Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study

Abstract

Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-na€ ve or pretreated patients with nonsmall 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 Â6) and paclitaxel (200 mg/m 2 ) 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.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.

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…82 Some efficacy with acceptable safety has been suggested in a phase II study of patients with asymptomatic untreated brain metastases from NSCLC with bevacizumab in combination with paclitaxel and carboplatin (class IIb). 83 A recent early analysis of a phase II trial of the programmed cell death protein 1 inhibitor pembrolizumab has shown activity in untreated or previously irradiated brain metastases from NSCLC, 84 but the trial is still ongoing.…”

Systemic therapy of brain metastases: non–small cell lung cancer, breast cancer, and melanoma

“…Intracranial responses with cytotoxic chemotherapy usually correlate with systemic responses in patients with NSCLC. Intracranial response rates as high as 68% have been reported with chemotherapy in asymptomatic patients 81 ; however, PFS is usually limited to several months, and OS ranges from 5 to 16 months (Table 4). The best intracranial outcomes were achieved using regimens containing cisplatin and pemetrexed 82,83 or bevacizumab, carboplatin, and paclitaxel.…”

Anti-angiogenetic therapies for central nervous system metastases from non-small cell lung cancer

“…An increasing body of evidence indicates that the use of bevacizumabbased therapy seems to be feasible and safe in patients with CNS metastases from NSCLC (33). Moreover first-line bevacizumab in combination to standard chemotherapy demonstrated promising activity in patient with asymptomatic BM from NSCLC in the BRAIN trial (36). Even if treated CNS metastases were allowed in phase II (47,48) and III (46) with ramucirumab, no data are actually available about the efficacy of ramucirumab in this subgroup of patients.…”

“…Besse et al conducted a non-randomized, phase II trial to investigate bevacizumab-based regimens in both first and second line setting in patients with NSCLC and asymptomatic, untreated BM (BRAIN trial) (36). Sixtyseven patients were treated with first line bevacizumab in combination with carboplatin and paclitaxel and 24 patients received second line bevacizumab in combination with erlotinib.…”