Novel Agents Show Signs of Efficacy Against Brain Metastases

Director, Brain Metastasis Research Program

Professor, Department of Medicine

Dean and Diane Miller Family Endowed Chair in NeuroOncology

Neurological Institute

Cleveland Clinic

Cleveland, Ohio

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.

Lung Cancer

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.¹ The second-generation anti-EGFR TKIs have shown more promising intracranial responses in the subset of patients with the EGFR T790M mutation.² 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.² 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.³ Responses of approximately 50% were reported with avitinib, another drug specific to the EGFR T790M resistance mutation.

Breast Cancer

Melanoma

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).⁴ 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%.^5,6 A pooled analysis of patients with ALK translocation lung cancer and brain metastases treated with alectinib showed response rates in excess of 60%.⁷ 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.⁸Brain metastases are common in patients with metastatic breast cancer, particularly with HER2- positive or triple-negative disease.⁹ 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.¹⁰ 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.¹¹Approximately 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.^12,13 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.¹⁴ 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.¹⁵ Preliminary results of a phase II study of pembrolizumab in melanoma showed an intracranial response of 22%.⁸ 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.^{16, 17}

References

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2. 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.
3. 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.
4. 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).
5. 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.
6. 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.
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9. 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.
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12. 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.
13. 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.
14. 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.
15. 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).
16. 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.
17. 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.
18. 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. Journal of Clinical Oncology. 2017;35(9507).