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For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 12 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 11 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 9 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 9 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 8 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
À l'occasion du Masa, l'émission Légendes Urbaines a investi la légendaire place Ficgayo de Yopougon, à Abidjan, pour une émission spéciale tournée en public avec de nombreux artistes. Ce plateau exceptionnel a réuni plus de 7 500 personnes venues assister au spectacle de Dydy Yeman, TRK, Dopelym, Kadja, Suspect 95, Roseline Layo, Serge Beynaud, Yodé & Siro. De nombreuses surprises ont été concoctées en live avec le concours de Dj Mano, Good Of War, le Yoro Gang et Black M. 2h45 de show diffusées en deux parties sur nos ondes ! ► Abonne-toi à la chaîne YouTube @LUrbainesOff
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 7 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
À l'occasion du Masa, l'émission Légendes urbaines a investi la légendaire place Ficgayo de Yopougon à Abidjan pour une émission spéciale tournée en public avec de nombreux artistes. Ce plateau exceptionnel a réuni plus de 7 500 personnes venues assister au spectacle de Dydy Yeman, TRK, Dopelym, Kadja, Suspect 95, Roseline Layo, Serge Beynaud, Yodé & Siro. De nombreuses surprises ont été concoctées en live avec le concours de Dj Mano, Good Of War, le Yoro Gang et Black M. 2h45 de show diffusées en deux parties sur nos ondes ! Émission spéciale enregistrée en public à Yopougon avec Dydy Yeman, TRK, Kadja, Dopelym, Suspect 95, Roseline Layo, Serge Beynaud, Yodé & Siro ainsi que plein d'autres surprises ! ► Abonne-toi à la chaîne YouTube @LUrbainesOff
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 6 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 5 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-6-7/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 3 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-5/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 3 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! : https://www.therealitykingdom.com/survey/reality-rewind-season-5/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss episode 2 of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! : https://www.therealitykingdom.com/survey/reality-rewind-season-5/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
For the first time, TRK will be recapping Real Housewives!! Join us as we discuss the Premiere episode of #RHOA Join our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! : https://www.therealitykingdom.com/survey/reality-rewind-season-5/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Advanced practice providers discuss biomarker testing in patients with colorectal cancer. Listen in to learn from Ann Marie Siney, RN, MSN, ANP-BC, and Kathleen Boyle, DScPAS, PA-C, about familial cancer syndromes associated with colorectal cancer and key biomarker testing often used in patients with colorectal cancer, including their thoughts on overcoming key barriers to testing, education of patients and caregivers, and improving equity in the application of biomarker for all patients. Presenters: Ann Marie Siney, RN, MSN, ANP-BC Division of Hematology/Oncology UCLA Health Santa Monica, California Kathleen Boyle, DScPAS, PA-C Gastrointestinal Cancer Center Dana-Farber Cancer Institute Boston, Massachusetts Link to full program: https://bit.ly/4spkxiC Get access to all our new podcasts by subscribing to the Decera Clinical Education Oncology Podcast on Apple Podcasts, YouTube Music, or Spotify. Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.
Join Pharaoh, Lee, A'ja, Torre for TRK's 4th installment of Reality Rewind to recap episodes 12 & 13 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Join Pharaoh, Lee, A'ja, Torre for TRK's 4th installment of Reality Rewind to recap episodes 8 & 9 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Join Pharaoh, Lee, A'ja, Torre, and Dave for TRK's 4th installment of Reality Rewind to recap episodes 10 & 11 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Join Pharaoh, Lee, A'ja, Torre, and Dave for TRK's 4th installment of Reality Rewind to recap episodes 6 & 7 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Join Pharaoh, Lee, A'ja, Torre for TRK's 4th installment of Reality Rewind to recap episodes 4 & 5 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Join Pharaoh, Lee, A'ja, Torre, and Dave for TRK's 4th installment of Reality Rewind to recap episode 2 & 3 of Bad Girls Club Season 7: New Orleans #BGC #BGC7 #Baddies #RealityRewindJoin our Patreon for the exclusive TEA: https://www.patreon.com/cw/TheRealityKingdomUse this Link to cast your VOTE for what show you want us to cover next for our Reality Rewind! Maybe it'll make the list!: https://www.therealitykingdom.com/survey/reality-rewind-season-4-candidates/Join our Discord Here!: https://discord.gg/fsNhjTn9GS.JOIN OUR #REALITYREWIND COMMUNITY HERE!: https://twitter.com/i/communities/1864154372973973632Subscribe to The Scripted Kingdom Here!: https://www.youtube.com/@TheScriptedKingdomThank you so much for watching! We love doing this content for you guys so comment what you want to hear from us!If you would rather just listen, here's a link to the podcast version of our videos:Spotify: https://open.spotify.com/show/1m9Kzqe...Apple Podcasts: https://t.co/k5unAtBLn7?amp=1Follow Us:https://linktr.ee/TheRealityKingdomSupport the show
Are you regularly testing for TRK fusions in cancers with high fusion frequency? Credit available for this activity expires: 12/17/26 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/navigating-advances-trk-fusion-positive-cancers-2025a1000z5i?ecd=bdc_podcast_libsyn_mscpedu
MOSSAD'A SATILIK TÜRK DİPLOMAT
Year in Review: Clinical Investigator Perspectives on the Most Relevant New Datasets and Advances in Therapeutic Targets Beyond EGFR for Non-Small Cell Lung Cancer | Faculty Presentation 1: Therapeutic Approaches Targeting ALK, ROS1, RET, TRK and NRG1 — Jessica J Lin, MD CME information and select publications
