Case Report
Brain Metastasis and Response to Ado-Trastuzumab Emtansine: A Case Report and Literature Review Richa Kalsi,1 Steven Feigenberg,2 Young Kwok,2 Katherine Tkaczuk,1 Minesh Mehta,2 Saranya Chumsri3 Clinical Practice Points Despite promising preclinical studies that demon-
strated the ability of lapatinib to cross the bloodebrain barrier (BBB), single-agent lapatinib only has modest central nervous system (CNS) activity. However, higher response rates were observed with the combination of lapatinib and capecitabine. Despite the relatively large molecular size of trastuzumab, results of some studies suggest that trastuzumab can cross the disrupted BBB, especially in patients with leptomeningeal carcinomatosis.
Furthermore, radiation can further facilitate permeation of the BBB. The combination of trastuzumab and capecitabine provides better systemic control compared with lapatinib and capecitabine, especially in trastuzumab-naive patients. The incidence of CNS progression as the first site of relapse is low in trastuzumab and lapatinib combinations. Ado-trastuzumab emtansine might also cross the BBB, but its true level of activity in the CNS is inadequately defined.
Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Ado-trastuzumab emtansine, CNS metastasis, HER2, Lapatinib, Radiation
Introduction Since the advent of HER2-targeted therapies, systemic control and overall survival of patients with HER2-positive (HER2þ) breast cancer have drastically improved. However, brain metastases (BM) continue to pose a major challenge and become increasingly common.1,2 Previous studies suggest that 28% to 43% of patients treated with trastuzumab develop BM.3,4 Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of trastuzumab backbone attached by a stable linker to a potent antimicrotubule agent, emtansine (DM1).5 T-DM1 has the ability to combine the HER2-specific antitumor activity of trastuzumab with the cytotoxic effects of DM1, and allow the intracellular delivery of chemotherapy drug directly to HER2-overexpressing cells and sparing non-HER2-expressing tissues. T-DM1 has been 1 Department of Medicine, University of Maryland School of Medicine, The Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 2 Department of Radiation Oncology, University of Maryland School of Medicine, The Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 3 Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
Submitted: Sep 22, 2014; Accepted: Oct 15, 2014 Address for correspondence: Saranya Chumsri, MD, Mayo Clinic Florida, 4500 San Pablo Rd S, Jacksonville, FL 32224 Fax: 904-953-2315; e-mail contact:
[email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.10.003
shown to improve progression-free survival (PFS) and overall survival (OS) with substantially less toxicity compared with a chemotherapy combination in metastatic HER2þ breast cancer patients.5,6 Despite this promising activity systemically, there are limited data on the activity of T-DM1 in BM. In this case report, we present a patient with advanced HER2þ breast cancer whose brain responded markedly to T-DM1 therapy after disease progression with multiple lines of chemotherapy and radiation therapy.
Case Report A 28-year-old female presented for treatment of unresectable inflammatory breast cancer that was positive for estrogen (90%) and progesterone receptor (40%) with high Ki-67 (> 90%), and HER2þ. She initially received 6 cycles of TCH (docetaxel, carboplatin, and trastuzumab) and progressed during this therapy. Subsequently, she was referred to our institute and was treated with multiple lines of therapies, including the combination of a panhistone deacetylase inhibitor, vorinostat, and lapatinib in a phase II trial followed by ixabepilone, trastuzumab, and lapatinib. She had an excellent response and was considered for surgery. However, the patient was lost to follow-up and presented several months later with lymphedema due to lymph node progression. At that time, she was found to have multiple asymptomatic BM and received whole-brain
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Brain Metastasis and Response to Ado-Trastuzumab Emtansine radiation (WBRT), palliative right breast, and ablative ovarian radiation to a total dose of 20 Gy (in 8 fractions of 2.5 Gy per fraction) because of transportation limitations for a longer treatment course. Three months after completion of WBRT and during fulvestrant, trastuzumab, and lapatinib treatment, she developed progressive BM, and WBRT was repeated to a total dose of 20 Gy, also in 8 fractions of at 2.5 Gy per fraction. She subsequently received multiple lines of trastuzumab-containing regimens, including gemcitabine, eribulin, and vinorelbine. Approximately 5 months after the second course of WBRT, she developed further intracranial progression and underwent frameless stereotactic radiotherapy to the 2 symptomatic lesions in her brainstem and left cerebellum, and received 18 Gy in 3 fractions. After approval of pertuzumab, her treatment was switched to pegylated liposomal doxorubicin, trastuzumab, and pertuzumab during which her disease progressed systemically after 3 cycles. The treatment was switched to T-DM1 and after 3 cycles, her follow-up brain magnetic resonance imaging (MRI) scan showed a striking central nervous system (CNS) improvement, including several lesions that did not receive radiosurgical treatment (Figure 1). The superficial and deep enhancing metastatic lesions in cerebral and cerebellar hemispheres, and the brainstem all decreased in size. The largest cerebral lesion in the thalamus decreased from 20 mm to 9 mm and the largest cerebellar lesion diminished from 25 mm to 20 mm. The edema and original midline shift associated with these lesions also almost entirely resolved.
