{"id":4631,"date":"2017-09-27T11:05:13","date_gmt":"2017-09-27T15:05:13","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=4631"},"modified":"2021-07-02T08:51:39","modified_gmt":"2021-07-02T12:51:39","slug":"sitravatinib-plus-nivolumab-in-nsclc","status":"publish","type":"post","link":"https:\/\/blogs.shu.edu\/cancer\/2017\/09\/27\/sitravatinib-plus-nivolumab-in-nsclc\/","title":{"rendered":"Sitravatinib plus nivolumab in NSCLC"},"content":{"rendered":"<p>Sitravatinib (MGCD516)\u00a0is an oral multi-tyrosine kinase inhibitor being developed by <a href=\"http:\/\/ir.mirati.com\/news-releases\/news-release-details\/mirati-therapeutics-presents-positive-preliminary-data-going\" target=\"_blank\" rel=\"noopener\">Mirati Therapeutics<\/a>. Last week, the company announced that three of eleven patients with non-small cell lung cancer (NSCLC) with genetic alterations in MET, AXL, RET, TRK, DDR2, KDR, PDGFRA, KIT or CBL who were resistant to checkpoint [anti PD-(L)1 therapy] had confirmed partial responses; because of this, dosing in the <a href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02219711\" target=\"_blank\" rel=\"noopener\">34-patient expansion cohort<\/a> will proceed.<!--more--><\/p>\n<p>Sitravatinib <a href=\"https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB4795_IASLC-Chicago2017_MRTX-500_SitravatinibCombo.pdf\" target=\"_blank\" rel=\"noopener\">selectively targets receptor tyrosine kinases (RTKs)<\/a> including TAM receptors (Tyro, Axl, MER), split family receptors (VEGFR2, KIT), RET and MET. These represent about 9% of NSCLC:<\/p>\n<div id=\"attachment_4635\" style=\"width: 985px\" class=\"wp-caption aligncenter\"><a href=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib.png\" data-rel=\"lightbox-image-0\" data-rl_title=\"\" data-rl_caption=\"\" title=\"\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-4635\" class=\"size-full wp-image-4635\" src=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib.png\" alt=\"\" width=\"975\" height=\"443\" srcset=\"https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib.png 975w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib-300x136.png 300w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib-768x349.png 768w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Genetic-alterations-targeted-by-sitravatinib-624x284.png 624w\" sizes=\"auto, (max-width: 975px) 100vw, 975px\" \/><\/a><p id=\"caption-attachment-4635\" class=\"wp-caption-text\">Figure 1. Genetic alterations in NSCLC targeted by sitravatinib. <a href=\"https:\/\/www.mirati.com\/mgcd516\/\" target=\"_blank\" rel=\"noopener\">https:\/\/www.mirati.com\/mgcd516\/<\/a><\/p><\/div>\n<p>In addition to targeting the driver mutations of the cancer, itself, these targets may enhance the antitumor response via direct effects on immune cells within the tumor microenvironment (TME):<\/p>\n<ul>\n<li><em>Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the TME.<\/em><\/li>\n<li><em>Targeting MERTK and Axl induces M1 macrophage responses, as opposed to immune-suppressive M2 responses.<\/em><\/li>\n<li><em>Targeting split receptors reduces Treg and MSDC (myeloid-derived suppressor cells) and releases brakes on the expansion of CD8+ cells induced by PD-1 inhibition.<\/em><\/li>\n<\/ul>\n<div id=\"attachment_4636\" style=\"width: 891px\" class=\"wp-caption aligncenter\"><a href=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs.jpg\" data-rel=\"lightbox-image-1\" data-rl_title=\"\" data-rl_caption=\"\" title=\"\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-4636\" class=\"size-full wp-image-4636\" src=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs.jpg\" alt=\"\" width=\"881\" height=\"1116\" srcset=\"https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs.jpg 881w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs-237x300.jpg 237w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs-768x973.jpg 768w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs-808x1024.jpg 808w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-1.