Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF)

BackgroundNintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC).DesignEORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety.ResultsRAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9–6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0–5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42–0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2–not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3–4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9–8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0–5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16–1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1–24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1–NR) in the placebo arm. Grade 3–4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo.ConclusionThis study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC

Rôle potentiel de la tomographie par émission de positons couplée à la tomodensitométrie (TEP-TDM) au 18F-fluoro-désoxy-glucose ([18F]-FDG) dans l'imagerie des tumeurs urothéliales

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF)

Nintedanib; Triple-angiokinase inhibitorNintedanib; Triple inhibidor de la angiocinasaNintedanib; Triple inhibidor de la angiocinasaBackground: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9–6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0–5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42–0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2–not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3–4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9–8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0–5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16–1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1–24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1–NR) in the placebo arm. Grade 3–4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Boehringer Ingelheim France through an educational grant. Boehringer Ingelheim had no role in the design, analysis, or interpretation of the results in this study. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations

Identification of a recurrent STRN/ALK fusion in thyroid carcinomas.

Thyroid carcinoma is the most common endocrine malignant tumor and accounts for 1% of all new malignant diseases. Among all types and subtypes of thyroid cancers that have been described so far, papillary thyroid carcinoma is the most frequent. The standard management treatment of these tumors consists of surgery, followed by radioiodine treatment in case of high risk of relapse. The most aggressive forms are commonly treated by chemotherapy, radiotherapy or experimental drug testing. We recently reported the case of a patient presenting an anaplastic thyroid carcinoma with lung metastases. Fluorescence in situ hybridization analysis allowed us to detect a rearrangement of the anaplastic lymphoma kinase (ALK) gene in both tumors. The patient was treated with crizotinib and presented an excellent drug response. We present here the subsequent investigations carried out to further characterize this genetic alteration and to assess the prevalence of ALK rearrangements in thyroid lesions. High resolution array-comparative genomic hybridization data complemented by RT-PCR and sequencing analyses, allowed us to demonstrate the presence of a STRN/ALK fusion. The STRN/ALK transcript consisted of the fusion between exon 3 of STRN and exon 20 of ALK. Subsequent screening of 75 various thyroid tumors by RT-PCR revealed that 2 out of 29 papillary thyroid carcinomas exhibited the same fusion transcript. None was detected in other types of malignant or benign thyroid lesions analyzed. These findings could pave the way for the development of new targeted therapeutic strategies in the treatment of papillary thyroid carcinomas and point to ALK inhibitors as promising agents that merit rapid evaluation

The medical treatment of radioiodine-refractory differentiated thyroid cancers in 2019. A TUTHYREF® network review

International audienc

Génotypage moléculaire dans les cancers réfractaires de la thyroïde en 2021 : quand, comment, et pourquoi ? Un travail du réseau TUTHYREF

International audienceRefractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting.Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire

ALK Interphase fluorescence <i>in situ</i> hybridization and immunohistochemistry.

<p>(A) On the representative picture of the FISH, realized using the LSI ALK Dual Color Break Apart Rearrangement Probe, we could observe <i>ALK</i> probe break-aparts highlighted by arrows in the two positive PTC cases. Magnification: X1000. (B) Pictures of immunohistochemical labeling for ALK in the two PTC samples. Pictures of hematoxylin, eosin and safran (HES) staining of the two samples are also presented. Magnification for HES: X200, Magnification for IHC: X400.</p

MERAIODE: A Phase II Redifferentiation Trial with Trametinib and 131I in Metastatic Radioactive Iodine Refractory RAS Mutated Differentiated Thyroid Cancer

International audienceNo abstract availabl