scholarly journals A Systematic Review of Phase II Targeted Therapy Clinical Trials in Anaplastic Thyroid Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 943 ◽  
Author(s):  
Josip Ljubas ◽  
Therese Ovesen ◽  
Maria Rusan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Anaplastic Thyroid Cancer ◽  
Anaplastic Thyroid Carcinoma ◽  
Braf V600e ◽  
Novel Treatments ◽  
Molecular Alterations ◽  
Molecular Landscape

Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. Recent efforts towards the characterization of the molecular landscape of ATC have led to the identification of pro-oncogenic targetable alterations, lending promise for novel targeted therapeutic approaches. This systematic review summarizes the results of phase II clinical trials of targeted therapy in ATC, providing an overview of efficacy and safety profiles. The majority of trials to date have consisted of small single-arm studies and have presented modest results. However, only a minority of trials have selected or stratified patients by molecular alterations. In the setting of BRAF V600E mutated ATC, dabrafenib/trametinib combination therapy and vemurafenib monotherapy have both demonstrated efficacy. Everolimus has furthermore shown promising results in patients with PI3K/mTOR/AKT pathway alterations. These studies underscore the importance of molecular profiling of tumors for appropriate patient selection and determination of genomic correlates of response. Clinical trials are underway testing additional targeted therapies as monotherapy, or as a part of multimodal treatment, and in combination with immunotherapy.

scholarly journals Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer

2019 ◽  
Vol 7 ◽  
pp. 232470961989094 ◽  
Author(s):  
Sasan Fazeli ◽  
Edina Paal ◽  
Jessica H. Maxwell ◽  
Kenneth D. Burman ◽  
Eric S. Nylen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Side Effects ◽  
Combination Therapy ◽  
Braf Inhibitor ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Aggressive Tumor ◽  
Well Differentiated

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

scholarly journals Systemic treatment options for advanced biliary tract carcinoma

2020 ◽  
Vol 55 (10) ◽  
pp. 944-957
Author(s):  
Changqing Xie ◽  
Nicole A. McGrath ◽  
Cecilia Monge Bonilla ◽  
Jianyang Fu
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Biliary Tract ◽  
Treatment Options ◽  
Single Agent ◽  
Current Status ◽  
Dna Mismatch ◽  
First Line Therapy ◽  
Molecular Landscape ◽  
Line Setting

Abstract Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.

scholarly journals NTRK2 Fusion Driven Pediatric Glioblastoma: Identification of key molecular drivers by personalized oncology

2019 ◽  
Vol 46 (s2) ◽  
pp. S64
Author(s):  
Levine ◽  
Y Shen ◽  
K Mungall ◽  
J Serrano ◽  
M Snuderl ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Braf V600e ◽  
Current Status ◽  
Driver Mutations ◽  
List Type ◽  
Idh1 R132h ◽  
Tyrosine Kinase 2 ◽  
Cerebellar Glioblastoma ◽  
Molecular Landscape

We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2 (Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2A deletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2 fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3 and IDH demonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRK fusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2 fusion in a glioblastoma.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explore the current molecular landscape of pediatric high grade gliomas2.Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors3.Discuss the current status of NTRK inhibitor clinical trials

Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 629-629
Author(s):  
Akihito Kawazoe ◽  
Kohei Shitara ◽  
Masaaki Noguchi ◽  
Shota Fukuoka ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Large Scale ◽  
Phase Ii Trial ◽  
Japanese Patients ◽  
Clinicopathological Features ◽  
Braf V600e

