There was some nausea [33%], hypertension [32%], fatigue [24%], and headache [26%]. I had a patient who has been on surveillance for 20 years; I [started seeing] her at 10 [years in]. There were quite a few more patients that had a performance status of 1 or 2. Approximately 10-20% of patients with papillary thyroid cancer (the most common type of thyroid cancer) carry RET fusions, and approximately 50-90% of patients with advanced MTC (approximately 2-5% of thyroid cancers) carry RET mutations. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50% probability of inheriting the mutant RET proto-oncogene from the affected parent. These patients were doing well for a really long time. 2017;28(11):2813-2819. doi:10.1093/annonc/mdx479, 2. ALK + NSCLC as first-line treatment or after crizotinib resistance: For the label click here: 1/6: Capmatinib. They diagrammed the earliest reported age at the onset of MTC according to specific RET mutation. Thyroid cancer treatments include surgery, radiation therapy, radioactive iodine therapy, chemotherapy, hormone therapy, targeted therapy, and observation. These were healthy patients overall. Established at the end of 2015, CStone Pharmaceuticals has assembled a world-class management team with extensive experience in innovative drug development, clinical research, and commercialization. CStone's vision is to become a world-renowned biopharmaceutical company leading the way to conquering cancer. It just takes a bit of finesse and knowledge of what to look for and how to [counsel] patients to help themselves; make sure that they know how to take loperamide [Imodium] for diarrhea. Schlumberger M, Elisei R, Müller S, et al. Germline RET mutations happen in kids; it’s important that if you have a germline mutation, send the patient for genetic counseling so they can get the kids screened because you can save some lives by doing a good screening. Except as required by law, we undertake no obligation to update or publicly revise any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. Ann Oncol. Again, there was diarrhea [all grade with cabozantinib, 70.1%] and weight decrease [57.9%]. For PFS, 23.6 months [for treatment naive] or not reached [for previously treated] was the median. The ZETA trial [NCT00410761] had patients who were not actively progressing, so in the placebo arm, patients were [19.3] months out for their progression-free survival [(PFS), and PFS was not reached for the vandetanib arm].3 It’s hard to compare these data with anything else, but there was an improved hazard ratio of 0.46 with vandetanib, so it was approved based on that [95% CI, 0.31-0.69; P <.001]. GAVRETO has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with metastatic RET fusion-positive NSCLC as detected by an FDA approved test, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in patients with medullary thyroid cancer, RET-altered NSCLC and other RET-altered solid tumors. This affected the ECOG status. Interestingly, this patient had the RET M918T mutation. How was the trial for this designed? A couple of the patients who were cabozantinib or vandetanib na.ve were treated with immunotherapy… but it was not something that I think we’re regularly doing in thyroid cancer because there are no good data right now for immunotherapy in thyroid cancer, as it turns out. As with other tyrosine kinase inhibitors, these numbers tended to be higher in the initial trials and were lower as people got better at using these drugs and managing the AEs. Crude annual incidence rate of medullary thyroid cancer and RET mutation frequency. Blueprint Medicines and Roche are co-developing GAVRETO globally (excluding Greater China) for the treatment of patients with RET-altered NSCLC, thyroid cancer, and other solid tumors. In the inherited forms of medullary thyroid cancer, the growing C … How did patients with MTC do when given selpercatinib? Pralsetinib…[is] right under selpercatinib. There was a small number of complete responders [1.8% and 10%, respectively], as there was with selpercatinib, and median duration of response was not reached. Possible Diagnoses. The parafollicular C cells of the thyroid begin to have unregulated growth. What was the efficacy of the cabozantinib trial you mentioned previously? I think when you get used to these drugs, you can treat patients. Medullary thyroid cancer is a rare type of thyroid cancer. The C cells make a hormone that helps maintain a healthy level of calcium in the blood. Both papillary [thyroid cancer] and MTC have RET alterations. You need to monitor electrolytes as well for the QTc prolongation. It was a very significant hazard ratio and was approved on that basis. There were RET M918T mutations in over half the patients [57% of 143 patients with MTC]. What testing do you order for patients with thyroid cancer? Ann Oncol. With a strategic emphasis on immuno-oncology combination therapies, the Company has built an oncology-focused pipeline of 14 drug candidates. Mechanism of RET gene mediated EGFR signaling pathway on epithelial-mesenchymal transition, proliferation and apoptosis of papillary thyroid carcinoma cells. Within the first year of life or the first months of life based upon specialist and parental discussions. What that means is: when I have a patient and I don’t know them, or they’ve just received a diagnosis, I have no clue what their velocity is, and letting them go 6 months without a scan is a very long time, especially when they weren’t adequately staged upfront. