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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3182762d20
Case Reports

High-Dose Pemetrexed in Combination with High-Dose Crizotinib for the Treatment of Refractory CNS Metastases in ALK-Rearranged Non–Small-Cell Lung Cancer

Gandhi, Leena MD, PhD*†‡; Drappatz, Jan; Ramaiya, Nikhil H.; Otterson, Gregory A. MD§

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Departments of *Medical Oncology, Dana-Farber Cancer Institute; Medicine, Radiology, Brigham and Women’s Hospital; Harvard Medical School, Boston, Massachusetts; §Department of Internal Medicine, Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio; and Departments of Neurology and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Disclosure: Dr. Gandhi has served on the Advisory Board of Chugai Pharmaceuticals and Dr. Otterson was a consultant for Genentech, Abraxis/Celgene. The other authors declare no conflcit of interest.

Address for correspondence: Leena Gandhi, MD, PhD, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215. E-mail:

A 28-year-old never-smoking man presented with 6 months of gradually worsening low back pain, weight loss, and leg weakness. Computed tomography scans in January 2009 showed a 1.4 × 2.3 cm spiculated left lower-lobe mass with adjacent subcentimeter nodules, multiple areas of adenopathy, bony lesions in the lower spine and pelvis, and liver lesions. A magnetic resonance imaging of the brain on February 3, 2009 demonstrated multiple, small, enhancing lesions consistent with metastatic disease, the largest of which was 1.7 × 1.6 × 1.6 cm in the left occipital lobe.

A biopsy of a left supraclavicular lymph node on February 2, 2009 demonstrated metastatic poorly differentiated lung adenocarcinoma. Genetic testing demonstrated an EML4-ALK translocation.

The patient underwent a course of whole-brain radiation concurrently with radiation to the lumbar spine, finishing on March 3, 2009. After completion of whole-brain radiation, he underwent stereotactic boost to four lesions on March 17, 2009. Thereafter, he was enrolled to a phase I trial (A8081001) of crizotinib (Xalkori; Pfizer, New York, NY) at a dose of 250 mg twice daily on April 1, 2009 and had a partial response to this therapy. During his course on study (close to 3 years), he underwent stereotactic radiosurgery to additional new central nervous system (CNS) lesions in May and August 2011.

In January 2012, routine restaging computed tomography showed overall stable systemic disease other than growth in an isolated right paratracheal node. However, brain magnetic resonance imaging showed the new development of more than 30 small lesions throughout the cerebrum and cerebellum in addition to increase in pre-existing lesions.

At this juncture, we initiated therapy with high-dose pemetrexed (900 mg/m2) (Alimta; Lilly, Indianapolis, IN) in combination with the highest tested dose of crizotinib without dose-limiting toxicity as of January 2012 (600 mg once daily) with the rationale of giving the highest doses that could be safely administered of both agents to maximize potential cerebrospinal fluid penetration.

Scans performed 6 weeks after initiation of this therapy demonstrated reduction in multiple CNS lesions (Fig. 1). The growing right paratracheal node also regressed on therapy (Fig. 2). In addition, lesions that were previously stable on crizotinib showed further decrease on being treated with this combination (Fig. 3), suggesting additive or synergistic effects. The patient continues to have minimal adverse effects and overall stable cerebral and systemic disease 7 months after initiation of therapy.

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Figure 2
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Figure 3
Figure 3
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Pemetrexed has previously been identified to have activity in CNS metastases in non–small-cell lung cancer1 and some studies (but not all) have suggested ALK rearrangements are associated with durable responses to pemetrexed.2–4 This patient had not previously received chemotherapy and pemetrexed alone may have given a similar result. However, because at the time of initation of therapy, the patient remained asymptomatic with largely stable disease, we felt that he was still receiving clinical benefit from crizotinib and that CNS growth likely represented the inadequate CNS penetration of crizotinib.5 Although now Food and Drug Administration–approved,6 dose escalation is still ongoing in the A8081001 phase I study of crizotinib. Therefore, on the basis of nonoverlapping toxicities, we used high-dose crizotinib in combination with high-dose pemetrexed, which has shown equivalent systemic safety and efficacy in non–small-cell lung cancer7 and promising activity in CNS lymphoma.8 Although we do not know whether the response seen here was attributable to one or both drugs given at high dose, the minimal toxicity and sustained clinical benefit seen here suggest the combination is worthy of further exploration.

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Grants were received by Pfizer, Genentech, GSK and Celgene.

Crizotinib dosing decision was made in consultation with Drs. Geoffrey I. Shapiro of Dana-Farber Cancer Institute and Keith Wilner of Pfizer.

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1. Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer. 2010;8:e3–e5

2. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774–80

3. Lee JO, Kim TM, Lee SH, et al. Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer. J Thorac Oncol. 2011;6:1474–1480

4. Shaw AT, Varghese AM, Solomon BJ, et al. Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann Oncol. August 10, 2012 [Epub ahead of print].

5. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5

6. Administration. UFaD.. FDA labeling information–Xalkori. Available at Accessed November 2012.

7. Cullen MH, Zatloukal P, Sörenson S, et al. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2008;19:939–945

8. Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118:3743–3748

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This article has been cited 1 time(s).

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© 2013International Association for the Study of Lung Cancer


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