{"id":27194,"date":"2021-06-25T12:00:00","date_gmt":"2021-06-25T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2021\/fda-sotorasib-lung-cancer-kras"},"modified":"2024-11-03T15:14:52","modified_gmt":"2024-11-03T15:14:52","slug":"fda-approval-of-kras-inhibitor-sotorasib-for-lung-cancer-hailed-as-milestone","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/fda-approval-of-kras-inhibitor-sotorasib-for-lung-cancer-hailed-as-milestone\/","title":{"rendered":"FDA Approval of KRAS Inhibitor Sotorasib for Lung Cancer Hailed as Milestone"},"content":{"rendered":"

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Mutated KRAS-driven lung cancer cells (purple) in a genetically engineered mouse model of lung cancer. <\/p>\n

Credit: NCI\/University of Utah<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/div>\n

Doctors and scientists have known for decades that harmful mutations in a gene called KRAS<\/em> are the root cause of cancer for hundreds of thousands of people. But there have been no effective treatments that counteract the cancer-fueling actions of mutant KRAS proteins<\/a>\u2014until now. On May 28, the Food and Drug Administration (FDA) granted accelerated approval<\/a> to the first KRAS-blocking drug, called sotorasib (Lumakras)<\/a>.<\/p>\n

The approval is \u201creally exciting, no question about that. It\u2019s a big breakthrough in the whole field,\u201d said Frank McCormick, Ph.D., scientific consultant for NCI\u2019s RAS Initiative<\/a>. For many years, KRAS was considered an \u201cundruggable\u201d target. But a better understanding of the protein\u2019s biology, paired with new technologies, has made the once seemingly impossible goal of a KRAS inhibitor a reality<\/a>.<\/p>\n

Under the new approval, sotorasib can be used to treat people with non-small cell lung cancer (NSCLC) that has spread nearby (locally advanced<\/a>) or to distant locations (metastatic<\/a>) in the body. Patients must have previously received at least one other systemic<\/a> cancer treatment, such as chemotherapy, and have a particular KRAS<\/em> mutation<\/a>, known as G12C, in their tumors. <\/p>\n

FDA also approved two tests\u2014Qiagen therascreen KRAS RGQ PCR<\/a> kit and Guardant360 CDx\u2014that can be used to check for the G12C mutation in a person\u2019s tumor tissue or blood, respectively. Around 13% of people with NSCLC have the G12C mutation.<\/p>\n

The new approval is based on initial results from a study that included 124 people with KRAS<\/em> G12C-mutant NSCLC who had previously received other treatments. In the clinical trial<\/a>, called CodeBreaK100, sotorasib shrank the tumors of 36% of participants<\/a>. And those tumor responses<\/a> lasted for a median<\/a> of 10 months. In contrast, standard therapies shrink tumors in less than 20% of people with NSCLC that has come back after previous treatment, and those effects are usually short-lived.<\/p>\n

\u201cI have many patients with KRAS<\/em> G12C that have had several lines of therapy and \u2026 now we have a new option for them to try. That\u2019s pretty exciting,\u201d said David Carbone, M.D., Ph.D., a lung cancer specialist at the Ohio State University Comprehensive Cancer Center. <\/p>\n

Under FDA\u2019s accelerated approval, Amgen\u2014the company that makes sotorasib\u2014must carry out an additional trial to confirm that the treatment helps patients with NSCLC live longer without their cancer getting worse.<\/p>\n

A larger study comparing sotorasib with standard chemotherapy for advanced NSCLC<\/a> is currently under way. Other studies are testing sotorasib in combination with other cancer treatments. <\/p>\n

Sotorasib Shrinks Lung Tumors<\/h2>\n

The CodeBreaK100 trial, funded by Amgen and NCI, is testing sotorasib (previously called AMG510) as a treatment for people with solid tumors<\/a> that have KRAS<\/em> G12C. The mutation, a hallmark of damage from cigarette smoke, is most common in lung cancer. It is also found less frequently in colorectal cancers and in a small fraction of pancreatic cancers.  <\/p>\n

Most trial participants with NSCLC had previously received treatment with immunotherapy and\/or chemotherapy. Everyone in the study received sotorasib\u2014taken as a pill once a day\u2014until their disease worsened, they withdrew from the trial, or they had to stop taking it because of side effects. Participants\u2019 outcomes were tracked for a median of 15 months. <\/p>\n

Of the 124 patients with NSCLC who could be evaluated, tumors completely disappeared in 4 people and partially shrank in 42 people. An additional 54 people had stable disease<\/a>, meaning their cancer didn\u2019t get better or worse.<\/p>\n

