{"id":2116,"date":"2015-07-08T11:05:52","date_gmt":"2015-07-08T15:05:52","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=2116"},"modified":"2021-07-02T08:51:53","modified_gmt":"2021-07-02T12:51:53","slug":"lung-cancer-drug-for-patients-with-resistant-t790-mutation","status":"publish","type":"post","link":"https:\/\/blogs.shu.edu\/cancer\/2015\/07\/08\/lung-cancer-drug-for-patients-with-resistant-t790-mutation\/","title":{"rendered":"Lung Cancer Drug for Patients with Resistant T790 EGFR Mutation"},"content":{"rendered":"

The epidermal growth factor receptor (EGFR)<\/a>\u00a0receives signals from outside the cell that promote cell division and block apoptosis<\/a>, leading to proliferation, invasion, and metastasis.<\/p>\n

Drugs that inhibit\u00a0EGFR, which can be antibodies that block\u00a0EGFR\u00a0on the outside of the cell (e.g., \u00a0Erbitux – cetuximab, and Vectabix – panitumumab) or tyrosine kinase inhibitors (e.g., Iressa and Tarceva) that act on the inside of the cell on the cytoplasmic end of the receptor, block the cancer-promoting effects of an activated\u00a0EGFR\u00a0molecule.<\/p>\n

\"egfr-molecule-and-actions\"<\/a><\/p>\n

Constitutive Epidermal Growth Factor Receptor expression<\/a> is common in patients with adenocarcinoma of the lung. While monoclonal antibodies<\/a> (Erbitux and Vectibix) block binding of ligands that bind to the EGFR receptor, they are not effective when mutations that cause constitutive firing of the receptor emerge. Tyrosine kinase inhibitors (Iressa<\/a> \u2013 gefitinib, and Tarceva<\/a> – erlotinib) have provided effective treatment of patients with mutations leading to constitutive activity of the EGFR receptor.<\/p>\n

\"egfr-figure-moabs-vs-tkis\"<\/a><\/p>\n

However, patients receiving tyrosine kinase inhibitors become resistant to therapy, principally due to the T790 mutation of the EGFR. The T790M mutation<\/a> can be detected as a “second-site mutation”\u00a0in more than 50% of\u00a0EGFR<\/em>-mutated lung cancers that have developed acquired resistance to erlotinib or gefitinib (Kobayashi et al. 2005<\/a>;\u00a0Pao et al. 2005<\/a>).<\/p>\n

\"mutations<\/a><\/p>\n

Clovis Oncology has developed an EGFR tyrosine kinase inhibitor that targets the T790 mutation called rociletinib (CO-1686)<\/a>. T790M is rarely (<5%) found in untreated\u00a0EGFR-<\/em>mutated tumors. In approximately half of patients with baseline T790M mutations in their lung cancer, the T790M may be present as an underlying germline mutation.\u00a0These germline T790M mutations occur infrequently (~0.5% of never smokers with lung cancer;\u00a0Girard et al. 2010<\/a>) and may be associated in some instances with familial cancer syndromes (Bell et al. 2005<\/a>). AstraZeneca is also developing<\/a> an inhibitor of the EGFR tyrosine kinase inhibitor with the T970m mutation.<\/p>\n

Clovis started its rolling NDA submission – at the 500 mg twice daily dose, the overall response rate was 60% and the disease control rate was 90%. An active metabolite of rociletinib, M502, inhibits IGF1-R\/IR (insulin receptor), which leads to insulin resistance; this is why grade three\/four (of four) hyperglycemia occurred in 17% of patients.<\/p>\n

A number of clinical trials continue to assess rociletinib for patients with NSCLC. The phase II\/III TIGER 1 trial is comparing rociletinib with erlotinib as first-line therapy in treatment-na\u00efve patients with\u00a0EGFR\u00a0mutations who have not been screened for\u00a0T790M\u00a0status. TIGER 2, a single-arm phase II trial, is evaluating rociletinib as second-line therapy in patients with\u00a0EGFR-mutated NSCLC who are\u00a0T790M-positive. The randomized phase III TIGER 3 trial is evaluating rociletinib versus chemotherapy in patients who have progressed on a first-line EGFR TKI and are also\u00a0T790M-positive.<\/em><\/p>\n

In addition to monotherapy trials, multiple trials are planned to assess rociletinib in combination with other therapies. Studies looking at rociletinib with inhibitors of PD-L1, PD-1, and MEK are anticipated to begin enrolling patients in the second half of 2015.<\/em><\/p>\n

 <\/p>\n

\u00a0<\/em><\/p>\n

 <\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

The epidermal growth factor receptor (EGFR)\u00a0receives signals from outside the cell that promote cell division and block apoptosis, leading to proliferation, invasion, and metastasis.<\/p>\n","protected":false},"author":2252,"featured_media":394,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[21,24,22,37,1],"tags":[621,177,985,173,174,617,622,984],"class_list":["post-2116","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-growth-receptors","category-mutations","category-oncogenes","category-resistance","category-uncategorized","tag-clovis","tag-egfr","tag-epidermal-growth-factor-receptor","tag-erlotinib","tag-gefitinib","tag-lung-cancer","tag-rociletinib","tag-t970-mutation"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/2116","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=2116"}],"version-history":[{"count":4,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/2116\/revisions"}],"predecessor-version":[{"id":4958,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/2116\/revisions\/4958"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media\/394"}],"wp:attachment":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=2116"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=2116"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=2116"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}