629 Background: Recently, anti-programmed death 1 (PD-1) antibody has shown promising efficacy in a phase II trial for patients with microsatellite instability-high (MSI-H) tumors, especially in those with metastatic colorectal cancer (mCRC). Currently, several clinical trials of anti-PD-1 antibody for patients with MSI-H mCRC are ongoing. However, little is known about the frequencies and clinicopathological features of MSI-H mCRC in Japanese patients. Methods: Patients with histologically confirmed adenocarcinoma of mCRC were eligible for this observational study. MSI status was analyzed in tumors using the MSI Analysis System (Promega) composed of 5 mononucleotide markers. KRAS, NRAS, BRAF and PIK3CA mutations were also evaluated using the multiplex kit. Results: A total of 232 patients were enrolled until August 31, 2015, of which MSI-H was detected in 5 patients (2.1%). Among five patients with MSI-H mCRC, median age was 45 years (28-75), four had tumors on right-sided colon, five had moderately differentiated adenocarcinoma, one had poorly differentiated adenocarcinoma, and three had stage IV disease at presentation. Overall survival for patients with MSI-H mCRC from the start of first-line systemic chemotherapy ranged from 8.1 to 62.0 month. All five patients with MSI-H mCRC had RAS wild-type tumors and two had BRAF V600E mutation. One patient with MSI-H mCRC was enrolled in a phase II trial of anti-PD-1 antibody. Conclusions: MSI-H mCRC is rare in Japanese patients. A large scale nationwide cancer genome screening project together with MSI status is required to evaluate more detailed clinicopathological features and facilitate the enrollment of patients with MSI-H mCRC for clinical trials with anti-PD-1 antibody.

Targeted therapy for non-small cell lung cancer (NSCLC) with HER2, BRAF, or hedgehog alterations: Interim data from MyPathway.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9073-9073 ◽  
Author(s):  
John D. Hainsworth ◽  
Ron Bose ◽  
Christopher Sweeney ◽  
Funda Meric-Bernstam ◽  
Herbert Hurwitz ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Objective Response ◽  
Complete Response ◽  
Braf V600e ◽  
Egfr Mutations ◽  
Efficacy Analysis ◽  
Molecular Alterations ◽  
Activating Mutations ◽  
Previously Treated ◽  
Tumor Types

9073 Background: Treatments targeting critical molecular alterations (EGFR, ALK, and ROS1) in NSCLC are highly effective. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatment in non-indicated tumor types harboring alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. Interim results in NSCLC are presented. Methods: Patients with previously treated advanced NSCLC and alterations in the HER2 (amplification and/or mutation), BRAF (V600E or other mutations), Hh (SMO or PTCH-1 mutations), or EGFR (mutations other than known activating mutations) pathways received standard doses of pertuzumab + trastuzumab, vemurafenib, vismodegib, or erlotinib, respectively, until disease progression or unacceptable toxicity. The HER2, BRAF, and Hh cohorts are included in this analysis. The primary endpoint is investigator-assessed objective response rate (ORR, defined as complete response [CR] + partial response [PR]) by RECIST v1.1. Results: As of November 30, 2016, 61 patients with NSCLC and HER2 (n = 36), BRAF (n = 22), or Hh (n = 3) alterations have been treated (median age of 64 years, 49% male, 85% adenocarcinoma, and a median of 2 previous regimens). Median treatment duration was 1.8 (range, 0–21.4) months. Efficacy in the 55 patients with the minimum required follow-up for efficacy analysis is summarized in the table. Conclusions: Targeted therapy is active in patients with previously treated NSCLC harboring BRAF V600E mutations or HER2 alterations (amplifications and/or mutations). These cohorts have been expanded as MyPathway accrual continues. Additional efficacy data and details regarding molecular alterations will be presented. Clinical trial information: NCT02091141. [Table: see text]

scholarly journals LGG-12. SAFETY AND EFFICACY OF DUAL THERAPY WITH DABRAFENIB AND TRAMETINIB IN AN INFANT WITH BRAF V600E MUTANT INOPERABLE LOW GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i34-i34
Author(s):  
Sage Green ◽  
Andrew Walter ◽  
Joseph Piatt ◽  
Gurcharanjeet Kaur
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Cauda Equina ◽  
Dual Therapy ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Global Developmental Delay ◽  
Low Grade ◽  
Who Grade ◽  
Safety And Efficacy

