , Anne-Marie Ruppert , Roland Schott13, Herve 15 16 17 ment-Duche ^ ne , Xavier Quantin , Pierre Jean Souquet , Jean Tre daniel18, Christelle Cle 19 20 21 rol , Anne-Catherine Madroszyk , and Denis Moro-Sibilot , Maurice Pe Jean-Charles Soria1
Abstract Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-na€ve or pretreated patients with non– small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup. Experimental Design: Patients with stage IV nonsquamous 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 þ CP), or second-line bevacizumab plus erlotinib (150 mg/d; B þ E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B þ CP) or more than two (B þ E) intracranial hemorrhages.
1
Gustave Roussy, Villejuif France and Paris Sud University, France. ^ pital d'Instruction des Arme es du Val-de-Gra ^ ce, Paris, France. Ho 3 ^ pital De Larrey, Toulouse, France. 4Institut De CHU Toulouse – Ho rologie De l'Ouest, Site Rene Gauducheau, France. 5Aix-MarCance ^ pitaux de Marseille, Marseille, seille University, Assistance Publique Ho tiel, Cre treil, France. 7CLCC Oscar Lambret, Lille, France. 6CHI Cre ^ pital d'Instruction des Arme es Sainte Anne, France. France. 8Ho 9 ^ pital Nord Ouest, Villefranche Sur Saone, France. 10Centre L'Ho ^ pital Fran¸cois Baclesse, Caen, France. 11CHU Morvan, Brest, France. 12Ho Tenon, APHP, Paris, France. 13Centre Paul Strauss, Strasbourg, France. 14 ^ pital Pontchaillou, Rennes, France. 15Ho ^ pital de CHU Rennes, Ho s-Nancy, France. 16CHU Montpellier and ICM Brabois, Vandoeuvre-le Val d'Aurelle, Montpellier, France. 17Centre Hospitalier de Lyon Sud, ^ pital Saint-Joseph, Paris, France. 19CHU De GrenoLyon, France. 18Ho rard, ^ pital A. Michalon, La Tronche, France. 20Centre Leon Be ble, Ho Lyon, France. 21Institut Paoli Calmettes, Marseille, France.
Results: In first-line B þ CP cohort (n ¼ 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (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 ¼ 24), efficacy results for the second-line B þ 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. Conclusions: 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. Clin Cancer Res; 21(8); 1896–903. 2015 AACR.
Introduction
2
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Benjamin Besse, Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France. Phone: 33-142114322; Fax: 33142115219; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-14-2082 2015 American Association for Cancer Research.
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 neurologic 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%; ref. 5). The primary score used to predict prognosis of patients with brain metastases remains the recursive partitioning analysis (RPA) score, which splits patients into 3 classes (class 1: patients with Karnofsky performance status 70% and age
Clinical Cancer Research
Cancer Therapy: Clinical
Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study res3, He le ne Senellart4, Benjamin Besse1, Sylvestre Le Moulec2, Julien Mazie 5 6 7 rard8, Lionel Falchero9, Fabrice Barlesi , Christos Chouaid , Eric Dansin , Henri Be 10 11 12 Le na14, Radj Gervais , Gilles Robinet , Anne-Marie Ruppert , Roland Schott13, Herve 15 16 17 ment-Duche ^ ne , Xavier Quantin , Pierre Jean Souquet , Jean Tre daniel18, Christelle Cle 19 20 21 rol , Anne-Catherine Madroszyk , and Denis Moro-Sibilot , Maurice Pe Jean-Charles Soria1
Abstract Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-na€ve or pretreated patients with non– small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup. Experimental Design: Patients with stage IV nonsquamous 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 þ CP), or second-line bevacizumab plus erlotinib (150 mg/d; B þ E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B þ CP) or more than two (B þ E) intracranial hemorrhages.
1
Gustave Roussy, Villejuif France and Paris Sud University, France. ^ pital d'Instruction des Arme es du Val-de-Gra ^ ce, Paris, France. Ho 3 ^ pital De Larrey, Toulouse, France. 4Institut De CHU Toulouse – Ho rologie De l'Ouest, Site Rene Gauducheau, France. 5Aix-MarCance ^ pitaux de Marseille, Marseille, seille University, Assistance Publique Ho tiel, Cre treil, France. 7CLCC Oscar Lambret, Lille, France. 6CHI Cre ^ pital d'Instruction des Arme es Sainte Anne, France. France. 8Ho 9 ^ pital Nord Ouest, Villefranche Sur Saone, France. 10Centre L'Ho ^ pital Fran¸cois Baclesse, Caen, France. 11CHU Morvan, Brest, France. 12Ho Tenon, APHP, Paris, France. 13Centre Paul Strauss, Strasbourg, France. 14 ^ pital Pontchaillou, Rennes, France. 15Ho ^ pital de CHU Rennes, Ho s-Nancy, France. 16CHU Montpellier and ICM Brabois, Vandoeuvre-le Val d'Aurelle, Montpellier, France. 17Centre Hospitalier de Lyon Sud, ^ pital Saint-Joseph, Paris, France. 19CHU De GrenoLyon, France. 18Ho rard, ^ pital A. Michalon, La Tronche, France. 20Centre Leon Be ble, Ho Lyon, France. 21Institut Paoli Calmettes, Marseille, France.
Results: In first-line B þ CP cohort (n ¼ 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (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 ¼ 24), efficacy results for the second-line B þ 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. Conclusions: 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. Clin Cancer Res; 21(8); 1896–903. 2015 AACR.
Introduction
2
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Benjamin Besse, Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France. Phone: 33-142114322; Fax: 33142115219; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-14-2082 2015 American Association for Cancer Research.
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 neurologic 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%; ref. 5). The primary score used to predict prognosis of patients with brain metastases remains the recursive partitioning analysis (RPA) score, which splits patients into 3 classes (class 1: patients with Karnofsky performance status 70% and age