En este episodio especial de Dame Rueda, el equipo se adentra en el complejo universo de las marcas de motos chinas. Con humor, análisis técnico y experiencias personales, intentan arrojar luz sobre la confusa red de fabricantes, marcas, sub-marcas y fusiones que dominan el sector. El episodio repasa los principales grupos industriales como QJ Motor, Loncin, CF Moto, Zontes, entre otros, y cómo muchas marcas occidentales están hoy fabricando en China. También se debate sobre la calidad, los controles de producción, la percepción del público, y se incluyen visitas a concesionarios y experiencias con modelos como Benelli, Boge, Voge, Zontes, Keeway, MITT, Macbor, FB Mondial, entre muchas otras. El episodio mezcla análisis de mercado, comparativas entre modelos, historia de las marcas y sus fusiones, y debate sobre la evolución tecnológica y la fiabilidad de las motos chinas en el mercado europeo y latinoamericano. Temas tratados: Grupos industriales chinos y su red de marcas (QJ Motor, Loncin, CF Moto…) Marcas europeas e hispanas fabricadas en China (Benelli, MITT, Macbor…) Análisis de calidad, repuestos y servicio postventa Opiniones desde España y México Experiencias personales en concesionarios Comparativas entre modelos populares (TRK, Leoncino, Napoleon, Imperiale…) Evolución del mercado de motos chinas en Europa y Latinoamérica Encuéntranos en: Whatsapp: http://wa.me/34644020615 +34 644 020 615 Email: Damerueda@gmail.com TIENDA: https://www.latostadora.com/shop/damerueda/?shop_trk Youtube: http://www.youtube.com/@damerueda Instagram Dame Rueda: https://acortar.link/bqWGOu Instagram Bicho Raro: https://www.instagram.com/bichoraro_damerueda/?hl=es Instagram Diez-Once: https://www.instagram.com/diezonce_damerueda/?hl=es Instagram TBO en moto: https://www.instagram.com/tboenmoto_damerueda Facebook: https://www.facebook.com/damerueda Telegram: https://t.me/dameruedagrupo Blog Dame Rueda: https://damerueda.home.blog/ Email: Damerueda@gmail.com TikTok: https://www.tiktok.com/@damerueda?_t=8jFKY9ClhWC&_r=1 Playlist Spotify: https://open.spotify.com/playlist/5nuJ547mcCQJPxzKJPL3jq?si=2216c3ad90d74240 Hashtags: #MotosChinas #Benelli #QJMotor #CFMoto #Zontes #Voge #MITT #MotoAventura #DameRueda #PodcastMotero #Motociclismo #Motos2025 #MadeInChina
Send us a textYou can tell a lot about Ted Russell Kamp from his grin. When he is playing a song or talking about touring, he lights up with a deep joy. Being an independent artist is not easy calling. You wear many hats, slog many miles, and suffer setbacks from missing strings to club cancellations. But those who can show they can take licks and deliver some guitar licks all the same with a sense of fun are the ones who make it. TRK has 17 albums out and his latest, California Son celebrates not only the free spirit that is California, but also is an anthem of love for his craft of songwriting and his love of those who have supported him through the years. We get to hear Ted talk about how he started and where he has been in the business. And we get a wonderful visit to his studio, where he plays us some of his favorite songs, including one with only a bass guitar for accompaniment. His website is www.tedrussellkamp.com.Support the showWe are always grateful to have you listening to STRUNG OUT. Here are some important links:SUPPORT THE SHOW:https://www.buymeacoffee.com/MartyfineaKMARTIN'S WEBSITE:http://www.MARTINMcCORMACK.COM (note---you can get my weekly bulletin when you sign up on the list!)MARTIN'S MUSIC: Music | Martin Laurence McCormack (bandcamp.com)Martin McCormack | SpotifyMARTIN'S YOUTUBE CHANNELMartin McCormack - YouTubeFACEBOOKFacebook...
HerpTime joins us to talk all things anole, how to keep them, how to breed them, and his philosophies regarding line breeding them. JOIN US ON PATREON: https://www.patreon.com/ReptilesandResearchPRODUCTS TO USE: https://www.amazon.com/shop/reptilesandresearchPHAILOZOO 15% OFF DISCOUNT CODE: R&RPHAILOZOO ENCLOSURES: https://phailozoo.co?sca_ref=8248864.jO3NsidwAzTHE REPTILE KEEPER 15% OFF DISCOUNT CODE: RNR15THE REPTILE KEEPER: https://thereptilekeeper.com/?amc=TRK-7-5601fbEMAIL► reptilesandresearch@gmail.com
Are you up to date on the use of tropomyosin receptor kinase (TRK) inhibitors in pediatric patients with TRK fusion-positive cancers? Credit available for this activity expires: 11/29/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/pediatric-trk-fusion-positive-cancer-optimizing-care-trk-2024a1000lmh?ecd=bdc_podcast_libsyn_mscpedu
BUFFALO, NY- February 19, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland.” Selective tropomyosin receptor kinase (TRK) inhibitors are approved targeted therapies for patients with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Country-specific estimates of NTRK gene fusion frequency, and knowledge on the characteristics of affected patients, are limited. In this new study, researchers Wei Zhang, Arndt A. Schmitz, Roosa E. Kallionpää, Merja Perälä, Niina Pitkänen, Mikko Tukiainen, Erika Alanne, Korinna Jöhrens, Renate Schulze-Rath, Bahman Farahmand, and Jihong Zong from Bayer HealthCare Pharmaceuticals Inc., University of Turku, Turku University Hospital, Technical University Dresden, and Western Finland Cancer Centre identified patients with histologically-confirmed papillary thyroid cancer (PTC) from Finland's Auria Biobank. “The study objectives were to determine the frequency of NTRK gene fusion in patients with PTC in Finland, and to describe co-occurring genetic alternations, clinical characteristics, disease progression, and treatment pathways in NTRK gene fusion positive patients.” TRK protein expression was determined by pan-TRK immunohistochemistry. Immuno-stained tumor samples were scored by a certified pathologist. Gene fusions and other co-occurring gene alterations were identified by next generation sequencing. Patient characteristics and vital status were determined from linked hospital electronic health records (EHRs). Patients were followed from 1 year before PTC diagnosis until death. 6/389 (1.5%) PTC patients had an NTRK gene fusion (all NTRK3); mean age 43.8 years (and none had comorbidities) at PTC diagnosis. Gene fusion partners were EML4 (n = 3), ETV6 (n = 2), and RBPMS (n = 1). Of 3/6 patients with complete EHRs, all received radioactive iodine ablation only and were alive at end of follow-up (median observation, 9.12 years). “In conclusion, NTRK gene fusion is infrequent in patients with PTC. Linkage of biobank samples to EHRs is feasible in describing the characteristics and outcomes of patients with PTC and potentially other cancer types.” DOI - https://doi.org/10.18632/oncotarget.28555 Correspondence to - Jihong Zong - jihong.zong@bayer.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28555 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, NTRK gene fusion, papillary thyroid cancer, clinicogenomic, epidemiology, biobank About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.
