Director, Brain Metastasis Research Program

Dean and Diane Miller Family Endowed Chair in NeuroOncology

Although many new therapies have been introduced in a range of cancer types, brain metastases remain a serious neurological complication in patients with advanced malignancies. In the past, patients with a single brain metastasis were treated with surgery followed by some form of radiation. Patients with multiple brain metastases received either stereotactic radiosurgery or/and whole-brain radiation therapy. Traditional chemotherapy had a limited role in the treatment of these patients due to poor blood-brain barrier penetration.

Medical therapies are now increasingly coming to the frontline in the management of brain metastases, as novel agents have shown promising results in this patient population. The activity of targeted therapies and immunotherapies demonstrates the increased role of medical therapy in the management of patients with brain metastases, and it represents additional options for our patients.

The most common cancers that metastasize to the brain include lung cancer, breast cancer, and melanoma, and most of the medical therapy clinical trials have focused on these malignancies.

Lung cancer is the most common cause of brain metastases in patients with cancer. Tyrosine kinase inhibitors (TKIs) that target the EGFR pathway and ALK translocations have shown impressive results in this setting. Initial studies show good intracranial activity with the firstgeneration EGFR-targeting TKIs such as erlotinib and gefitinib in patients with non—small cell lung cancer (NSCLC). Sometimes, when the standard doses of targeted agents such as erlotinib are not effective, there is evidence for using higher pulsed doses of erlotinib.

The second-generation anti-EGFR TKIs have shown more promising intracranial responses in the subset of patients with the EGFR T790M mutation.

 The initial analyses from the phase II AURA study and expansion cohort reported an intracranial response rate of 56% to osimertinib, which targets the EGFR T790M resistance mutation.

 At the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, the initial results of the BLOOM study that evaluated AZD3759 in patients with EGFR-mutant NSCLC with leptomeningeal metastasis showed promising initial results.

Responses of approximately 50% were reported with avitinib, another drug specific to the EGFR T790M resistance mutation.

A number of drugs are approved for patients whose tumors harbor the ALK translocation. There are reports of increased incidence of brain metastases in patients treated with crizotinib, a first-generation ALK inhibitor that has limited penetration in the central nervous system (CNS).

 The next-generation ALK inhibitors such as alectinib and ceritinib have shown better intracranial activity. A phase I study of ceritinib showed intracranial response rates of 45%.

 A pooled analysis of patients with ALK translocation lung cancer and brain metastases treated with alectinib showed response rates in excess of 60%.

 Now that immunotherapy agents are being approved for metastatic NSCLC, studies are testing the intracranial activity in these patients. A preliminary report of 18 patients treated with pembrolizumab showed an intracranial response rate of 33% in the NSCLC arm.

Brain metastases are common in patients with metastatic breast cancer, particularly with HER2- positive or triple-negative disease.

 The limited CNS penetration of trastuzumab, an anti-HER2 monoclonal antibody, has been reported in various studies, with intracranial and leptomeningeal lesions being among the common sites of disease progression. Lapatinib is a TKI targeting the HER2 and EGFR receptors. The LANDSCAPE trial investigated the combination of lapatinib and capecitabine as a firstline combination therapy in patients without any local radiation therapies.

 An intracranial response of 66% was seen in 45 patients. At 2017 ASCO, a study of a combination of neratinib and capecitabine showed a CNS response of 49% (volumetric assessment) and 24% response rate by the criteria of the Response Assessment in Neuro-Oncology Brain Metastases working group.

Approximately 50% of patients with advanced melanoma develop brain metastases; about half of those with metastatic melanoma harbor BRAF mutations. Clinical trials have shown intracranial response rates of 30% to 40% with dabrafenib and approximately 20% with vemurafenib, both BRAF inhibitors.

 The combination of dabrafenib and trametinib, a MEK inhibitor, resulted in higher response rates of up to 58% in radiation-naïve patients with BRAF V600E mutations in the COMBI-MB trial.

 The use of ipilimumab, an anti— CTLA-4 antibody, resulted in higher responses in patients who were not receiving steroids when diagnosed with brain metastases compared with those who were taking steroids.

 Preliminary results of a phase II study of pembrolizumab in melanoma showed an intracranial response of 22%.

 Preliminary results from 2 trials reported at 2017 ASCO showed higher response rates of 50% to 55% with the combination of ipilimumab and nivolumab in patients with asymptomatic melanoma brain metastases.