Abstract Objective To describe safety and efficacy of dual targeted therapy with dabrafenib (BRAFi) and trametinib (MEKi) in an infant with inoperable low grade glioma with BRAF V600E mutation. Introduction Safety and efficacy of dual targeted therapy with BRAFi and MEKi for pediatric low grade glioma (pLGG) is currently being evaluated, however, infants are usually not included in these clinical trials. Case We report a case of a 2-month-old male infant who presented with involuntary movements and gaze deviation concerning for seizures. MRI brain revealed a tumor involving the medulla, T2/FLAIR dimensions: 2.5 x 2.2 x 2.7 cm and drop metastases to the cauda equina. An EEG ruled out seizure activity. Tumor biopsy was performed revealing Ganglioglioma, WHO grade I. IHC and somatic next generation sequencing revealed BRAF V600E point mutation. Germline testing was negative. Due to tumor progression on traditional chemotherapy, compassionate use of dual targeted therapy with dabrafenib (5.25mg/kg/day divided twice daily) and trametinib (0.032mg/kg daily) was initiated at 4.5 months of age. The patient has tolerated dual therapy for nearly 1 year without significant toxicity with exception of grade I skin rash. In terms of functional outcomes, previously noticed vocal cord paresis has resolved and our patient with global developmental delay continues to make developmental gains, albeit slowly. On recent neuroimaging, pLGG has continued to grow T2/FLAIR dimensions: 3.5 x 3.5 x 3.7 cm, however, combination therapy has halted the rate of growth of this tumor. Conclusion To our knowledge, our patient is the youngest to receive combination of BRAFi and MEKi. Tumor targeted therapy could be an important treatment option for infants with inoperable pLGG where aggressive surgery and radiation therapy are associated with significant morbidity. Multi-institutional clinical trials that include infants are needed to further comment on safety and efficacy of these agents.

scholarly journals P13.14 Use of Foundation one CDx for molecular screening in patients with primary brain tumors: Gustave Roussy Experience

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii65
Author(s):  
C Baldini ◽  
W Boulfoul ◽  
L Lacroix ◽  
E Rouleau ◽  
J Scoazec ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Tumors ◽  
Tumor Tissue ◽  
Therapeutic Strategies ◽  
Braf V600e ◽  
Tumor Type ◽  
Molecular Screening ◽  
Primary Brain Tumors ◽  
Molecular Alterations ◽  
Multidisciplinary Meeting

Abstract BACKGROUND Patients with primary brain tumors usually have poor prognosis and few therapeutic options. However recent report showed that they may benefit from molecular screening to improve treatment benefit and enrollment in clinical trials. We aimed to evaluate if molecular screening using Foundation One Dx may help therapeutic strategies in primary brain tumor patients. MATERIAL AND METHODS Between October 2018 and December 2018, we enrolled prospectively patients in the MOSCATO (Molecular Screening for cancer Treatment Optimization) 02 trial using the Foundation One Dx test. Patients were eligible if they had good Performans status (PS) (0 or 1) and tumor tissue material available. Results were reviewed during a molecular multidisciplinary meeting weekly at the Drug Development Department at Gustave Roussy to decide on orientation and matched therapy according to molecular alterations. RESULTS Finally thirty-three patients were enrolled in the study. Twenty six tumor tissues were analysed and 7 patients were screen failures due to tumor tissue unavailability. Median age was 49 years old (19 - 72). Patients had a good PS with a median of 1 (0–2) and were mostly males (76%). The most common tumor type was glioblastoma (79%). Five patients had a high grade tumor including 2 medulloblastomas. Median time between consent and multidisciplinary meeting was 70 days (49 - 156). Median percentage of tumor cells was 78% (30–80%). The tumor mutational burden (TMB) was available in 26 patients. The median TMB was 4 mutations per megabase (0 - 277). The most frequent alterations were TERT promoter mutation 22/26 (85%), CDKN2A loss 14/26 (54%), MTAP loss 11/26 (42%), EGFR amplification (38%) including 4 EGFRvIII amplification, TP53 mutation and PTEN deletion 9/26 (35%) respectively, PIK3CA mutation 5/26 (19%), CDK4 or 6 amplification 4/26 (15%), NF1 mutation 3/26 (12%), 2 IDH1 mutations, 2 MET amplifications, 2 HGF amplifications, 1 FGFR2 mutation, 1 BRAF V600E mutation, 1 PDGFRA amplification, 1 EZH2 mutation and 1 SMARCA4 mutation. Finally 11 patients (42%) were oriented according to molecular alterations (EGFR amplifications, BRAF mutation), 1 patient was treated and is ongoing with a BRAF inhibitor and 1 patient is in screening in atrial with an EGFR inhibitor. CONCLUSION Molecular screening with Foundation One Dx test is feasible in patients with primary brain tumors and can help therapeutic strategies. However the time between consent and multidisciplinary meeting was the main limitation to our study and affected enrollment in clinical trials.

