Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI.Experimental Design: We established "RETgistry," a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan-Meier method.Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1-16.6] and 17.3 months (95% CI, 14-20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022).Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

HintergrundDie Kampagne «choosing wisely» geht auf eine 1989 gegründete Stiftung des «American Board of Internal Medicine» zurück.Sie bezweckt, Patientinnen und Patienten in Entscheidungsprozesse einzubinden, um Überbehandlung zu vermeiden und das Vertrauen in die Ärztinnen und Ärzte zu stärken.Mit ähnlichen Zielen wurde 2017 in der Schweiz der Trägerverein «smarter medicine» gegründet, an dem sich zahlreiche Spitäler und Fachgesellschaften beteiligen.Auf smartermedicine.chfinden sich onkologische Empfehlungen der Schweizerischen Gesellschaften für Chirurgie und Radio-Onkologie.Auch im Bereich der medikamentösen Tumortherapien besteht das Problem der Überbehandlung [1].Die «American Society of Clinical Oncology» (ASCO) berücksichtigt dies in ihren «choosing wisely»-Empfehlungen (Tab. 1) [2].Wir diskutieren diese und zeigen, dass weitere Möglichkeiten für «choosing wisely» -respektive «less is more» -in der medizinischen Onkologie vorhanden sind und wo diese evidenzbasiert und ohne Abstriche bei der Behandlungsqualität umgesetzt werden können.

ContexteLa campagne «choosing wisely» émane d'une fondation créée en 1989 par l'«American Board of Internal Medicine».Elle a pour but d'impliquer les patientes et patients dans les processus décisionnels afin d' éviter les surtraitements et de renforcer la confiance dans les médecins.C' est avec des objectifs similaires qu'a été fondée en Suisse en 2017 l'association de soutien «smarter medicine», à laquelle participent de nombreux hôpitaux et sociétés de discipline.Sur smartermedicine.chse trouvent les recommandations oncologiques de la Société Suisse de Chirurgie et de la Société Suisse de Radio-Oncologie.Le problème du surtraitement existe également dans le domaine des traitements médicamenteux des cancers [1].L'«American Society of Clinical Oncology» (ASCO) en tient compte dans ses recommandations «choosing wisely» (tab. 1) [2].Dans cet article, nous les discutons et montrons qu'il existe des possibilités supplémentaires de «choosing wisely» -ou de «less is more» -en oncologie médicale et où celles-ci peuvent être mises en oeuvre de façon basée sur l' évidence et sans faire de compromis sur la qualité du traitement.Grâce à ces connaissances, les médecins de premier recours peuvent eux aussi «Choosing wisely» «Less is more» pour les traitements médicamenteux des cancers Les progrès réalisés dans les traitements médicamenteux des cancers sont considérables et importants, mais ils comportent aussi le risque d'un surtraitement.La complexité croissante complique l' évaluation critique des options thérapeutiques par les médecins de premier recours et par les patientes et patients.La campagne «choosing wisely» et le principe «less is more» gagnent en importance.

6073 Background: Selpercatinib, is a first-in-class, highly selective, CNS active and potent RET inhibitor approved in multiple countries for treatment of RET-fusion positive lung or thyroid cancers. Reported is an update of efficacy and safety results in RET-altered thyroid cancer, with a longer follow up (30 Mar 2020 data cutoff vs 16 Dec 2019) and additional enrolment. Methods: Patients (pts) with RET-mutant medullary thyroid cancer (MTC) and RET-fusion positive thyroid cancer (TC) were enrolled in the global (16 countries, 89 sites) Phase 1/2 LIBRETTO-001 trial (NCT03157128). The primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. The integrated analysis set (IAS, n = 143) includes efficacy evaluable MTC pts previously treated with cabozantinib and/or vandetanib (cabo/vande). The primary analysis set (PAS), a subset of IAS, is the first 55 enrolled pts. Cabo/vande naïve MTC pts (N = 112) and TC pts with prior systemic treatment (N = 22) were also analyzed. Safety population includes all pts who received ≥1 dose of selpercatinib (MTC N = 315; TC N = 42) by data cutoff. Results: For MTC patients, the ORR for IAS was 69.2%, in the PAS it was 69.1%, and 71.4% for cabo/vande naïve MTC pts. The ORR for TC pts (n = 22) was 77.3% (see table). Most treatment-emergent adverse events (TEAEs) were low grade; the most common (≥25% of MTC and/or TC pts treated with selpercatinib) were dry mouth, diarrhea, hypertension, fatigue and constipation for both MTC and TC pts, increased ALT/AST, peripheral edema and headache in MTC pts and nausea in TC pts. 4.8% of MTC and TC pts discontinued selpercatinib due to TEAEs but only 1.9% with MTC and none with TC discontinued due to treatment-related adverse events. Conclusions: In this updated analysis, selpercatinib continued to show marked and durable antitumor activity in pts with RET-altered thyroid cancers. Selpercatinib was well tolerated and no new safety concerns were identified. A global, randomized, phase 3 trial (LIBRETTO-531) evaluating selpercatinib compared to cabo/vande in kinase inhibitor naïve MTC pts is ongoing. Clinical trial information: NCT03157128. [Table: see text]