L09.03THE EVALUATION OF SELUMETINIB A MEK-INHIBITOR WITH AND WITHOUT THE ADDITION OF ERLOTINIB IN KRAS MUTATED NON-SMALL CELL LUNG CANCER

Second line and beyond treatment of advanced Non-Small Cell Lung Cancer (NSCLC) for recurrent or progressive disease includes treatment with an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Several mechanisms of resistance to EGFR tyrosine kinase inhibitors have been discovered, to include the presence of Kristen-Ras (KRAS) oncogene mutations. The presence of a KRAS mutation have been found in approximately 20% of NSCLC and have been associated with a lack of response to EGFR tyrosine kinase inhibitors. Ras mutations result in constitutive activation of the Ras/Raf/MEK/MAPK pathway. Selumetinib (AZD6244) is an investigational drug that is orally available and selectively targets the critical kinase (MEK) in the mitogen-activated protein (MAP) kinase signal transduction pathway. MEK is activated downstream of both EGFR and RAS.We evaluated 47 patients with advanced NSCLC who had a mutation in the KRAS oncogene. Selumetinib was given at a dose of 75 mg by mouth twice a day as monotherapy to 19 patients with one response (5% RR). Of these 19 patients, 12 of the patients only had 1st or 2nd line treatment. Selumetinib was given at a dose of 150 mg once per day in combination with erlotinib at a dose of 100 mg once per day to 28 patients with two responses (7% RR). All 28 patients only had 1st or 2nd line treatment. The most common treatment related toxicities were fatigue, rash and diarrhea. Specific toxicities associated with selumetinib included lower extremity edema, reduction in left ventricular ejection fraction, myalgias and myositis (with an elevation in serum creatine kinase).Selumetinib as monotherapy has a response rate of 5% in advanced KRAS mutated NSCLC. Selumetinib in combination with erlotinib has similar activity in KRAS mutated advanced NSCLC as reported monotherapy erlotinib in advanced NSCLC without a known RAS mutation. Second line and beyond treatment of advanced Non-Small Cell Lung Cancer (NSCLC) for recurrent or progressive disease includes treatment with an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Several mechanisms of resistance to EGFR tyrosine kinase inhibitors have been discovered, to include the presence of Kristen-Ras (KRAS) oncogene mutations. The presence of a KRAS mutation have been found in approximately 20% of NSCLC and have been associated with a lack of response to EGFR tyrosine kinase inhibitors. Ras mutations result in constitutive activation of the Ras/Raf/MEK/MAPK pathway. Selumetinib (AZD6244) is an investigational drug that is orally available and selectively targets the critical kinase (MEK) in the mitogen-activated protein (MAP) kinase signal transduction pathway. MEK is activated downstream of both EGFR and RAS. We evaluated 47 patients with advanced NSCLC who had a mutation in the KRAS oncogene. Selumetinib was given at a dose of 75 mg by mouth twice a day as monotherapy to 19 patients with one response (5% RR). Of these 19 patients, 12 of the patients only had 1st or 2nd line treatment. Selumetinib was given at a dose of 150 mg once per day in combination with erlotinib at a dose of 100 mg once per day to 28 patients with two responses (7% RR). All 28 patients only had 1st or 2nd line treatment. The most common treatment related toxicities were fatigue, rash and diarrhea. Specific toxicities associated with selumetinib included lower extremity edema, reduction in left ventricular ejection fraction, myalgias and myositis (with an elevation in serum creatine kinase). Selumetinib as monotherapy has a response rate of 5% in advanced KRAS mutated NSCLC. Selumetinib in combination with erlotinib has similar activity in KRAS mutated advanced NSCLC as reported monotherapy erlotinib in advanced NSCLC without a known RAS mutation.