-Rationale-for-targeting-split-receptos-and-TAMs-624x790.jpg 624w\" sizes=\"auto, (max-width: 881px) 100vw, 881px\" \/><\/a><p id=\"caption-attachment-4636\" class=\"wp-caption-text\">Figure 2. Rationale for Targeting TAM and Split RTKs to Enhance Response to Immune Checkpoint Inhibitors. <a href=\"https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB4795_IASLC-Chicago2017_MRTX-500_SitravatinibCombo.pdf\" target=\"_blank\" rel=\"noopener\">https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB4795_IASLC-Chicago2017_MRTX-500_SitravatinibCombo.pdf<\/a><\/p><\/div>\n<p><strong><em>How can sitravatinib turn \u201ccold tumors hot?\u201d<\/em><\/strong><\/p>\n<p>Sitravatinib is being developed in patients who have progressed on checkpoint therapy. These tumors no longer have activated infiltrating T-cells that are launching an effective immune attack. This is why checkpoint inhibition therapy is not working \u2013 if there is no anti-tumor immune activity ongoing, then, blocking the immune-abrogating signal (PD-L1) will not result in tumor kill.<\/p>\n<p>But, PD-L1 expression is not the only reason that tumors escape immune attack \u2013 the presence of Treg cells that blunt CD8+ antigen specific reactions, MDSC\u2019s, and M2 macrophage activity also contribute to making the tumor microenvironment immunologically cold.<\/p>\n<p>So, the goal of treatment with sitravatinib in combination with Opdivo is several-fold:<\/p>\n<ol>\n<li>Sitravatinib therapy will kill many cancer cells that are driven by mutations in the tyrosine kinases that sitravatinib inhibits. This will result in the spilling of neo-antigens, epitopes against which the immune system has yet to launch an attack and to which the immune system has yet to be tolerized (Treg cells).<\/li>\n<li>Once an immune response against neo-antigens is initiated, Opdivo will block PD-L1-miedated immune response abrogation.<\/li>\n<li>Sitravatinib will also block the activation of Treg\u2019s, promote M1 macrophage responses, and deplete the tumor microenvironment of MSDC\u2019s.<\/li>\n<\/ol>\n<p><strong><em>Rationale for targeting CBL mutations with sitravatinib<\/em><\/strong><\/p>\n<p><strong><em>\u00a0<\/em><\/strong>CBL is a gene that encodes an E3 ubiquitin ligase, which is an enzyme that targets substrates for degradation by the proteasome. <a href=\"http:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CBL\" target=\"_blank\" rel=\"noopener\">It mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates<\/a>:<\/p>\n<ul>\n<li><em>CBL also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia.<\/em><\/li>\n<\/ul>\n<p>Loss of function mutations in CBL result in <a href=\"https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB78_IASLC-Chicago_MGCD-516_Sitravatinib_CBL.pdf\" target=\"_blank\" rel=\"noopener\">increased target RTK activation in tumor cells and may act as oncogenic drivers<\/a>. CBL is commonly inactivated by missense mutations in the RING domain or by deletions that occur in selected human cancers including NSCLC, melanoma, and sarcomas.<\/p>\n<p>CBL is <a href=\"https:\/\/www.mirati.com\/assets\/001\/5060.pdf\" target=\"_blank\" rel=\"noopener\">negative regulator for MET, AXL, PDGFR\/KIT signaling<\/a>, therefore, blocking the tyrosine kinase activity of these RTKs with sitravatinib will address the loss of function of the CBL tumor suppressor gene when it is mutated.<\/p>\n<div id=\"attachment_4637\" style=\"width: 1085px\" class=\"wp-caption aligncenter\"><a href=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation.jpg\" data-rel=\"lightbox-image-2\" data-rl_title=\"\" data-rl_caption=\"\" title=\"\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-4637\" class=\"size-full wp-image-4637\" src=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation.jpg\" alt=\"\" width=\"1075\" height=\"723\" srcset=\"https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation.jpg 1075w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation-300x202.jpg 300w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation-768x517.jpg 768w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation-1024x689.jpg 1024w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Figure-3.