Discussion The HER2-targeted therapies, mainly lapatinib and trastuzumab, have been shown to have only modest single-agent activity in the
CNS.7,8 Because of the large size of monoclonal antibodies, there is doubt as to the ability of trastuzumab to penetrate the bloodebrain barrier (BBB). In the normal state, it had been shown that trastuzumab penetrates the BBB poorly with a plasma:cerebrospinal fluid (CSF) drug concentration ratio of 420:1.9 Furthermore, several retrospective studies show that up to 50% of metastatic HER2þ breast cancer patients treated with trastuzumab developed BM over time.3,4 In contrast to trastuzumab, lapatinib is a lipophilic dual small-molecule inhibitor of epidermal growth factor receptor and HER2. Preclinical studies showed that lapatinib can penetrate the BBB and significantly decreased phosphorylation of HER2 in metastatic CNS lesions.10 Based on these results, a number of prospective clinical trials were conducted to evaluate the efficacy of lapatinib in controlling BM (summarized in Table 1).11-17 Despite the promising preclinical studies, lapatinib monotherapy seems to have only modest CNS activity. In a large multicenter phase II study,12 there was only a 6% CNS objective response rate (ORR) with single-agent lapatinib. In the extension part of this study, the addition of capecitabine to lapatinib increased the CNS ORR to 20%. Subsequent studies confirmed the CNS activity of this regimen with the CNS ORR ranging from 18% to 66% (Table 1). Based on the promising activity of this combination and the fact that WBRT is associated with the risk of neurocognitive dysfunction, in the LANDSCAPE trial upfront treatment with lapatinib and capecitabine before WBRT was evaluated.16 Interestingly, almost twothirds (65.9%) of patients had a CNS objective response to lapatinib and capecitabine without WBRT. The median time to progression was 5.5 months for systemic and CNS progression. Among 6 patients who had progressive disease, 1 had extra-CNS progression
Figure 1 (A) Brain Magnetic Resonance Image (MRI) at Baseline Before Ado-Trastuzumab Emtansine (T-DM1) Treatment. (B) Brain MRI After 3 Cycles of T-DM1 Treatment
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Richa Kalsi et al Table 1 Previous Clinical Trials of Single-Agent and Combination of Lapatinib and CNS Response Rate Reference
Phase
Treatment
n
Patient Population
Lin et al11
II
Lapatinib
39
Progressive brain metastasis despite previous trastuzumab
Lin et al12
II
Lapatinib
237
Progressive brain metastasis despite previous trastuzumab and previous cranial radiotherapy
Lapatinib with capecitabine
50
Option to continue with lapatinib and capecitabine
20%
NA
Lapatinib with capecitabine
138
Progressive brain metastasis despite previous trastuzumab
18%
II
Lapatinib with capecitabine
22
Progressive brain metastasis despite previous trastuzumab, but no previous capecitabine, or lapatinib
31.8% 21%
Boccardo et al13 Metro et al14 Sutherland et al15
CNS ORR
NA
Lapatinib with capecitabine
34
Progressive brain metastasis despite previous trastuzumab
Bachelot et al16
II
Lapatinib with capecitabine
45
Progressive brain metastasis with no previous cranial radiotherapy, capecitabine, or lapatinib
Lin et al17
II
Lapatinib with capecitabine
45
Progressive brain metastasis despite previous trastuzumab, but no previous cranial radiotherapy
Lapatinib with topotecan
22
2.6% 6%
65.9% 38% 0%
Abbreviation: CNS ¼ central nervous system.