As care teams seek new ways to engage and support patients with rare cancers, CANCER BUZZ speaks with Jim Palma, executive director of TargetCancer Foundation, a patient-founded nonprofit organization dedicated to supporting patients living with, and researchers focused on, rare cancers. In this episode, hear about the fully remote TRACK (Target Rare Cancer Knowledge) clinical trial and its unique approach to providing access to biomarker testing for patients in community care settings by leveraging technology. “It [access to biomarker testing] really is one of the biggest challenges that patients with rare cancer face, as well as access to interpretation of results in a way that leads them to the right treatment. So, what we've done is developed a [fully remote] clinical trial that offers testing to patients at no cost and eases their ability to enroll in the trial through remote consenting.” – Jim Palma, Executive Director This is the third episode in a podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Jim Palma, Executive Director TargetCancer Foundation Cambridge, MA Additional Reading/Sources: · Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) · NTRKers Patient Community & Support (ntrkers.org) · NTRK Gene Fusion Infographic (ntrkers.org) · NTRK fusion-positive cancers and TRK inhibitor therapy
Building awareness of rare cancers, such as NTRK gene fusion-positive cancers, is critical to improving access to biomarker testing and new treatment options for patients. In this episode, CANCER BUZZ speaks with Susan Spinosa, president and patient founder of NTRKers, an organization created to support patients with NTRK fusion-positive cancer, about her care journey and the importance of testing for NTRK gene fusions. “What we want to have for every patient who is diagnosed with NTRK is accessibility...We need to test for it…it's a rare biomarker but in my mind, it should not be rare—the more testing we do the more routine it will become—and my hope is that 5 or 10 years from now, biomarker testing is routine and NTRK is not rare...” – Susan Spinosa, President of NTRKers This is the second episode in a podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Susan Spinosa President and Patient Founder NTRKers Additional Reading/Sources: · Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) · NTRKers Patient Community & Support (ntrkers.org) · NTRK Gene Fusion Infographic (ntrkers.org) · NTRK fusion-positive cancers and TRK inhibitor therapy
JCO PO authors Dr. Michael J. Kelley and Dr. Katherine I. Zhou share insights into their JCO PO article, “Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion–positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.” Host Dr. Rafeh Naqash, Dr. Kelley, and Dr. Zhou discuss the robust Veterans Affairs (VA) National Precision Oncology Program (NPOP), accurate identification of gene fusions, and toxicities landscape of TRK inhibitors. Click here to read the article! TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and assistant professor at the OU Stephenson Cancer Center in the Division of Medical Oncology. Today, I'm thrilled to be joined by Dr. Michael J. Kelley. Dr. Kelley is the executive director of Oncology for the Department of Veterans Affairs. He's also the chief of Hematology-Oncology at the Durham VA Medical Center, and also a Professor of Medicine at the Duke University School of Medicine. And he's also a member of the Duke Cancer Institute. We are also joined by Dr. Katherine I. Zhou who is a Hematology-Oncology fellow at the Duke University. Dr. Zhou also spent time at the Duke Medical Center as part of her fellowship training, which I believe is how this project that was led by her came to fruition. So thank you both for joining today. This is going to be, hopefully, of very high interest to our listeners and I look forward to chatting with you both. Dr. Michael Kelley: Great, thanks for having us. Dr. Katherine Zhou: Thank you for having us. Dr. Rafeh Naqash: Thank you so much for joining. So I was very intrigued with this paper, and this paper follows a recent podcast that we had with Dr. Alexander Drilon, who's led some of the NTRK tropomyosin receptor kinase inhibitor studies that have been published in the last several years. And we had a very interesting discussion a couple of weeks back and I felt this was going to be a very interesting subsequent discussion into what was also an interesting discussion with Dr. Drilon. So what caught my attention is obviously the fact that you guys in this report, which is a real-world report, did not exactly see what we generally expect from clinical trials as far as response to target therapies in NTRK fusions. So before I ask you questions related to this project, one of the very interesting things at least I found was the fact is that the Veterans Health Administration is the largest integrated health system. Studies, whether conducted in the UK, for that matter European countries, or in Canada, they have integrated health systems which we do not. But we do have this advantage of the VA trying to do things in a very unique, centralized manner. So I wanted to ask Dr. Kelley first, how is it that you have implemented this National Precision Oncology Program, the NPOP as you call it, into the VA precision medicine workflow and how does it help in conducting research studies like the one that you published in the JCO Precision Oncology? Dr. Michael Kelley: Yeah, thanks for that question, Dr. Naqash. The NPOP started in 2016 as a national program and right from the beginning it grew out of an effort that was a joint collaboration between both clinical operations in the VA and the Research Office or the Office of Research and Development. It was designed from the very beginning to support discovery, new knowledge generation, and identifying patients for clinical trials in addition to bringing them best-in-class molecular testing and a consultation service. So it was initially funded out of the Cancer Moonshot 1 in 2016 when President Biden was then Vice President. The VA endorsed the model going forward in 2019 and now it's continued on and grown even bigger, it's expanded both in terms of scope and the complexity of the testing that's been done. So it was offered as services to facilities. They didn't have to do this, but I think they all saw the value of using NPOP to provide this group of services and that's what led to the generation of the robust underlying dataset that Dr. Zhou has used for this paper. Dr. Rafeh Naqash: Definitely. Thank you so much for that explanation. I did not know, and was not well aware, of how robust this program is. So I think it's a great learning opportunity for our listeners to know that a program like this exists. As we all know, there are different platforms, sequencing platforms, that each institution uses, whether it's commercial or whether it's in-house based. But the fact is, until and unless we have big pool datasets like the ones that you have generated or have access to, it's not easy to answer real-world questions. So first of all, I'd like to congratulate you and the rest of the VA administration to set up a program like this that hopefully is helping in matching the right patients to the right therapies and in clinical trial approvals. Now, before we take a deeper dive into the study that Dr. Zhou led, I did want to ask you, you have access to this amazing centralized platform, what are the kind of sequencing strategies or platforms that you use as part of this program? And is there an incorporation of molecular tumor boards to help understand some of these sequencing results that sometimes can be a little complicated to understand even for oncologists who look at these reports on a daily basis? So could you tell us a little bit more about that, Dr. Kelley? Dr. Michael Kelley: Yeah, certainly. So the VA contracts for the sequencing service, currently we're contracting with Foundation Medicine and Tempus for the comprehensive genomic profiling. There are some other services, and before we started using Foundation, there were two other companies that we used. There is a molecular tumor board. Our molecular oncology tumor board is designed primarily for case-based education. But there's also an asynchronous on-demand consultation service that occurs electronically because we have a unified electronic health record system. So any oncology provider in the country can enter a request through what's called an interfacility consult. It comes to a team, that team vets that, discusses it with the appropriate experts; that includes molecular oncologists, molecular pathologists. A lot of oncology pharmacists have been trained at a course that's at the University of Kentucky. And we have a lot of experience in doing this since that service was set up in 2016 as well, right from the beginning, because we understood the complexity of the data and the need for every oncologist across our enterprise to have access to the very best interpretation of that. We also have educational sessions that are integrated into the molecular tumor board time slot we call primers in terms of the underlying science of why you do the interpretations the way you do. And then there's also some additional education that we'll be endeavoring to offer to our staff and