{"id":12359,"date":"2019-09-17T12:00:00","date_gmt":"2019-09-17T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2019\/fda-entrectinib-ntrk-fusion"},"modified":"2024-11-03T15:17:08","modified_gmt":"2024-11-03T15:17:08","slug":"fda-approves-entrectinib-based-on-tumor-genetics-rather-than-cancer-type","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/fda-approves-entrectinib-based-on-tumor-genetics-rather-than-cancer-type\/","title":{"rendered":"FDA Approves Entrectinib Based on Tumor Genetics Rather Than Cancer Type"},"content":{"rendered":"

\n
\n
\"Graphic<\/div>
\n
\n

NTRK<\/em> gene fusions are found in around 1% of people with solid tumors but close to 90% of people with certain rare cancers like mammary analogue secretory carcinoma and infantile fibrosarcoma.<\/p>\n

Credit: National Cancer Institute<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/div>\n

On August 15, the Food and Drug Administration (FDA) granted accelerated approval to entrectinib (Rozlytrek)<\/a> for adults and adolescents aged 12 or older who have solid tumors<\/a> that harbor a specific genetic alteration.\u00a0<\/p>\n

This is the third cancer drug that has been approved for a \u201ctissue agnostic\u201d indication<\/a>, meaning for tumors with a specific genetic feature rather than a certain type of tumor.<\/p>\n

In the case of entrectinib, patients must have an alteration that causes one of the three NTRK<\/em> genes to fuse with another gene, leading to the production of TRK fusion proteins. Entrectinib is a targeted therapy<\/a> that blocks the activity of TRK and other proteins that can drive cancer growth.\u00a0<\/p>\n

The approval covers the use of entrectinib in people with either metastatic cancer that has gotten worse after receiving systemic treatment<\/a> or locally advanced cancer<\/a> that cannot be surgically removed. In addition, patients must have no other effective treatment options available.<\/p>\n

Entrectinib is the second drug approved by FDA for the treatment of cancers with NTRK<\/em> fusions. The first, called larotrectinib (Vitrakvi)<\/a>, was approved by the agency in November 2018<\/a>.\u00a0<\/p>\n

\u201cIt\u2019s great that another agent that is tissue agnostic has been approved, because that broadens the availability of different drugs for physicians to treat patients with these fusions,\u201d said Nita Seibel, M.D., head of Pediatric Solid Tumor Therapeutics in NCI\u2019s Cancer Therapy Evaluation Program<\/a>.<\/p>\n

\u201cI don\u2019t think we\u2019re going to get rid of tissue-specific therapies any time soon, but we\u2019re going to see more and more of these tissue agnostic therapies in the future,\u201d said David Hong, M.D., who leads phase 1 trials of new cancer therapies at M.D. Anderson Cancer Center. \u00a0Dr. Hong led the early clinical studies of larotrectinib.<\/p>\n

Also on August 15, FDA approved entrectinib for adults with non-small cell lung cancer (NSCLC)<\/a> that has a gene fusion involving the ROS1<\/em> gene<\/a>. Entrectinib also blocks the activity of ROS1 proteins.\u00a0<\/p>\n

Solid Tumors with NTRK Fusions<\/h2>\n

The approval of entrectinib for solid tumors with NTRK<\/em> gene fusions was based in part on results from three small clinical trials: ALKA-372-001, STARTRK-1, and STARTRK-2. The trials were sponsored by Hoffmann-La Roche, the manufacturer of entrectinib.\u00a0<\/p>\n

Trial participants had different types of cancer\u2014mostly sarcoma<\/a>, lung cancer, and salivary gland cancer<\/a>\u2014that was either metastatic or locally advanced. NTRK<\/em> gene fusions were identified by a genetic test.\u00a0<\/p>\n

Among the 54 trial participants with NTRK<\/em> fusions who were included in the analysis, 31 (57%) saw their tumors shrink, including four whose tumors were totally eliminated (a complete response<\/a>). Among the participants whose tumors shrank, 61% had responses that lasted 9 months or longer.\u00a0<\/p>\n

Entrectinib was also tested in a fourth trial, called STARTRK-NG, that included 30 children with fusions involving NTRK<\/em>, ROS1<\/em>, or another gene called ALK<\/em>. Most of the children had neuroblastoma<\/a>, brain and spinal cord tumors, or sarcoma.\u00a0<\/p>\n

Early study findings showed that \u201centrectinib produced striking, rapid, and durable responses,\u201d the trial investigators reported earlier this year<\/a>. The treatment shrank tumors in several children with brain and spinal cord tumors, they noted.<\/p>\n

These findings \u201clook very promising,\u201d said Dr. Seibel. \u201cAnytime we see activity with brain and spinal cord tumors we get excited\u201d because there are very few treatment options for such patients, she added.<\/p>\n

Data on how well the treatment worked in children did not contribute to the agency\u2019s approval, however.\u00a0<\/p>\n

Under an accelerated approval, the drug manufacturer must further study and verify a treatment\u2019s clinical benefit.\u00a0<\/p>\n

NSCLC with ROS1 Alterations<\/h2>\n

The approval of entrectinib for people with NSCLC harboring ROS1<\/em> gene fusions was also based on results from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials.\u00a0<\/p>\n