scholarly journals Systematic Review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy

2019 ◽  
Vol 15 (21) ◽  
pp. 2543-2553 ◽  
Author(s):  
Paolo Bossi ◽  
Laura Botta ◽  
Paolo Bironzo ◽  
Cristina Sonetto ◽  
Gianna Musettini ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Adverse Events

scholarly journals Hypofractionated Radiotherapy for Anaplastic Thyroid Cancer: Systematic Review and Pooled Analysis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2506 ◽  
Author(s):  
Dmytro Oliinyk ◽  
Teresa Augustin ◽  
Viktoria Florentine Koehler ◽  
Josefine Rauch ◽  
Claus Belka ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multimodal Treatment ◽  
Survival Rates ◽  
Treatment Resistance ◽  
Patient Characteristics ◽  
Anaplastic Thyroid Cancer ◽  
Pooled Analysis ◽  
Anaplastic Thyroid Carcinoma ◽  
Cumulative Radiation Dose ◽  
And Gender

Anaplastic thyroid carcinoma (ATC) is associated with a poor prognosis due to aggressive tumor growth and high treatment resistance. Hypofractionated treatment concepts may be more effective and less time consuming compared to normofractionated radiotherapy (RT). In this retrospective study, we aim to evaluate the outcome of hypofractionated regimens and perform a systematic review concerning hypofractionated RT and pooled analysis of this treatment modality. A systematic review using the MEDLINE/Pubmed and Cochrane databases was performed. Data from all eligible studies were extracted, and a pooled analysis of literature and our cohort (n = 60) was carried out to examine patient characteristics, toxicity, and outcomes of patients with ATC. As a result, median overall survival (OS) of the single center cohort was four (range 1–12) months. Survival rates at one, three, and six months were 82%, 55%, and 36%, respectively. In univariate analyses, multimodal treatment (p = 0.006) and gender (p = 0.04) were correlated with an improved OS. Six studies with a total number of 152 patients undergoing hypofractionated RT treatment were analyzed. The pooled analysis included four patient cohorts with 60 patients and showed median OS of 5.3 (range: 1–24) months. Multimodal treatment (p < 0.001) and a cumulative radiation dose ≥50 Gy in equivalent dose in 2 Gy fractions (EQD2) (p = 0.014) correlated with an improved OS. On multivariate analysis, multimodal treatment (p = 0.003, hazard ratio (HR): 0.636, 95% confidence interval (CI): 0.469–0.861) was an independent predictor for longer OS. After propensity score matching (PSM), hypofractionated RT appears to be non-inferior compared to normofractionated RT concerning OS. In conclusion, hypofractionated RT is effective with manageable toxicity. A dose escalation with ≥50 Gy (EQD2) correlated with a longer OS. Hypofractionated RT could be an integral part in multimodal treatment with a promising outcome.

Sign in / Sign up

Export Citation Format

Share Document