our oncologists coming up this year. Dr. Rafeh Naqash: Excellent. It sounds like you definitely have taken this into a very multidisciplinary approach where you're incorporating oncologists, pharmacists, and perhaps even genetic counselors and then, obviously, keeping the patient at the center and trying to find the best possible therapies that are most relevant for that individual. Now, going to Dr. Zhou's study here. Dr. Zhou, first of all, it's great to see a fellow lead a study and then especially, I think you're our first fellow on the podcast. We've had a lot of different individuals, but we have not had a fellow before. So thanks for coming. Could you tell us, for our listeners, what drove your interest into NTRK fusions? As we know, they are rare, something that is not commonly seen, and we do have clinical trial data in this space. So what was the idea behind looking at a real-world data set? Did you start out with a hypothesis or were you just interested to see how targeting these fusions in the real-world setting, actually, what kind of results does it lead to? Dr. Katherine Zhou: Yeah, well, first of all, thanks for the question. And I do just want to mention that although I did sort of bring this project to the finish line, it was started by another fellow, Vishal Vashistha. So just wanted to mention that. And I think the interest was really just that NTRK is such a rare fusion and just a difficult one to be able to study, like you said, in the real-world setting. And we have the advantage of having so much data through the VA and through NPOP, specifically. And so having seen such great results with the TRK inhibitors and clinical trials, I think there's this big question of how that translates into the real-world setting. We have the ability to do that with our large patient population. Dr. Rafeh Naqash: Excellent. And again, it's nice to acknowledge the support that you had from the other individual who co-led this study. Now, since you would have, I'm guessing, done most of the analysis here and looked into the whole idea of the kind of results that you saw—and from my understanding, you looked at the entire VA data set and tried to understand first the incidence or frequency of NTRK fusions and also responses to treatment, which I think is the main message—but could you tell us a little bit more about the data set? How did you acquire the data set, and what it took to analyze? Because obviously every project has a very unique story, and I'm guessing there's one very unique story here, since as a fellow you have limited time to do all this interesting work. So how did you navigate that and analyze and work with some of the things that you had to look at to get to the results? Dr. Katherine Zhou: Yeah, so again, this was work that was done with multiple people involved, of course. And we used what we had, the resources we had available, some tools we had available through the VA. So first, looking at NPOP and looking at patients who are sequenced through NPOP, we could just find all the ones who had an NTRK rearrangement of some kind. The second way we went about finding patients was through the CDW or the Corporate Data Warehouse where we could see which patients were prescribed larotrectinib or entrectinib and kind of go backwards from there and see which of those patients had NTRK alterations or specifically NTRK rearrangements. And so we combined the patients from both of those different methods to come up with our cohort at the end of 33 patients with NTRK rearrangements and 12 patients who are treated with TRK inhibitors. Dr. Rafeh Naqash: Excellent. Could you walk us through what was the subsequent analysis as far as how many NTRK fusions? I know you mentioned in the paper about DNA versus RNA-based testing. So how many were DNA-based, how many were RNA-based? I think there's some element of ctDNA-based testing also, or what tumor types those people had so that we get an understanding of what's the landscape of the findings that you had. Dr. Katherine Zhou: Sure. Since this is a real-world setting, as you may expect, the vast majority of the sequencing was done through tissue DNA sequencing, and that was the case. So for the 25 patients who were sequenced through NPOP that we found who had NTRK rearrangements, 23 of them had tissue DNA sequencing. And then one was tissue DNA RNA, and one was cell-free DNA sequencing. And so using that and being able to go back and look at how many patients have been sequenced in NPOP in total, we could kind of come up with a yield, although the numbers are very small. But we do see that there does seem to be probably a lower yield, for example, with cell-free DNA sequencing, as one might expect. And then looking at our total group of 33 patients, if we look at what types of cancers they had, we did have quite a few patients just based on prevalent tumors at the VA, I think, and in the population, prostate cancer was common, lung cancer, and then we had smaller numbers of colon and bladder, and I think there's a pancreatic cancer patient. We did have some of these rarer tumor types that more commonly have NTRK fusions as well, so like papillary thyroid carcinoma, and salivary gland cancers as well as soft tissue sarcomas. Dr. Rafeh Naqash: Question for you, Dr. Kelley, related to this data set: do you think that given that the denominator that you have is a unique population, the VA population, that's often males, they're usually above the age of 18, could the frequency have been influenced by that denominator where you may not have been able to capture, let's say, some of the rarer tumors that happen in the younger patient population, for that matter? Could that be a little bit of a bias here? Dr. Michael Kelley: Definitely. The population of veterans that have cancer that is treated in the Veterans Health Administration do represent generally adult males in the United States, but there is some skewing in certain regards. One of them is towards a higher frequency of smoking status. So not current smoking, which is actually about the same as the national average of about 11%, but the former smoking rate is about twice as high as it is in the rest of the United States. So we may have a lower frequency of some actionable variants in cancers in general because there's a higher etiological role for tobacco smoke in our population. But overall, looking at adult men if we look at like EGFR mutations, our incidence of EGFR mutations in adenocarcinoma is similar to what is reported in other real-world evidence bases from the United States, which is significantly lower than that which is found in academic medical centers. Dr. Rafeh Naqash: Thank you. I'm a big fan personally of real-world data sets. I do a lot of this with some other collaborators and generally, I do phase I trials, which is why I'm interested in precision medicine. And two weeks back, actually, I had a patient with prostate cancer, who ended up having NTRK fusion on a liquid biopsy. Now, you do talk about some of this related to in-frame or out-of-frame fusions and how that can have interesting aspects related to the kinase domain functionality and RNA expression. Dr. Zhou, for the sake of our listeners, could you briefly describe why understanding some of that is important and what implications it has? Dr. Katherine Zhou: Yeah, so I think the oncogenic NTRK fusion that we think of and that's being targeted by the TRK inhibitors is a fusion 5-prime of a protein that forms a dimer and on the 3-prime end is the kinase domain of the tropomyosin receptor kinase. And so you have to have some kind of a gene fusion that results in not only the transcription of that RNA fusion, RNA transcript, but then the translation of that fusion protein. So that needs to be, like you mentioned, that has to be in frame so that the entire protein is translated and expressed and it needs to include the kinase domain. It can't be the other end of the NTRK gene. And both of the genes need to be in the same orientation, of course. And then also the partner gene probably matters in that the ones that we know that actually cause activation of this oncogene are the ones that sort of spontaneously dimerize. And so that's a lot of requirements that we don't necessarily see when we just get, for example, a DNA sequencing result that says there's an NTRK rearrangement. Dr. Rafeh Naqash: Excellent way to describe the importance of understanding the functionality of the activated oncogenic fusion. Now, I know here in most of the patients that you have is DNA sequencing and I'm sure you'll talk about some of the results. And when you connect the results to the kind of data that you have, do you think not having the RNA assessment played a role in not knowing perhaps whether those fusions were functionally active? Dr. Katherine Zhou: Yes, I think we can't know for sure without having the RNA sequencing data. But certainly, that is a pattern in our small number of patients that we saw and something that makes sense just in terms of the mechanism of this oncogenic fusion protein. So I think that is a question of when should we be doing RNA sequencing to confirm that a fusion that we see on DNA sequencing is actually transcribed into RNA and how do we use RNA sequencing in a cost-effective and useful way to be