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. MEN2B. These patients were actively progressing, so it was a much more aggressive cohort of patients. Lung adenocarcinoma is further classified into several … Vandetanib [Caprelsa] and cabozantinib are the 2 multikinase inhibitors approved for MTC. This may expand the labeled indications for GAVRETO® in China to include advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and radioactive iodine-refractory (if radioactive iodine is appropriate). There is currently no effective approved standard treatment regimen for patients with RET-mutant MTC in China. What are the National Comprehensive Cancer Network guidelines recommendations in this setting? But I don’t trust [the disease], and I have to prove that the tumor is not going to misbehave before I would [watch and wait]. We can use that for these patients, and I teach people to give themselves loperamide, not [only] after the diarrhea, but prophylactically on standing doses of 2, 4, or 6 mg; whatever they need to prevent the diarrhea. Prior [treatments with cabozantinib or vandetanib] were 0 to 2 [in the previously treated arm]. But 79% and 84% of patients, at least at 6 months, were still responding. During a virtual Targeted Oncology Case-Based Roundtable event, Marcia S. Brose, MD, PhD, discussed the case of a 58-year-old patients with RET-mutated thyroid cancer. Decreased appetite [49.1%], nausea [46.7%], and fatigue [42.5%] are also things that we deal with commonly. According to the data released by the National Cancer Center in 2019, the incidence of thyroid cancer ranked 4th among all malignant tumors in female in urban areas and 7th in o among all cancer types in China. Not on your life. 4 A large number, 306 patients, were in the MTC cohort. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651, 5. The ARROW trial had patients with RET-mutant papillary thyroid cancer or MTC, and they were either cabozantinibor vandetanib-naive or previously treated with cabozantinib or vandetanib.5. Samples: Browse: Li-Fraumeni syndrome: 20301488: TP53 191170 Samples* Browse: Peutz-Jeghers syndrome: 20301443: STK11 602216 Samples* Browse: Lynch … As soon as I see [the tumor is not changing], maybe then I can use the calcium doubling time and say, “We haven’t bumped [up] and it’s been 6 months.” Then I’ll say, “OK, the next scan can be at 4 or 6 months,” and give them a bit more room. Currently, two products have been approved by China NMPA and multiple late-stage candidates are at pivotal clinical trials or registration stages. This is not the same as the diarrhea caused by calcitonin, which initially gets better when you treat patients. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection. Available Samples with Characterized Mutation Data. There was some significant hypertension [any grade with pralsetinib, 40%]. The age range was the same [15 to 84 years old]. About a quarter (25%) of medullary thyroid cancers are caused by an inherited faulty gene which runs in the family. It did seem like it was slightly more prevalent in ARROW with pralsetinib. When you know a drug well, you’re going to be managing the adverse effects [AEs] much more effectively, and sometimes that might be more important than which one has a slightly different profile. There has been a lack of precision medicines for RET-altered thyroid cancer in China and patients can only be treated with multi-targeted drugs. [Much] like an EGFR [inhibitor], it has EGFR inhibitor activity, and [the AE of] acneiform rash can be quite bothersome, especially with teenagers who are on [this drug]. This indication is approved under accelerated approval based on overall response rate and Dr. Jason Yang, Chief Medical Officer of CStone, said: "We are excited to see that this NDA has been accepted by the NMPA, which is six months in advance of our schedule. Epidemiologic studies have shown the prevalence of palpable thyroid nodules to be approximately 5% in women and 1% in men living in iodine-sufficient parts of the world (1,2).In contrast, high-resolution ultrasound (US) can detect thyroid nodules in 19%–68% of randomly selected individuals, … Medullary thyroid cancer. So I’ll take 7 years, no problem. This is well known to be the most common mutation that we would see. China International Consumer Products Expo, CStone Announces Acceptance of New Drug Application in Hong Kong for Avapritinib for the Treatment of Adults with Unresectable or Metastatic PDGFRA D842V Mutant Gastrointestinal Stromal Tumor, CStone Announces China NMPA New Drug Approval of Precision Therapy AYVAKIT® (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor, CStone Pharmaceuticals Reports Financial Results and Business Highlights for Full-year 2020, CStone Announces New Drug Approval of GAVRETO(R) (pralsetinib) as First Selective RET Inhibitor in China, Providing a New Therapy for a Subset of Non-Small Cell Lung Cancer Patients, CStone Pharmaceuticals Reports Efficacy and Safety Data from the ARROW Trial of Pralsetinib in Chinese Patients with Advanced RET Fusion-positive Non-Small Cell Lung Cancer after Platinum-based Chemotherapy at IASLC WCLC 2020, CStone's Partner Blueprint Medicines Announces U.S. FDA Approval of GAVRETO (pralsetinib) for the Treatment of Patients with Advanced or Metastatic RET-Mutant and RET Fusion-Positive Thyroid Cancer, Ortho Clinical Diagnostics Simultaneously Launches First Quantitative COVID-19 IgG Spike Antibody Test As Well As A Nucleocapsid Antibody Test to Help Differentiate Cause of Antibody Response, Recently Merged dMed and Clinipace Announce the Appointment of New Global COO, Johnson & Johnson Medical Korea Ltd. and Johnson & Johnson Innovation LLC Announce Launch of Seoul Innovation QuickFire Challenge on Smart Surgery in Collaboration with Seoul Metropolitan Government and Korea Health Industry Development Institute, Everest Medicines Announces China NMPA Has Granted Priority Review for Sacituzumab Govitecan-hziy in Metastatic Triple-Negative Breast Cancer, Regent Pacific's Deep Longevity Announces Partnership with LifeHub & LifeClinic in Hong Kong. control the diarrhea, they lose more weight, so controlling the diarrhea can be extremely important. Even when thyroid cancer is more advanced, effective treatment is available for the most common forms of thyroid cancer. 3.17/3.17 ... RET mutant medullary thyroid cancer; RET fusion-positive thyroid cancer: For the label click here: 3/8: Regorafenib. Dose decreases are fairly common when we use this in the clinic. Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutationpositive medullary thyroid cancer (RET+ MTC). That’s important because when you’re ordering genetic testing, you have to ensure that if your patient has papillary thyroid cancer, you’re getting a good gene fusion panel, whichever modality, wherever you’re sending it. The primary end point was an objective response (a complete or partial response), as determined by an independent review … LIBRETTO-001 had 2 arms; 1 was for RET fusion-positive papillary thyroid cancer, and then RET point mutation MTC. In 53 patients previously treated with cabozantinib or vandetanib, the overall response rate (ORR) was 60 percent (95% CI: 46%, 74%) with one response pending confirmation, and the median duration of response (DOR) was not reached (95% CI: not reached, not reached). During a virtual Targeted Oncology Case-Based Roundtable event, Marcia S. Brose, MD, PhD, director, Center for Rare Cancers and Personalized Therapy and director, Thyroid Cancer Therapeutics Program at the Abramson Cancer Center of University of Pennsylvania, discussed the case of a 58-year-old patients with RET-mutated thyroid cancer. There was an ORR in the previously treated group of 69%, but the na.ve group was 73%. LIBRETTO-001 had 2 arms; 1 was for RET fusion-positive papillary thyroid cancer, and then RET point mutation MTC.4 A large number, 306 patients, were in the MTC cohort. The FDA granted breakthrough therapy designation to GAVRETO for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no alternative treatments. Inherited medullary thyroid cancer, called familial medullary thyroid cancer (FMTC), is caused by a variant in the RET gene. J Clin Oncol. Age was pretty similar [in both arms for MTC], and ECOG performance status was almost all 0 or 1. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. Medullary thyroid cancer. 2020;31(suppl 4):S1084.doi:10.1016/j.annonc.2020.08.1401, Case-Based Roundtable Meetings Spotlight April 1, 2021. Hu M, Subbiah V, Wirth LJ, et al. But it is true that if you have a patient who is sick in front of you, you send the tissue first so that you get all the mutations, not just half of them. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. T hyroid nodules are a common clinical problem. We have 4 right answers here: vandetanib, cabozantinib, selpercatinib, and pralsetinib. Efficacy of selpercatinib in RET-altered thyroid cancers. All statements in this article are made on the date of publication of this article and may change due to future developments. © 2021 MJH Life Sciences™ , Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways. What data from the ARROW trial are relevant in this space? The European Society of Surgical Oncology, ESSO, was founded in 1981 to advance the art, science and practice of surgery for the treatment of cancer. The objective response rate [ORR] was 45%, so this was clearly an active agent. So I like to jump before we have symptoms. Patients can also get hand-foot syndrome with this drug [52.8%], which is a little different from vandetanib. Wells SA Jr, Robinson BG, Gagel RF, et al. I’m fine with watch and wait if you know what you’re waiting for. This NDA acceptance is based on efficacy and safety results from the global Phase 1/2 ARROW trial, designed to evaluate pralsetinib in patients with RET fusion-positive NSCLC, RET-mutant MTC, and other advanced solid tumors with RET fusions. Recommendations. Even though the diagnosis of cancer is terrifying, the prognosis for most patients with papillary and follicular thyroid cancer is usually excellent. We thank the NMPA for granting priority review for this indication and look forward to getting approval and hope benefit more patients in China in the future.". The EXAM study also had a very good hazard ratio [for PFS] [HR, 0.28; 95% CI, 0.19-0.40].1 In the placebo arm, patients progressed at [4] months, but on the drug, median PFS was 11 months. RET codon Mutation. GAVRETO is designed to selectively and potently target oncogenic RET alterations, including secondary RET mutations predicted to drive