Among participants with NSCLC harboring ROS1<\/em> fusions, entrectinib shrank the tumors of 40 out of 51 (78%) people, including 3 people who had complete responses. For more than half of the people whose tumors shrank, the response lasted for at least 12 months.\u00a0<\/p>\n

At the beginning of the studies, seven people with NSCLC harboring ROS1<\/em> fusions were found to have tumors that had spread to their brain or spinal cord, and entrectinib shrank these metastatic tumors in five people. \u00a0<\/p>\n

Although people with brain metastases have often been excluded from clinical trials<\/a> in the past, new guidelines aim to change that<\/a>.<\/p>\n

People with ROS1<\/em> fusion\u2013bearing NSCLC often develop metastatic tumors in the brain or spinal cord, Dr. Hong noted. Though radiation can sometimes shrink such tumors, treatments like targeted therapies and chemotherapy often don\u2019t work, he added.\u00a0<\/p>\n

Side Effects Include Heart Failure, Cognitive Effects\u00a0<\/h2>\n

The most serious side effects seen in the four clinical trials, as well as in other studies of entrectinib, were congestive heart failure<\/a>, central nervous system<\/a> effects (such as cognitive impairment and dizziness), and bone fractures. The most common side effects were fatigue, constipation, and a distorted sense of taste (dysgeusia).<\/p>\n

Children who received entrectinib were more likely than adults to experience certain adverse effects like neutropenia<\/a>, bone fractures, and weight gain.<\/p>\n

Effects on the central nervous system\u2014especially dizziness\u2014are expected from drugs that target NTRK<\/em>, Dr. Hong explained, because TRK proteins play important roles in the development and functions of the nervous system<\/a>.\u00a0<\/p>\n

\u201cOver time, patients can acclimate themselves and [those symptoms will] improve, but in a very small subset of patients, it can be a significant problem,\u201d he said.<\/p>\n

Overall, about 3% of patients experienced congestive heart failure, which, in most cases, resolved after entrectinib was paused or stopped and the patient was given other medicines to treat heart failure.<\/p>\n

Unlike larotrectinib\u2014which did not appear to cause congestive heart failure\u2014entrectinib targets multiple proteins. \u201cI suspect that\u2019s why it can cause heart failure,\u201d Dr. Hong said.<\/p>\n

A Choice of Treatment<\/h2>\n

The approval of entrectinib provides an additional treatment option for patients with advanced cancer, potentially creating the opportunity for patients and their doctors to choose between different therapies.<\/p>\n

For example, some adults and children with cancers that have an NTRK<\/em> fusion are also eligible for treatment with larotrectinib.<\/p>\n

For children, the choice between entrectinib and larotrectinib may come down to the patient\u2019s age and what type of cancer they have, Dr. Seibel said. Larotrectinib is available in a liquid formulation that is approved for children who are younger than 12 years old, she pointed out, whereas entrectinib is not. On the other hand, entrectinib may be effective for children with brain tumors, while larotrectinib\u2019s efficacy for brain tumors and brain metastases is currently being evaluated<\/a>. The two drugs also have different side effect profiles, Dr. Seibel added.<\/p>\n

And for people with NSCLC harboring a ROS1<\/em> fusion, the only other targeted therapy option<\/a> approved by the FDA is crizotinib (Xalkori)<\/a>.\u00a0<\/p>\n

Finding Rare Genetic Alterations<\/h2>\n

Gene fusions involving the NTRK<\/em> and ROS1<\/em> genes are found in around 1% of people with solid tumors and NSCLC, respectively. But for some specific tumor types, like mammary analogue secretory carcinoma (a rare salivary gland cancer) and infantile fibrosarcoma<\/a>, the prevalence of NTRK<\/em> fusions is nearly 100%, Dr. Hong noted.<\/p>\n

The gold standard for finding these fusions is a type of genetic test called next-generation sequencing.\u00a0<\/p>\n

\u201cThis approval, and the approval of larotrectinib, emphasize the need for next-generation sequencing profiling of patients\u2019 tumors, particularly metastatic cancer patients,\u201d Dr. Hong said, because sequencing can sometimes identify potential treatment options<\/a>. Although more people with metastatic cancer are getting these tests than ever before, it\u2019s nowhere near 100%, he added.\u00a0<\/p>\n

Yet some health care facilities are incorporating these tests into the standard procedure for people who are being diagnosed with cancer, Dr. Seibel pointed out.\u00a0<\/p>\n

\u201cIf we screen [patients] when they are first diagnosed, it may even turn out that [these gene fusions] are a bit more frequent than we think,\u201d she added.<\/p>\n

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

September 17, 2019, by NCI Staff NTRK gene fusions are found in around 1% of people with solid tumors but close to 90% of people with certain rare cancers like mammary analogue secretory carcinoma and infantile fibrosarcoma. Credit: National Cancer Institute On August 15, the Food and Drug Administration (FDA) granted accelerated approval to entrectinib […]<\/p>\n","protected":false},"author":2,"featured_media":12360,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-12359","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\/12359","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=12359"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/12359\/revisions"}],"predecessor-version":[{"id":44434,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/12359\/revisions\/44434"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media\/12360"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=12359"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=12359"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=12359"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}