able to detect more of these NTRK fusions that are actually clinically relevant. Dr. Rafeh Naqash: I absolutely agree with you and this is an ongoing debate. I know some platforms, commercial platforms that is, have incorporated RNA sequencing both bulk or whole transcriptome as part of their platform assessments, but it's still not made inroads into some other sequencing platforms that are commercially used. So it's an ongoing debate, but at the same time helping people understand that certain fusions need some level of RNA assessments to understand whether they're functionally active or not. Which again has implications, as you pointed out in terms of therapies are extremely relevant. Now, going to the results, which again was very interesting, could you tell us about the findings from the therapeutic standpoint that you observed and what your thoughts are about why you saw those results which were very different from what one would have expected? Dr. Katherine Zhou: Right. So in the clinical trials of larotrectinib and entrectinib, there were quite high objective response rates on the order of 60%, 70%, even almost 80%. In our very small real-world group of 12 patients who were treated with TRK inhibitors, nobody had an objective response and five patients had stable disease and everybody else, the other seven patients, progressed. And so the question is why did we see such a big difference compared to the trials? I sort of think of this as two big buckets. One is the population that we were looking at. So this is a real-world population. For example, in the clinical trials, there were almost no Black or African American patients, whereas here we had about 30%-40% Black or African American patients. Because it's a VA population, it was very heavily male, of course, the age groups are also different in that we didn't have children in the VA population whereas children were included in the trials. And the tumor types also differed because I think in the trials, which makes sense, there's a bias towards tumor types that have more NTRK fusions, and some of the tumor types we were looking at are just common tumor types like prostate and lung cancer where NTRK fusions are not common. But just because there are so many patients with these cancers, we did see them. And so certain of these groups, particularly certain racial and ethnic groups as well as certain tumor types, were not really represented in the trial to the extent that we can make conclusions about whether TRK inhibitors are effective in this population. So that's one. The second part, I think we've already talked about some, is just the method of detecting these NTRK fusions and how many of these NTRK fusions were actually truly producing oncogenic fusion proteins. And I tried to sort of categorize some of these fusions as being canonical in that they've been more studied. We know the partner gene, they are known to produce an oncogenic protein and to respond to TRK inhibitors. But actually of the four patients who had what we called canonical fusions, all four of them had stable disease at least, whereas the ones that were noncanonical mostly did not have a response or have even stable disease and mostly just progressed. And so then you wonder whether they even had the actual target protein we thought we were targeting. So this is where the real-world setting we're not doing the RNA sequencing or this additional testing to confirm that it's an oncogenic fusion protein. Dr. Rafeh Naqash: And I do see in your results there's a patient especially—you pointed out canonical and noncanonical fusions—you have a patient with a papillary thyroid cancer that I believe had a stable disease for close to two years plus. Is there anything interesting apart from an NTRK fusion in that specific patient where certain co-mutation could have played a role or certain other factors that do you think played into the fact that this patient had stable disease but didn't respond on the TRK inhibitor? Dr. Katherine Zhou: I don't have a great answer for that. I think this is one of the cancers that was well represented in the trials and that commonly has NTRK, or more likely has NTRK fusions. And this was a well-studied canonical NTRK fusion. So I think those are all reasons. The question of co-mutations I think is really interesting. We didn't have the data for every single patient, but for the ones we looked at a lot of the time, NTRK fusions are mutually exclusive with other driver mutations. So we didn't see a whole lot of commutations that we could sort of differentiate between responders or stable disease and progression. Dr. Rafeh Naqash: Thank you. Going to the toxicities, as a phase I trialist myself toxicity is the bane of my existence where we have to label toxicities, attribute toxicities, understand toxicities. The trial, obviously, as you very well know, that in the trials, they didn't have a lot of toxicities that caused patients to come off or required significant dose reductions, which is not the case compared to what you saw. Could you tell us a little bit about the landscape of toxicities for TRK inhibitors and what you saw in your cohort? That, again, I feel was interesting. Dr. Katherine Zhou: Of the 12 patients, I think two-thirds of them had either dose reduction or interruption or discontinuation, or some combination of the above. The toxicities we saw were more common than, or at least led to discontinuation and interruption and dose reduction more commonly than in the trials. But the toxicities we saw were also seen in the clinical trials. So LFT elevations, creatinine elevations, neurotoxicity, some cytopenias. We didn't actually see a whole lot of that, but those were present as well, and then some sort of nonspecific things like fatigue. And so, as much as we could tell from retrospective trial review, at least these were severe enough to lead to holding the drug. Dr. Rafeh Naqash: Thank you so much, Dr. Zhou. Question for you, Dr. Kelley. Putting this into perspective, the analysis that you did, how would you connect it to other real-world questions that one could answer using these kinds of data sets? So basically, what are the lessons learned from this amazing program that you guys have run successfully and are, I'm guessing, expanding in different directions? And how can you use a program like this to look at some of these unique questions using real-world data sets? Dr. Michael Kelley: There are a couple of, I guess, next steps for us that are based off this study and other information that we've gotten in other analyses from our NPOP data set. So, first of all, access to an RNA-Seq test. So that has been resolved to some extent, in that we now have two options for comprehensive genomic profiling, one of which does have RNA-Seq. And then the other approach that we're doing is to do more robust data generation. So we're going to be launching a study to collect prospective data on patients who are treated with off-label drugs. And as part of that, we will also have an on-label cohort for rare populations or any investigator in the VA who's interested in a particular drug or a particular genetic variant. They'll be able to tie into this protocol, and we will then collect data from across the system prospectively, which we think will improve the quality to some degree. And then thirdly, I think there's an opportunity to merge the initial generation of data in rare genetic types or other populations, which are highly selected by doing a distributed type of clinical trial where patients can be enrolled in prospective treatment trials. So we're not just generating data based on their real-world exposure to FDA-approved drugs, but we're generating data as we're developing the new drugs, we can have a much more heterogeneous and representative population of patients enrolled in clinical trials. So this is called the decentralized clinical trial model. We're starting to launch some trials with industry partners in this area to test out the model. If it works, I think we'll be able to help contribute to the knowledge that we all can use in terms of the patient types, the patient characteristics, but also some of the different tumor characteristics, and also to bring clinical trial opportunities to a more representative group. A lot of the initial clinical trials are done in urban areas, rural populations in VA are about a third of our patients live in rural areas, compared to only 14% of the country. So we think this is a very important diversity issue that should be addressed. Those are some of the ways that we're taking a lesson from this trial and other data that we have to sort of bring it forward. Dr. Rafeh Naqash: Those are excellent next steps and I think the kind of work that the VA is doing and this specific program, Precision Oncology Program, the NPOP program is doing, it's definitely setting up a unique standard in the United States where we have been limited by not having a centralized database. So setting something up of this sort hopefully will help answer a lot of these unique, interesting questions as you have access to data. And then the fact that you mentioned decentralized clinical trials and trying to cater to this access issue for patients in the VA system, I think that would be huge. And again, I congratulate you and your team on these efforts, and once again, thank you for joining us today and making JCO Precision Oncology a destination for your interesting work. We hope to see more of this work subsequently and hopefully, I get a chance to talk to you more about all the exciting stuff that you guys are leading within the VA health system. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Bios: Michael J. Kelley, MD, is Executive Director of Oncology for the Department of Veterans Affairs, Chief of Hematology-Oncology, Durham VA Medical Center, Professor of Medicine at Duke University School of Medicine and Member of the Duke Cancer Institute. Katherine I. Zhou, MD, PhD is a hematology-oncology fellow at Duke University. She also spends time at the Durham VA Medical Center as part of her fellowship training. COIs: Michael J. Kelley, MD Research Funding: Novartis (Inst), Bristol-Myers Squibb (Inst), Regeneron (Inst), Genentech (Inst), EQRx (Inst) Katherine I. Zhou, MD, PhD: No disclosures