-CBL-RTK-degradation-624x420.jpg 624w\" sizes=\"auto, (max-width: 1075px) 100vw, 1075px\" \/><\/a><p id=\"caption-attachment-4637\" class=\"wp-caption-text\">Figure 3. CBL degradation pathway of receptor tyrosine kinases. <a href=\"https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB78_IASLC-Chicago_MGCD-516_Sitravatinib_CBL.pdf\" target=\"_blank\" rel=\"noopener\">https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB78_IASLC-Chicago_MGCD-516_Sitravatinib_CBL.pdf<\/a><\/p><\/div>\n<div id=\"attachment_4639\" style=\"width: 1063px\" class=\"wp-caption aligncenter\"><a href=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC.jpg\" data-rel=\"lightbox-image-3\" data-rl_title=\"\" data-rl_caption=\"\" title=\"\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-4639\" class=\"size-full wp-image-4639\" src=\"http:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC.jpg\" alt=\"\" width=\"1053\" height=\"355\" srcset=\"https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC.jpg 1053w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC-300x101.jpg 300w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC-768x259.jpg 768w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC-1024x345.jpg 1024w, https:\/\/blogs.shu.edu\/cancer\/files\/2017\/09\/Fig-4.-Activity-of-sitravatanib-in-CBL-mutated-NSCLC-624x210.jpg 624w\" sizes=\"auto, (max-width: 1053px) 100vw, 1053px\" \/><\/a><p id=\"caption-attachment-4639\" class=\"wp-caption-text\">Figure 4. Sensitivity of NSCLC cell lines harboring CBL mutations to sitravatinib. <a href=\"https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB78_IASLC-Chicago_MGCD-516_Sitravatinib_CBL.pdf\" target=\"_blank\" rel=\"noopener\">https:\/\/www.mirati.com\/wp-content\/uploads\/2017\/09\/AB78_IASLC-Chicago_MGCD-516_Sitravatinib_CBL.pdf<\/a><\/p><\/div>\n","protected":false},"excerpt":{"rendered":"<p>Sitravatinib (MGCD516)\u00a0is an oral multi-tyrosine kinase inhibitor being developed by Mirati Therapeutics. Last week, the company announced that three of eleven patients with non-small cell lung cancer (NSCLC) with genetic alterations in MET, AXL, RET, TRK, DDR2, KDR, PDGFRA, KIT or CBL who were resistant to checkpoint [anti PD-(L)1 therapy] had confirmed partial responses; because [&hellip;]<\/p>\n","protected":false},"author":2252,"featured_media":3979,"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":[711,595,28,18,24,19,13,1],"tags":[1183,2062,264,2057,1747,89,749,2053,2060,2054,2061,2058,2055,1237,2056,1150,2059],"class_list":["post-4631","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-active-immunotherapy","category-biomarkers","category-checkpoint-inhibitors","category-heterotypic-cellular-interactions","category-mutations","category-receptor-tyrosine-kinase-inhibitors","category-tumor-microenvironment","category-uncategorized","tag-axl","tag-cbl","tag-kit","tag-mer","tag-neo-antigens","tag-nivolumab","tag-opdivo","tag-receptor-tyrosine-kinases","tag-ret-and-met","tag-rtk","tag-sitravatinib","tag-split-family-receptors","tag-tam-receptors","tag-tumor-microenvironment","tag-tyro","tag-ubiquitin","tag-vegfr2"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4631","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=4631"}],"version-history":[{"count":4,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4631\/revisions"}],"predecessor-version":[{"id":4642,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4631\/revisions\/4642"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media\/3979"}],"wp:attachment":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=4631"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=4631"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=4631"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}