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RESPONSE TO LENVATINIB IN PROGRESSIVE METASTATIC PARAGANGLIOMA Sina Jasim,M.D.1, Chintakuntlawar, Ashish,M.D.PhD 2, Keith Bible, M.D.PhD 2 1Division of Endocrinology, 2Division of Medical Oncology Mayo Clinic, Rochester, MN BACKGROUND: • Paragangliomas are rare, sometimes malignant, vascular endocrine tumors that highly express vascular endothelium growth factor (VEGF). • Anti-angiogenic agents may thus play a role in the treatment of these tumors. • We report a dramatic clinical response to the oral VEGFR 1-3 and multi-kinase inhibitor lenvatinib. CASE DESCRIPTION • A 49-year-old female with longstanding metastatic pelvic PGL with SDHB (p.V140F--c.418G>T) mutation. • Multiple surgical resections, chemotherapeutic regimens (etoposide, cisplatin; cyclophosphamide, doxorubicin, cisplatin; cyclophosphamide, vincristine, dacarbazine) as well as with local therapies at metastatic sites (radiation, cryoablation). • She benefited from pazopanib (VEGFR and multi-kinase inhibitor) for ~2 years, attaining a partial response, but ultimately progressed with the development of hypertension. • CT scans of chest, abdomen and pelvis showed progression of hilar, pelvic and peritoneal metastatic lymphadenopathy. • Laboratory values: Metanephrine level < 0.20 nmol/L (<0.50 nmol/L),nor-metanephrines 5.7 nmol/L (<0.90 nmol/L), Chromogranin A 1018 ng/mL (< 93 ng/mL) • Radiotherapy to the right hilar lymphadenopathy (4000 cGy, 10 fractions; irradiated disease progress despite radiotherapy) • Alpha and beta blockade (phenoxybenzamine and atenolol) as well as calcium channel blockers started to maintain controlled blood pressure while initiating lenvatinib (24 mg daily). RESULTS • Within 48 hours of lenvatinib initiation, she had dramatic nodal clinical tumor regression associated with fever. Work up revealed no infectious source for fever. • Laboratory evaluation were consistent with mild tumor lysis syndrome. • Biochemical response (Figure 1) • Follow up imaging showed interval decreases in hilar and retroperitoneal adenopathy and a confirmed RECIST response (Figure 2) • Side effects prominently included fatigue. RESULTS Figure 1A: Chromogranin A level Figure 1B: Normetanephrine level Chromogranin A (ng/mL) 1200 Normetanephrine (nmol/L) 1018 6 1000 5.7 5 800 4 600 400 200 3 3 306 93 93 280 2 93 1 1.7 0.9 0.9 0.9 1.1 Jul-15 Aug-15 Sep-15 Oct-15 0 0 Jul-15 Aug-15 Patient Sep-15 Reference Oct-15 Patient Reference FIGURE 2: CT CHEST BEFORE AND ON THERAPY DISCUSSION/CONCLUSION • Like other VEGFR-targeted kinase inhibitors, lenvatinib may represent a promising drug for further development in treating refractory metastatic paraganglionoma. • Systemic therapies, like multi-kinase inhibitors , can induce hypertensive episodes, which require close monitoring, as well as have potential to induce tumor lysis-like phenomena. • Special care must be taken to respond emergently to minimize patient risks in the event of rapid tumor regression.