As biomarker testing can play a critical role in the diagnosis of rare cancers, such as NTRK gene fusion-positive cancers, hear what care teams need to know about identifying patients who may be eligible for this testing. In this episode, CANCER BUZZ speaks with Eric Konnick, MD, MS, associate professor of Laboratory Medicine and Pathology and associate director of Genetics and Solid Tumor Laboratory at the University of Washington Medical Center Fred Hutch Cancer Center about the importance of testing for NTRK gene fusions. “It's really important to test our patients for these [NTRK gene fusions] because there are very effective treatments now that can have dramatic effects on the outcome of these patients' disease course, so identifying patients that can be eligible for therapy is critical…” - Eric Konnick, MD, MS This is the first episode in a four-part podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Dr. Eric Konnick, MD, MS Associate Professor of Laboratory Medicine and Pathology Associate Director of Genetics and Solid Tumor Laboratory Director of Genetics Preanalytical Services Fred Hutch Cancer Center, University of Washington Medical Center Seattle, WA Additional Reading/Sources: · Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) · NTRKers Patient Community & Support (ntrkers.org) · NTRK Gene Fusion Infographic (ntrkers.org) · NTRK fusion-positive cancers and TRK inhibitor therapy
JCO PO author Alexander E. Drilon, MD, shares insights into his article, “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers” and the article's findings of the activity of larotrectinib in patients with advanced lung cancer harboring NTRK gene fusions. Host Dr. Rafeh Naqash and Dr. Drilon discuss drug development, testing for fusions, resistance mechanisms, and cancer metastases. Click here to read the article! TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center. Today we are excited to be joined by Dr. Alexander Drilon, Chief of the Early Drug Development Service and Medical Oncologist on the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center and lead author of the JCO Precision Oncology article “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers.” Our guests' disclosures will be linked in the transcript. Dr. Drilon, welcome to the podcast and thank you for joining us today. We're really excited to be discussing this topic with you. Dr. Alexander Drilon: It's my pleasure and thank you for the invitation. Dr. Rafeh Naqash: For the sake of this podcast, we will refer to each other using our first names. So, Alex, you've led the development for some of these agents targeting NTRK. So it's really timely that you're coming onto this podcast to not just discuss this very interesting paper that you published in JCO Precision Oncology, but also the general landscape of NTRK. So could you briefly tell us about the history of the drug development process behind NTRK fusions, when it started, how you got involved, and where it stands currently? Dr. Alexander Drilon: Sure. So, as you mentioned, my background is in lung cancer, where when I came on as a fellow, there was a lot of excitement around EGFR and ALK, but then subsequently other oncogene drivers were also discovered and many of them were fusion. So, as we know, ALK in the fuse state is a driver of many tumors, as is ROS1 and RET. And interestingly, NTRK fusions share many similarities with ALK, RET, and ROS1 in that you have an intact kinase domain that's in the three prime position, it's fused to a different gene in the five prime position and basically describes oncogenesis. And the beautiful thing about NTRK fusions is that they are widely found across many different cancers. And I like to think of these cancers in two major buckets. So there is a bucket for cancers that are rare where we see these NTRK fusions with a very high frequency. And examples here are your secretory carcinomas of the salivary gland and the breast, for example, more congenital fibrosarcoma, where the frequency exceeds 90% in some series, and then there are much more common tumors where the frequency is much lower. So lung cancer is an example where you find it in less than 1% of cases. There are some other tumors like GI cancers also where the frequency is low. And beyond these two major groups, we also see these NTRK fusion-positive cancers occur not just in the adult population, but the pediatric population. All of that thrown together means that it was a really great setup for exploring the activity and safety of targeted therapy in what we call a ‘basket trial' paradigm, where you design a trial and instead of selecting patients based on cancer type, you ignore cancer type and, of course, you accrue by an enrolling alteration, which in this case is the NTRK fusion. Dr. Rafeh Naqash: Excellent. Thank you for that summary. It's interesting that just yesterday in my phase I clinic, I had an individual who was supposed to go on a certain study, and liquid biopsy came back and showed an NTRK fusion for a very odd presentation of a prostate cancer, which, again, got me thinking about the paper that you published trying to read about NTRK and then this happened and I got thinking about a bunch of other questions. But, for starters, though, from a receptor standpoint and I know you published on this in different journals, could you briefly tell, for the sake of the audience, describe the pathway and the tyrosine kinase signaling and associated resistance pathways that are concurrently acting in a different direction, perhaps, and also discuss briefly from neural development? I know the pathway, the NTRK gene or TRK gene as such is involved in different neuronal signaling aspects. Could you briefly touch on that? Dr. Alexander Drilon: Sure. And thankfully there are a lot of parallels with other things that perhaps some of the listeners are more familiar with. We'll start with the fact that it is a receptor tyrosine kinase, NTRK. It's a gene that encodes a receptor tyrosine kinase just like other receptor tyrosine kinases that may be fused such as ALK, RET, and ROS1. But remember also that other RTKs are EGFR, FGFR, which are also well known. The important thing to remember for NTRK is that you have three different genes, NTRK 1, 2, and 3 that encode three different proteins which are called TRK A, B, and C. And as you intimated, in the non-oncogenic state, these are very important for the development and the maintenance of the nervous system. And in the fused state, of course, similar to other fusions that we spoke about, the chimeric oncoprotein will drive downstream signaling and tumor growth and metastases. And in general, these cancers can be very reliant on downstream signaling in the MAP Kinase pathway but may also on occasion activate other downstream pathways like the PI3 Kinase pathway. Dr. Rafeh Naqash: And I know some of that could potentially play into resistance mechanisms for some of these first or second-generation NTRK inhibitors. From a fusion partner standpoint, the data that I came across that you're very well aware of is different fusion partners, and maybe some have a slightly better prognosis than some other fusions. But, in your practice and in your experience, does it matter what the other fusion partner is if the kinase domain is intact, meaning the signaling for the NTRK gene is intact? Have you seen any differences there from the other fusion partner standpoint? Dr. Alexander Drilon: From a patient-matching perspective, as long as you think the fusion is real, and by that I mean that you look at the report and you're sure the kinase domain is there and you're sure it's in frame, meaning connected well to the five prime partner so that the DNA strand is read through, the five prime partner does not play a major role in my deciding to give a TRK inhibitor or not. I would give anyone with a functional NTRK 1, 2, or 3 fusion a TRK inhibitor. Now, the data on whether or not select fusions do better than others is, I would say, still a little immature and perhaps conditioned by a few things. There are some of the cancers in the first bucket that we talked about, like the secretory carcinomas that harbor a recurrent event such as ETV6 NTRK3. And those cancers, in my experience in clinic, patients with those tumors can be on a TRK