Abstract P1-19-03: A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib
Authors: Morikawa A , Jhaveri K , Grkovski M , Tang K , Humm JL , Holodny A , Beal K , Schoder H , Seidman AD 
Published: May 2019

Abstract
Background: WBRT is a standard therapy for metastatic breast cancer (MBC) patients (pts) with brain metastases (BM), but disease progression in the brain is common. Sorafenib, a tyrosine kinase inhibitor with anti-VEGF activity, has demonstrated anti-tumor efficacy in MBC and radiosensitizing activity preclinically. [18F] 3'deoxy-3'-fluorothymidine (FLT) is a new PET tracer which correlates with cellular proliferation and may improve response assessment in the brain. Methods: A phase I trial of sorafenib with WBRT in MBC pts with BM was conducted using a 3+3 design. Sorafenib was given orally daily at the start of WBRT for a total of 21 days with 3 doses levels: 200mg, 400mg, and 600mg. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was central nervous system progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment with serial MRI brain imaging. Key eligibility criteria include MBC with new or progressive ≥ 1cm BM, ECOG PS 0-2, non-escalating corticosteroid dose, and no other concurrent anti-tumor therapy except trastuzumab. In parallel, we conducted a correlative FLT-PET imaging study (baseline, 7-10 days (FU1), and 10-12 weeks (FU2) after the WBRT) to assess radiographic changes among pts receiving WBRT + sorafenib and in a separate WBRT only cohort. FLT standard uptake value (SUV) and kinetic parameter data were obtained. Results: 13 pts were treated in the dose escalation phase and evaluable for dose-limiting toxicity (DLT). The median age was 56 years (range: 43-77). There were 4 HER2 positive (31%) and 3 triple negative (23%) pts. 2 pts had prior stereotactic radiosurgery. DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was determined to be 200mg. 10 pts were evaluable for response (at least 1 follow up brain imaging). The overall response rate was 70%: 4 complete responses (CR) + 3 partial responses. All 13 pts were evaluated for CNS PFS with a median follow up of 29.7 months (min 19.6, max 57.4mo). Median CNS-PFS was 8.2 months (95%CI: 3.4-31.8). Median OS was 15.4 months (95% CI: 3.4-NR). A total of 10 pts with WBRT and sorafenib and 5 pts with WBRT only were enrolled in the FLT-PET study: all 15 pts had baseline FLT PET, 14 with FU1, and 9 with FU2. 55 baseline lesions, 38 at FU1 and 15 at FU2 were observed and analyzed. All lesions with FLT uptake had MRI correlates. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib and 2/4(50%) of WBRT only pts at FU1. A complete disappearance of FLT uptake was noted in 1 pt at FU1 and 2 more pts at FU2. Conclusions: Concurrent WBRT with sorafenib appears safe at 200mg daily dose with a higher rate of CR compared to historical WBRT data. We are currently enrolling patients in the safety-expansion cohort. This combination should be considered for further efficacy evaluation. Additional analysis of FLT-PET as a complementary imaging modality to MRI is currently ongoing. Clinical trial registry: NCT01724606 and NCT01621906. Support: Bayer, Susan G Komen, ASCO Gianni Bonadonna Breast Cancer Award
Citation Format: Morikawa A, Jhaveri K, Grkovski M, Tang K, Humm JL, Holodny A, Beal K, Schoder H, Seidman AD. A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-03.