July 2015, Special ASCO Edition
Targeted and Immunologic Approaches to Brain Metastases
Targeted agents and immunotherapeutic approaches hold promise for the treatment of patients with brain metastases, which occur in up to 30% of adults with cancer. Given that most cancer patients die of metastases rather than their primary tumor, and the potentially devastating effects of central nervous system (CNS) impairment due to brain metastases, they represent cancer’s most serious neurologic challenge.
At an educational session, Manmeet S. Ahluwalia, MD, Cleveland Clinic, OH; Frank Winkler, MD, University of Heidelberg, Germany; and Minesh P. Mehta, MD, University of Maryland School of Medicine, Baltimore, endorsed a multidisciplinary approach to the treatment of brain metastases involving surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and systemic therapeutic agents. The multidisciplinary team consists of a neurosurgeon, a medical oncologist, and a radiation oncologist.
At this time, there is no level 1 evidence to recommend the use of systemic treatment over local agents. However, newer cytotoxic agents and targeted therapies with better blood-brain barrier penetration have become available in the past few years, providing some optimism about using systemic therapies to treat brain metastases.
Agents that target epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase mutations are of particular interest in this regard because they target the brain endothelial cell, the main cell type to react to angiogenic growth factors produced by tumor cells. The panel addressed the current status of these modalities in the treatment of brain metastases arising from the most common cancers that metastasize to the brain: tumors of the lung, HER2-positive breast cancer, and melanoma.
The brain is the most common site of lung cancer metastasis. Forty percent to 50% of patients with non–small cell lung cancer (NSCLC) develop brain metastases. Mutated or overactive EGFR occurs in 10% to 15% of NSCLC, providing a target for reversible tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib.
A signal from a small phase 2 trial of 40 patients with NSCLC and brain metastases suggested benefit of erlotinib as a radiation sensitizer with no additional neurotoxicity when given in combination with WBRT (J Clin Oncol. 2013;31:895-902). However, the benefit did not hold up in a phase 3 study (RTOG 0320) when erlotinib was given with WBRT and SRS. The panel suggested that the results of this study may have been compromised because patients in the study were not stratified according to EGFR mutational status. Higher response rates with EGFR inhibitors are seen in studies of patients with known EGFR mutations.
The most significant advances in systemic treatment of brain metastases have occurred in patients with HER2-positive breast cancer, where the gains are primarily due to the availability of HER2-targeted agents. One-third of patients with advanced HER2-positive breast cancer develop brain metastases, and one-half of them die of them.
89Zr-trastuzumab PET imaging has shown that trastuzumab emtansine (T-DM1) has the ability to cross a disrupted blood-brain barrier resulting in a CNS response in a limited number of patients in this subset. Patients receiving T-DM1 seem to get some additional benefit from continuing the drug after breast cancer brain metastases have developed.
The small-molecule TKI lapatinib has also had some positive results. The combination of this agent with capecitabine resulted in a 20% objective response rate in the brain in 10 of 50 patients with disease progression in a phase 2 study of HER2-positive breast cancer (J Clin Oncol. 2008;26:1993-1999). This same combination achieved an objective response rate of 64% (29 of 45 patients) in previously untreated patients with HER2-positive breast cancer with brain metastases in the LANDSCAPE study.
Other agents to watch that are under study include the HER2 inhibitors neratinib, afatinib, and ARRY-380.
Nearly half of melanoma metastases occur in the brain, and patients with BRAF, NRAS, and KIT mutations are at higher risk for brain metastases.
Several studies indicate promising activity for BRAF-targeted therapies. The BRAF inhibitor dabrafenib has activity against tumors with BRAF V600E and V600K mutations. In the open-label phase 2 BREAK-MB study, a 39% (29 of 74 patients) intracranial response rate was seen in patients with BRAF V600K mutations treated with dabrafenib monotherapy. The effectiveness of dabrafenib administered in combination with SRS against BRAF V600E mutations is currently being assessed in an ongoing study (NCT01721603).
According to the panel, another BRAF inhibitor, vemurafenib, also has shown promise in both a pilot study (Eur J Cancer. 2014;50:611-621) and in a phase 2 trial (Kefford R, et al. Society for Melanoma Research Congress; 2013). Partial responses, tumor regression, and intracranial objective response rates were seen in these trials.
The monoclonal antibody ipilimumab is also being tested in the treatment of brain metastases from melanoma. Favorable responses were seen with ipilimumab in combination with fotemustine in a prospective, open-label, single-arm phase 2 trial (Lancet Oncol. 2012;13:879-886). Intracranial disease control was achieved in 50% of 29 melanoma patients in the study with asymptomatic brain metastases. Five patients had either stable disease or a partial response, and 5 had a complete response.
The panel also noted that both nivolumab and pembrolizumab have shown some durable responses in metastatic melanoma. Pembrolizumab is currently in a phase 2 study of patients with brain metastases from NSCLC and melanoma.
Combinations of the new targeted and immunotherapeutic agents with local treatments require prospective clinical trials to more fully assess their potential and identify optimal applications, the panel agreed.
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