inhibitor for a very long time. And it's unclear if that's because of the exact fusion event or if it's because of the cancer type that might be more, say, genomically naïve compared to a gastrointestinal tumor, like a colorectal cancer with an NTRK fusion. So I hesitate to say that there are very strong and convincing data that if you have a particular five prime partner, you'll absolutely do better or worse. So, in the interim, I think the most important piece is just making sure that the event is real and actionable, and if it is, then you can give a TRK inhibitor. Dr. Rafeh Naqash: Thank you so much. I totally agree. And I think, for the sake of our listeners, as we see more and more sequencing being done on patients with cancer in the advanced stage setting especially, it's important to keep in mind when you have something that you can act on that has an actionable target that is FDA approved, then it's important to give the patient that option, especially in rare fusion events such as NTRK or TRK. Now, you've touched upon this in your paper, but before we go into the details of the paper, specifically, I wanted you to briefly talk about the testing mechanisms which are important for some of these fusions and play into, for example, ROS1 ALK fusions also. Could you tell us what are the most appropriate ways to test for these fusions in patients harboring cancers, both from a tissue standpoint and from a blood-based assay standpoint? Dr. Alexander Drilon: This is a great question because if you don't have a test that's optimally poised to pick up an NTRK fusion, then you can't act on it. And a patient who would have benefited very durably from a TRK inhibitor won't get access to it. So there are different ways of testing for NTRK fusions, and I like to think of the central dogma here where you have DNA becomes RNA becomes protein because that really helps anchor the different types of assays that you might use. We commonly use next-generation sequencing of DNA, but even if you have a very good next-generation sequencing assay, that does have its limitations because there are some fusions that are structurally just difficult to pick up even with a great DNA-based NGS assay. And for that reason, we and others have found that in tumors that have an equivocal NTRK fusion, or perhaps where you didn't find something but you really suspect that you missed something, particularly in cases where, historically, like congenital fibrosarcoma where you know there's a very good likelihood of finding NTRK fusion, we then reach for an RNA-based assay because at the RNA level, you've removed things like the intra-DNA based capture challenging. And so I think that from a nucleic acid standpoint, leveraging a test that looks both at DNA and RNA, maximizes the likelihood of finding this fusion. And just remember that there are different NGS assays in terms of the approach to design and some might be more Amplicon-based and that's less optimal, but the hybrid-capture-based ones tend to be better. The DNA and RNA tests can be done on tumors, and in blood, you could do a liquid biopsy. It's very hard to fish out RNA in blood given the current technology so we're still limited to circulating tumor DNA which shares the liabilities of doing DNA testing on a tumor sample. But if you find it and it looks real, then it's certainly actionable even if you detect an NTRK fusion with a liquid biopsy. Now going back to the central dogma there, the third piece which we haven't touched on is protein. And there have been many papers published now on the utility of immunohistochemistry, and this helps you confirm that the TRK A, B, and C proteins are actually expressed. And what tends to happen is in many fusions, the chimeric oncoproteins strongly express as TRK A, B, and C that helps provide a complementary test or assay that confirms that you're dealing with something that is actionable. So that is a very contemporary approach and a very thorough approach to looking for these NTRK fusions where you do DNA and RNA if possible. And if you still have questions, ask your pathologist to see if they can do Pan-TRK IHC. But depending on the resource environment that you're in, there are older tests like FISH which we use for ALK that can also find these fusions. RT-PCR which only finds particular events, these can detect NTRK fusions but really don't have the breadth and comprehensiveness as the other assays that we discussed like NGS. Dr. Rafeh Naqash: Thank you so much, Alex, for that amazing summary of all the methods that potentially could help detect this rare but important event. From a therapeutic standpoint, now, taking a deeper dive into your very interesting JCO Precision Oncology paper that looked at larotrectinib data from a pooled analysis of two trials, a phase II and a phase I. Could you tell us a little background about these two trials, the patient population and what kind of data were you trying to evaluate? And then we can discuss some of the interesting results that you showcase in the paper. Dr. Alexander Drilon: It really helps as a background to realize that the initial approach to this was really on a basket trial where the programs for larotrectinib, which is a selective TRK A, B, and C inhibitor, and the other drug entrectinib, which inhibits ROS1 in addition to TRK, really accrued pediatric and adult cancers with NTRK fusions. And this paper pulls out the lung cancer subset and we'll discuss that in detail. But before getting into that, it's important to know that in the tumor agnostic data set of all patients with an NTRK fusion of any type, larotrectinib achieved a response rate of approximately 80%, entrectinib of approaching 60%, and disease control was durable with a median PFS for larotrectinib of approximately 28 months, and with entrectinib numerically, the number was lower at 11 months. So with that background, this paper in JCO PO, in the interest of featuring the activity for lung cancers with NTRK fusions, pulled out 20 patients with NTRK fusion-positive lung cancers. And the punchline is that the activity was pretty comparable to that seen with a bigger data set. So the objective response rate was 73% and many patients had a partial response, 67% of the cases, 7% had a complete response, and really only a minority had primary progressive disease, 1 patient out of the 15 evaluable patients. These responses and clinical benefit overall were durable and the median duration of response was almost 34 months, with a median progression-free survival of almost 35 and a half months and an overall survival median of 40.7 months. And just to talk about how that stacks up compared to other targeted therapies, this certainly is in the ballpark of some of the best ALK inhibitors that we have for ALK fusion-positive lung cancer. It's also comparable to osimertinib for EGFR mutant lung cancer. So we can confidently view TRK inhibition in lung cancers with NTRK fusions as a highly-active therapy. Dr. Rafeh Naqash: Absolutely. I think you touched upon this earlier where in your cohort at least 50% of patients had central nervous system involvement, and it looks like larotrectinib does have CNS activity and benefit. Could you speak to the differences between potential entrectinib and larotrectinib from a CNS efficacy standpoint? And the second part of that question was going to be when you identify this fusion in patients, for example, with lung cancer, now, since TRK does have a role in neuronal development, do you think there is a role for closer CNS monitoring in these patients if they have not had brain metastasis identified because of the fact that they have an NTRK fusion? Is there some predilection for CNS involvement from a metastasis standpoint? It's just something that I've been thinking of over the last couple of days after I saw my patient who does have CNS involvement but with prostate cancer, which I have not seen in the phase I setting in all the prostate patients that I've come across. So what are your thoughts on that? Dr. Alexander Drilon: These are great questions. In lung cancers with NTRK fusions, there is a proclivity for metastasis to the CNS. And thankfully, both of these TKIs, larotrectinib and entrectinib, do have coverage of the CNS. Now, from a design perspective, the initial thought was perhaps entrechtinib was more CNS-penetrant. But if you look at the overall response rates in patients with brain metastases and the intracranial response rates where you have patients with target lesions in the brain that you're able to measure; if you look across the aisle, entrectinib and larotrectinib have comparable results, with the objective response rate being in the order of 50% to 60% and the intracranial response rate being also in the order of about 50% to 60%. So at the end of the day, it appears as if, despite the previous hypothesis that maybe one drug would work better in the CNS than the other, we're seeing equally good effects with both drugs. For the second question you asked, it's also a very interesting question because, like you mentioned, the TRK receptors play a role in nervous system development. But we have not observed a much higher frequency of CNS metastases in NTRK fusion-positive lung cancers or cancers in general that I know of, compared to cancers that