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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

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Abstract

Purpose

Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3′deoxy-3′-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases.

Methods

A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study.

Results

13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7–10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUVmax of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients.

Conclusions

Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases.

Trial and Clinical Registry

Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).

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Data availability

The datasets generated during and/or analyzed during the current study may be available from the corresponding author on reasonable request after an institutional and sponsor review and approval.

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Funding

Bayer (phase I trial, ADS), Susan G. Komen Foundation (FLT imaging, ADS), and American Society of Clinical Oncology Gianni Bonadonna Breast Cancer Research Fellowship (AM).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Aki Morikawa

  2. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Milan Grkovski & John L. Humm

  3. Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sujata Patil

  4. Breast Cancer Medicine Service, Evelyn Lauder Breast Center, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA

    Komal L. Jhaveri, Kendrick Tang & Andrew D. Seidman

  5. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrei Holodny & Heiko Schöder

  6. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kathryn Beal

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  1. Aki Morikawa
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Correspondence to Andrew D. Seidman.

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Conflict of interest

ADS: research support (Novartis, Bayer, Odonate, Nektar), consulting (Genomic Health, Genentech, Novartis, Lilly, Pfizer, Odonate, Nektar, Immunomedics), speaker (Genomic Health, Genentech, Novartis, Lilly, Pfizer, Immunomedics). AM: research support (Novartis, Lilly, Takeda Millenium, Eisai/H3B Biomedicine, Seattle Genetics, Pfizer/National Comprehensive Cancer Network) and consulting (Lilly). KJ: Consultant/Advisory Board (Novartis, Spectrum pharmaceuticals, ADC Therapeutics, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech, Synthon, Abbvie, Astra Zeneca, Lilly Pharmaceuticas) and research support (Novartis, Clovis Oncology, Genentech, Astra Zeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals, Zymeworks, Immunomedics, Puma Biotechnology).

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The authors confirm that the study was approved by the appropriate ethics committee (Memorial Sloan Kettering Institutional Review Board) and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Morikawa, A., Grkovski, M., Patil, S. et al. 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. Breast Cancer Res Treat 188, 415–425 (2021). https://doi.org/10.1007/s10549-021-06209-4

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