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• W2040374701 abstract "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.FIGURE 2Regression of growing lesion of combination pemetrexed + crizotinib therapy. A, A high right paratracheal node as imaged on October 14, 2011, in the setting of systemic stable disease (after 2.8 years on phase I trial of crizotinib at 250 mg orally twice daily. B, The same node on January 3, 2012, at the time of central nervous system progression. C, The same node on February 27, 2012, after 6 weeks of therapy.View Large Image Figure ViewerDownload (PPT)FIGURE 3Regression of previously stable lesion on combination pemetrexed + crizotinib therapy. A, Right subcarinal node at the time of entry onto study with crizotinib (250 mg twice daily) on March 27, 2009. B, The same node in the setting of systemic stable disease after 2.8 years on therapy (October 14, 2011). C, The node at the time of central nervous system progression on January 3, 2012 (still stable). D, The node on February 27, 2012 after 6 weeks on therapy.View Large Image Figure ViewerDownload (PPT) Pemetrexed has previously been identified to have activity in CNS metastases in non–small-cell lung cancer1Bearz A Garassino I Tiseo M et al.Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer.Lung Cancer. 2010; 8: e3-e5Google Scholar and some studies (but not all) have suggested ALK rearrangements are associated with durable responses to pemetrexed.2Camidge 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: 80-774Google Scholar, 3Lee 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: 1474-1480Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 4Shaw 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].)Google Scholar 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.5Costa DB Kobayashi S Pandya SS et al.CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.J Clin Oncol. 2011; 29: e443-5Crossref PubMed Scopus (506) Google Scholar Although now Food and Drug Administration–approved,6Administration UFaD FDA labeling information–Xalkori.Available at www.fda.govGoogle Scholar 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 cancer7Cullen 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: 939-945Crossref PubMed Scopus (65) Google Scholar and promising activity in CNS lymphoma.8Raizer JJ Rademaker A Evens AM et al.Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma.Cancer. 2012; 118: 3743-3748Crossref PubMed Scopus (61) Google Scholar 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. 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." @default.
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• W2040374701 title "High-Dose Pemetrexed in Combination with High-Dose Crizotinib for the Treatment of Refractory CNS Metastases in ALK-Rearranged Non–Small-Cell Lung Cancer" @default.
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