Participants lived for a median of 13 months overall and a median of 7 months without their cancer getting worse.<\/p>\n\n\n\n\n\n\n\n
Tumor response<\/strong><\/td>\nNumber of participants<\/strong><\/td>\nPercentage of participants<\/strong><\/td>\n<\/tr>\n
Disappeared completely<\/td>\n4<\/td>\n3%<\/td>\n<\/tr>\n
Partially shrank<\/td>\n42<\/td>\n34%<\/td>\n<\/tr>\n
Stayed the same (stable)<\/td>\n54<\/td>\n44%<\/td>\n<\/tr>\n
Got worse (progressed)<\/td>\n20<\/td>\n16%<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The fact that the treatment kept patients\u2019 cancer at bay for only 7 months was \u201cdisappointing,\u201d said Dr. Carbone. Some other targeted therapies for lung cancer have shown \u201cmuch better durability,\u201d he explained.<\/p>\n

But researchers still have to figure out the best way to use sotorasib to treat lung cancer, he continued. It\u2019s possible that the drug may be more effective as an initial, or first-line, therapy, he said.<\/p>\n

Another challenge is identifying patients who have the G12C mutation in their tumors and who qualify for sotorasib treatment. Although biomarker<\/a> testing\u2014a way to look for genes, proteins, and other substances that can provide information about a person\u2019s cancer\u2014is recommended for people with lung cancer, many patients aren\u2019t getting those tests<\/a>. <\/p>\n

\u201cThere\u2019s a lot of room for improvement in [the uptake of] testing,\u201d Dr. Carbone said.<\/p>\n

Side Effects of Sotorasib<\/h2>\n

Among people with NSCLC in the CodeBreaK100 trial, 70% experienced a treatment-related side effect\u2014most commonly diarrhea, pain in the muscles or bones, and nausea. Although most side effects were mild, 25 people (20%) experienced a serious side effect and one had a life-threatening side effect. <\/p>\n

There were no treatment-related deaths among people with NSCLC, but one person in the study with a different kind of cancer died of inflammation in the lungs (called interstitial lung disease or pneumonitis<\/a>) that was thought to be caused by the treatment. <\/p>\n

For 28 patients (22%), side effects led to a pause, a reduction, or both, in the dose of sotorasib. Nine people (7%) stopped the treatment because of side effects. <\/p>\n

Preliminary results from the full study group<\/a>, which includes people with several different kinds of cancer, were published September 2020 in the New England Journal of Medicine<\/em>.<\/p>\n

A Stampede of KRAS Research<\/h2>\n

A handful of other KRAS G12C inhibitors are on the heels of sotorasib and are currently being tested in clinical trials. And there are likely more to come.<\/p>\n

The discovery and approval of sotorasib \u201copens up opportunities for developing compounds that bind to other mutant [KRAS] proteins,\u201d Dr. McCormick said. G12C is one of several KRAS<\/em> mutations found in cancer cells. The two most common KRAS<\/em> mutations are called G12D and G12V.<\/p>\n

KRAS normally acts like a light switch, toggling between being \u201con\u201d and \u201coff.\u201d When it is on, the protein sends signals that tell the cell to grow and divide. When mutated, however, the protein rarely switches off, leading to uncontrolled cell growth. Sotorasib and other G12C inhibitors work by permanently locking KRAS G12C in the off position.<\/p>\n

But G12D and G12V can\u2019t be targeted the same way because they have different chemistries than G12C. \u201cIt\u2019s been a long and hard road to find compounds that bind effectively to those particular mutants,\u201d Dr. McCormick said. However, he added, what researchers have been learning from KRAS G12C inhibitors has accelerated progress toward inhibitors of G12D and G12V.<\/p>\n

In fact, several KRAS G12D inhibitors are in development and, according to Dr. McCormick, will likely enter clinical trials in the next year or so. <\/p>\n

Researchers involved in NCI\u2019s RAS Initiative, as well as others, have also made progress designing pan-KRAS inhibitors\u2014drugs that work against several different KRAS mutant proteins. A few of these drugs are also on track to reach clinical trials in the next few years.<\/p>\n

\u201cThere\u2019s a stampede of groups developing and testing different KRAS inhibitors right now,\u201d Dr. McCormick said.<\/p>\n

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

June 25, 2021, by NCI Staff Mutated KRAS-driven lung cancer cells (purple) in a genetically engineered mouse model of lung cancer.  Credit: NCI\/University of Utah Doctors and scientists have known for decades that harmful mutations in a gene called KRAS are the root cause of cancer for hundreds of thousands of people. But there have been […]<\/p>\n","protected":false},"author":2,"featured_media":27195,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-27194","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27194","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=27194"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27194\/revisions"}],"predecessor-version":[{"id":43737,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27194\/revisions\/43737"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media\/27195"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=27194"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=27194"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=27194"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}