Kris M, Arbour K, Riely G, Ni A, Beal K, Daras M, et al. Pulse-continuous dose erlotinib as initial targeted therapy for patients with EGFR-mutant lung cancers with untreated brain metastases. Journal of Clinical Oncology. 2017;35(9039).

Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. International journal of radiation oncology, biology, physics. 2013 Apr 1;85(5):1312-8. PubMed PMID: 23391814. Pubmed Central PMCID: PMC3740376. Epub 2013/02/09. Eng.

Ahn M, Tsai CM, Yang JCH, Shepherd FA, Satouchi M, Kim DW, et al. AZD9291 activity in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) and brain metastases: data from phase II studies. . European journal of cancer (Oxford, England : 1990). 2015;2015(51):S625—6.

Cho B, Ahn M, Lee J, Kim D, Kim S, John T, et al. Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy. Journal of Clinical Oncology. 2017;35(2069).

Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, et al. Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Aug 20;34(24):2858-65. PubMed PMID: 27022118. Epub 2016/03/30. eng.

Venur VA, Ahluwalia MS. Targeted Therapy in Brain Metastases: Ready for Primetime? American Society of Clinical Oncology educational book American Society of Clinical Oncology Meeting. 2016;35:e123-30. PubMed PMID: 27249714. Epub 2016/06/02. eng.

Gadgeel SM, Shaw AT, Govindan R, Gandhi L, Socinski MA, Camidge DR, et al. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non—Small-Cell Lung Cancer. Journal of Clinical Oncology.0(0):JCO684639.

Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. The Lancet Oncology. 2016 Jul;17(7):976-83. PubMed PMID: 27267608. Epub 2016/06/09. Eng.

Venur VA, Leone JP. Targeted Therapies for Brain Metastases from Breast Cancer. International Journal of Molecular Sciences. 2016;17(9):1543.

Bachelot T, Romieu G, Campone M, Dieras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. The Lancet Oncology. 2013 Jan;14(1):64-71. PubMed PMID: 23122784. Epub 2012/11/06. eng.

Freedman R, Gelman R, Melisko M, Anders C, Moy B, Blackwell K, et al. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). Journal of Clinical Oncology. 2017;35.

Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. The Lancet Oncology. 2012 Nov;13(11):1087-95. PubMed PMID: 23051966. Epub 2012/10/12. Eng.

Davies M, Robert C, Long L, Grob J, Flaherty K, Arance A, et al. COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600—mutant (mut) melanoma brain metastases (MBM). Journal of Clinical Oncology. 2017;35(9506).

Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. The Lancet Oncology. 2012 May;13(5):459-65. PubMed PMID: 22456429. Epub 2012/03/30. Eng.

Tawbi H, Forsyth P, Algazi A, Hamid O, Hodi S, Moschos S, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204. 

Articles

Although many new therapies have been introduced in a range of cancer types, brain metastases remain a serious neurological complication in patients with advanced malignancies.

Novel Agents Show Signs of Efficacy Against Brain Metastases

Manmeet Ahluwalia, MD, FACP, Miller Family Endowed Chair in Neuro-Oncology and Head of Operations, Burkhardt Brain Tumor NeuroOncology Center, discuses a new classification system for brain metastases.

Tumors are now classified based on molecular profiling, rather than the grade of the tumor. This allows oncologists to take a precision medicine approach to treatment, and use targeted therapies to go after actionable mutations, says Ahluwalia.

The goal is to minimize the toxicities of treatment while maximizing the benefit, he adds.

Patients with brain metastases are unique, says Ahluwalia, as patients have many different primary tumors. Lung cancer is the most common cause of brain metastases.

Every patient should be treated differently, and their extracranial disease as well as the disease of the brains should be considered.

The patient should also be treated with a multidisciplinary approach.

View more from the 2016 SNO Annual Meeting

Videos

Manmeet Ahluwalia, MD, FACP, Miller Family Endowed Chair in Neuro-Oncology and Head of Operations, Burkhardt Brain Tumor NeuroOncology Center, discuses a new classification system for brain metastases.
 

Manmeet Ahluwalia, MD, FACP

Articles

Novel Agents Show Signs of Efficacy Against Brain Metastases

Dr. Ahluwalia on Using Precision Medicine to Treat Brain Metastases