and only 5 patients had CNS progression. However, this trial was a single-arm phase II trial that lacked a standard WBRT arm. Despite the relatively large molecular size of trastuzumab, some studies suggest that trastuzumab can cross a partially disrupted BBB, especially in the setting of leptomeningeal involvement. Furthermore, radiation appears to facilitate BBB permeability and increases the level of trastuzumab measured in CSF.9,18 There were several studies in the past that evaluated CNS response using trastuzumab; however, these studies have been largely retrospective with heterogeneous study designs. Despite these limitations, results of these studies suggest that continuation of trastuzumab beyond progression in patients with BM might improve PFS and OS.19-24 More recently, the combination of trastuzumab and capecitabine was compared with lapatinib combined with capecitabine in the CEREBEL trial (EGF111438).25 The primary end point of this trial was to evaluate the incidence of CNS metastasis as the first site of relapse. A baseline brain MRI was required to exclude patients with asymptomatic BM. Despite the lack of symptoms, approximately 20% of screened patients were found to have asymptomatic BM. Unfortunately, the CEREBEL trial was terminated early because of a very low incidence of BM as the first site of progression (3% with the lapatinib combination and 5% with the trastuzumab combination (odds ratio, 0.65; P ¼ .36). Furthermore, the trastuzumab-based arm had superior efficacy with longer PFS (8.0 vs. 6.6 months; P ¼ .021), particularly in the trastuzumab-naive group. More recently, the retrospective analysis of the EMILIA trial, a phase III trial comparing T-DM1 with lapatinib and capecitabine, showed that the incidence of BM was quite low in both treatment arms (1.8% in T-DM1 and 0.6% in lapatinib and capecitabine). Furthermore, among 95 patients with BM at baseline, only 2% who received T-DM1 and 1.6% who received lapatinib and capecitabine developed CNS progressive disease during the study. The median PFS in patients with BM at baseline was similar in both groups (5.9 months in the T-DM1 and 5.7 months in the lapatinib group; hazard ratio [HR], 1.0; P ¼ .9998). Similar to the result of the whole trial,5 the median OS was also significantly longer in patients with baseline BM treated with T-DM1 compared with lapatinib and capecitabine (26.8 vs. 12.9 months; HR, 0.382; P ¼ .0081).26
Despite disease progression during multiple lines of systemic therapies including trastuzumab, pertuzumab, and lapatinib, our patient had a striking CNS response with T-DM1. A similar phenomenon has been reported in another case that described a patient who also showed significant CNS response to single-agent T-DM1.27 Based on the striking CNS response seen in these patients and the retrospective analysis from the EMILIA trial, it seems that T-DM1 might have the ability to cross the BBB and effectively target BM.
Conclusion Although targeted therapies such as combinations of lapatinib or trastuzumab have demonstrated some efficacy in the treatment of BM, the options available for these patients remain limited. This further emphasizes the immediate need to explore other options and conduct further preclinical and clinical research in this field. In addition, patients with progressive CNS metastases face diminished quality of life due to neurocognitive and/or neurologic decline. T-DM1 appears to show CNS and non-CNS activity and has demonstrated better tolerability. With its favorable side effect profile5 and known efficacy in the treatment of systemic metastasis of HER2þ breast cancer, a more rigorous investigation of its activity in the CNS is necessary. Moreover, the combination of these systemic therapies with stereotactic radiosurgery as a way to safely defer WBRT should also be further evaluated as a way to potentially improve quality of life by minimizing neurocognitive dysfunction. Finally, even in patients who require WBRT, combination approaches using these BBB-penetrating anti-HER2 therapies need to be investigated further.
Disclosure Dr. Katherine Tkaczuk recieves research funding from Genentech Inc.
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