Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

BMC Cancer, Jul 2016

Background Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Case presentation Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Conclusions Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients.

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Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

Casadei Gardini et al. BMC Cancer Efficacy of sorafenib in BRAF-mutated non- small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type- hepatocellular carcinoma: a case report Andrea Casadei Gardini 0 Elisa Chiadini Luca Faloppi Giorgia Marisi Angelo Delmonte 0 Mario Scartozzi Cristian Loretelli Alessandro Lucchesi 0 Devil Oboldi Alessandra Dubini Giovanni Luca Frassineti 0 Paola Ulivi 0 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS , 47014 Meldola , Italy Background: Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Case presentation: Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Conclusions: Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients. Case report; BRAF; HCC; NSCLC; Sorafenib Background Sorafenib is a multi-targeted kinase inhibitor with proven activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) [ 1, 2 ]. It was originally discovered as an inhibitor of Raf-1 kinase, but was found to have an expanded target profile with potent activity against other kinases including BRAF, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet derived growth factor (PDGFR)-β, KIT, Flt-3, and RET. It has a broad-spectrum efficacy in human tumor xenograft models including NSCLC [ 3, 4 ]. NSCLC seemed an ideal disease in which to further investigate sorafenib based on the frequency of RAS mutations, particularly in adenocarcinomas [ 5–7 ]. Several clinical trials have evaluated sorafenib in the treatment of advanced NSCLC alone or in combination with chemotherapy or targeted agents, without reaching consistent results on efficacy [ 8–11 ]. Markers of sorafenib efficacy or resistance have yet to be identified [ 12–15 ]. Case presentation We present a case of a 74-year-old man smoker patient with NSCLC with bone metastases (T2NXM1) and HCC (BCLC stage C). The patient had a related liver cirrhosis metabolic syndrome, good liver function (Child Pugh A5), and reported a diabetes mellitus type II in his past medical history. In July 2014 for chest and abdominal pain he performed a CT scan with evidence of lung and liver lesions, and bone metastasis. Lung biopsy performed on primary lung lesion showed pulmonary adenocarcinoma (TTF1 positive and p40 negative) (Fig. 1a-b) and liver biopsy showed HCC (grade 2 Edmondson) (Fig. 1c-d). As the patient was not in good clinical conditions due to grade 2 asthenia, we decided to start with gemcitabine in monochemotherapy in August 2014. After 2 months of chemotherapy a further CT scan showed a disease progression in both the lung and the liver. We decided to initiate treatment with sorafenib with standard schedule (400 mg bid continuously). CT scan before therapy showed that the primary liver lesion measured 97 mm × 98.3 mm (Fig. 2a). The primary lung lesion measured 40.9 mm × 29.3 mm (Fig. 2d) and the metastasis in the contralateral lung measured 27 mm × 25 mm (Fig. 2d). After 20 days we decided to reduce the dose of sorafenib to 400 mg per day for adverse events (hypertension grade 2 and mucositis grade 3). This dose was maintained until progression, without adverse events. CT scan after 2 months showed partial response in both lung lesions and stable disease in the liver and bone lesions. CT scan after 6 months of therapy showed partial response of the primary lung lesion and complete response of the lung metastasis (Fig. 2e). HCC was stable (Fig. 2b). After 13 months of therapy CT scan (...truncated)


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Andrea Casadei Gardini, Elisa Chiadini, Luca Faloppi, Giorgia Marisi, Angelo Delmonte, Mario Scartozzi, Cristian Loretelli, Alessandro Lucchesi, Devil Oboldi, Alessandra Dubini, Giovanni Luca Frassineti, Paola Ulivi. Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report, BMC Cancer, 2016, pp. 429, 16, DOI: 10.1186/s12885-016-2463-2