are wild type for an oncogene or have other oncogenes. So what's more important really to think about when you sort of chew on the fact that these TRK inhibitors are involved in nervous system development are the potential side effects that you may see in patients that you treat with these TRK inhibitors. Dr. Rafeh Naqash: Absolutely. Now, from the therapy standpoint that you discuss here, duration of responses, objective responses that you saw in your analysis were very impressive for these patients with lung cancer. In your clinical practice if you see a lung cancer patient with this fusion and you treat them with larotrectinib or entrectinib, and they have, let's say, de novo CNS metastases that are asymptomatic, do you generally try the targeted therapy first and hold off, perhaps, brain directed therapy in that setting? Similar to what one would do with osimertinib perhaps or alectinib? Dr. Alexander Drilon: Absolutely. It's the same paradigm because we know that we are seeing in a larger population of patients, just generally good activity, both extracranially and intracranially. The goal is to try to spare patients the extra side effects of doing radiation by only giving the TKI. And in practice, even outside of the trial, in patients that I've treated with CNS metastases, the activity has been very good. Dr. Rafeh Naqash: Thank you so much. Now, all TKI therapies have, unfortunately, resistance mechanisms that come up eventually, in my experience at least. What is your experience as far as understanding resistance mechanisms on TRK-based therapies and potential second options after that, whether it's second-generation TRK inhibitors or subsequent targeted therapies in this space? Dr. Alexander Drilon: Thankfully, this has been looked at extensively and I like to categorize resistance into two major groups. So there's a type of resistance which we call on-target resistance and another type which we call off-target resistance. In simple terms, cancers that acquire on-target resistance are still dependent on the NTRK or TRK pathway. And often what happens is, like with other oncogene-targeted therapy pairs, you see the acquisition of a resistance mutation in the kinase domain of NTRK 1, 2, 3 that either changes the dynamics of the kinase or sort of kicks the drug off of the binding site due to steric hindrance. And for those patients, companies have designed next-generation TRK inhibitors that abrogate resistance, meaning they were designed so that they would work despite the presence of these resistance mutations. And a few of them include repotrectinib, talatrectinib, and selitrectinib that are thought to have activity, but there are many other newer ones that are currently being explored. I will say that there's proof of concept that has been published as well showing that patients who progress on a first-generation TRK inhibitor like larotrectinib or entrectinib who develop acquired resistance that's on-target can respond very well to a next-generation NTRK inhibitor. And while these aren't approved just yet, these are of course available in clinical trials. Now, the second major group is more problematic. This is off-target resistance. And when I describe this to patients, what I usually say is that the cancer sort of ‘phones a friend' and activates a second gene perhaps that isn't NTRK. And examples of that include KRAS or MET or BRAF, very well-known oncogenes in other contexts, but it leads to a reliance outside of the NTRK or TRK pathway per se, which still effectively reactivates the MAP kinase pathway. What to do in that situation? Well, there are select cases and there have been case reports published of patients who get a combination. Say if it's acquired MET amplification, you give a MET inhibitor with a TRK inhibitor and that combination can work. But in many other cases where you don't have access to a combination on a clinical trial or on compassionate use, then you really default to the standard of care for that cancer type. So if it's lung cancer and they've never had chemotherapy before, then it would be platinum-based chemotherapy, say with pemetrexed and a third drug, perhaps if they have lung adenocarcinoma. Dr. Rafeh Naqash: Thank you so much. This is definitely an exciting field and exciting time to be in this space of drug development, and especially when we have so many interesting tumor-agnostic approvals that have come along in the last few years and more to come. And you've led a lot of this development with several other leaders in this field. So it was very nice discussing this with you, and hopefully, our listeners find it equally interesting and educationally relevant to what we see day in and day out as we perform more and more sequencing for patients with cancer and try to identify some of these rare or not so rare events that are targetable and can definitely change the course of a patient's therapy and outcomes. So thank you once again, Alex, for the discussion on this paper. But before we end, we'd like to spend a couple of minutes trying to know about the investigator. So could you tell us a little bit about your career trajectory, how you started your fellowship perhaps, how you ended up in drug development, and how you've successfully contributed so much in this field to date? Dr. Alexander Drilon: Sure. So I'm originally from the Philippines, was born there, finished med school, and really wanted to come to the United States to sort of broaden my education and my residency program in internal medicine, then called St. Luke's Roosevelt under Columbia, had a program that sent people to rotate through Memorial Sloan Kettering Cancer where I currently work. So that was my first exposure with oncology. I fell in love with it and eventually became a fellow, fortunately, at Memorial Sloan Kettering. And I mentioned earlier that during that time I had subspecialized in lung cancer and there was a lot of excitement around targeted therapy for oncogene-driven lung cancer. And that was my point of entry. I saw these drugs work very well and I said that if I were in a position to develop newer agents, perhaps for other oncogenes where there wasn't anything developed just yet, that would be really cool. And that was my entry into the phase I world where things later on expanded really the tumor agnostic interrogation using the same principles that were familiar to me in the lung cancer world. And I think I've been very fortunate with the environment and the ability, especially with good in-house sequencing, to match many patients to these trials. And it's been wonderful to see several of these drugs approved. Larotrectinib was the sort of seminal tumor-agnostic approval of a targeted therapy for the first time by any regulatory body. And like you said, the hope is that we see several more of these. Dr. Rafeh Naqash: Awesome. That sounds like a very interesting, phenomenal journey that you've had, and a lot of it is also probably related to the kind of people that you met, mentors, and other people who helped you along the way. And then, of course, you've done a lot for other fellows and trainees in this space of drug development. So thank you again, Alex, for joining us, and thank you for choosing JCO Precision Oncology as a destination for your work. I look forward to interacting with you further subsequently and hopefully seeing more development in this space of novel therapies for fusions and other interesting targets in the lung cancer space. So thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Bio: Alexander E. Drilon, MD, is a medical oncologist specializing in the treatment of lung cancer. He is chief of early drug development service at Memorial Sloan Kettering Cancer Center. He has clinical expertise in lung cancer and early-phase clinical trials. COIs Alexander Drilon Honoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare Therapeutics Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs
Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma
Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma
PeerView Kidney & Genitourinary Diseases CME/CNE/CPE Video Podcast
Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma
Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.
Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.
Featuring an interview with Dr Ezra Cohen, including the following topics: Spectrum of targetable mutations in thyroid cancer and impact on treatment selection (0:00) Comparative efficacy of TRK inhibitors in patients with thyroid cancer, including those with CNS disease (6:06) Current and emerging roles of immunotherapy alone and in combination with tyrosine kinase inhibitors for patients with head and neck cancer (10:17) Predicting clinical response to immunotherapy for patients with head and neck cancers (19:47) Role of dose reduction in managing toxicities associated with immunotherapy and targeted agents (26:01) Current and potential roles for cell-free DNA testing and minimal residual disease assessment in the management of head and neck cancer (32:08) Recently reported efficacy data with avasopasem in the treatment of radiation-induced oral mucositis (35:27) Factors affecting response to immunotherapy (42:07) CME information and select publications
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