resistance to treatment. The difference is that papillary thyroid cancer acts [more] like lung cancer and tends to have translocations, whereas medullary disease has point mutations. There are about 90,000 new cases of thyroid cancer and about 6,800 deaths each year in China. Many times, this was doselimiting. It can be sporadic or be inherited. Most patients with sporadic MTC have gene mutations only in their cancer … Gavreto (pralsetinib) is an oral selective RET kinase inhibitor for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion- positive non-small cell lung cancer (NSCLC), and adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC). In order to prescribe vandetanib, you have to go through a minitraining, and to order it, you have to provide your REMS number. Sorafenib [Nexavar] has some nice data in MTC, in the phase 2 setting, [but it is] definitely much lower down on my list. DNA analysis for RET germline mutation According to 2009 ATA guidelines, a calcitonin level >100 pg/mL should be considered suspicious of medullary thyroid carcinoma. Introduction. In ARROW, for RET-mutant MTC after [treatment with] cabozantinib or vandetanib, the ORR was 60%, and in the patients who were naive, it was about 66%. (2005) reported the alignment of the human RET protein sequence with the orthologous … If a high-risk mutation is found, the thyroid gland should be surgically removed to prevent cancer from developing. We’re talking about 11 to 15 months or 16 to 18 months with vandetanib and cabozantinib, and now we’re out to 22 months [or more]. I think any of these 4 are completely correct. Thyroid carcinoma, version 3.2020. In 19 systemic treatment-naïve patients who were ineligible for standard therapy per the study protocol, the confirmed ORR was 74 percent (95% CI: 49%, 91%), and the median DOR was not reached (95% CI: 7 months, not reached). People who have medullary thyroid cancer (MTC) have mutations in different parts of the RET gene than people with papillary carcinoma. As of a data cutoff date of February 13, 2020, the results showed that pralsetinib had robust and durable anti-tumor activity in response-evaluable patients who received a starting dose of 400 mg once daily. This was fairly well tolerated overall, just maybe not quite as low as what we saw with selpercatinib [in terms of AEs]. Vandetanib has good RET activity, and it was the entire reason that it was initially approved for MTC—that is part of the rationale that was used. Many patients who are pretreated will have ECOG status of 2 or greater [in the clinic]. In patients with a diagnosis of papillary thyroid cancer that are being prepared for radioactive iodine treatment, they are most commonly taken off of thyroid hormone and their doctor will measure their TSH level which should be markedly elevated (radioiodine scans require the body to be hypothyroid). They were broken down into people that were cabozantinib or vandetanib na.ve versus people who were not. 2012;30(2):134-141. doi:10.1200/JCO.2011.35.5040, 4. SUZHOU, China, April 26, 2021 /PRNewswire/ -- CStone Pharmaceuticals (CStone, HKEX: 2616), a leading biopharmaceutical company focused on developing and commercializing innovative immuno-oncology therapies and precision medicines, today announces that the National Medical Products Administration (NMPA) of China has accepted the New Drug Application (NDA) of selective inhibitor GAVRETO® (Pralsetinib) with priority review designation for the treatment of the patients with advanced or metastatic RET-altered thyroid cancer. A few patients with central nervous system metastases were treated. Results from the ARROW trial in patients with RET-mutant MTC were presented at the European Society for Medical Oncology Virtual Congress in September 2020. These patients tolerated the selpercatinib much better [compared with the other drugs I’ve discussed]. 3/5: 2012: VEGFR1/2/3, BCR-Abl, B-Raf, B-Raf(V600E), Kit, PDGFRα/β, RET, FGFR1/2, Tie2, Eph2A: CRC, GIST: For the label … Approximately 25% of all MTC runs in families and is associated with other endocrine tumors (see Medullary Thyroid Cancer brochure). Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. But once you’ve done it, it’s easy. Even though it does have some hypertension [any grade, 30%] and liver function test abnormalities [increased aspartate aminotransferase level, 28%], it is nothing compared with what we’ve been fighting with [the use of] both vandetanib and cabozantinib. Medullary thyroid cancer is a neuroendocrine tumor that develops in C cells of the thyroid. It aims to … Medullary thyroid cancer (MTC), accounts for approximately 2% of all thyroid cancers. Thyroid cancer is the most common endocrine malignancy with significantly increasing incidence in recent years. Interestingly, some patients had problems with anemia and blood count, probably because of some interaction with the JAK pathway. I don’t [know] OS data in this setting as it wasn’t in this trial, but the RET M918T population did quite well with vandetanib. Medullary thyroid cancer. GAVRETO is not approved for the treatment of any other indication in China by the NMPA or in the U.S. by the FDA, or for any indication in any other jurisdiction by any other health authority. The European Medicines Agency validated a marketing authorization application for GAVRETO for the treatment of RET fusion-positive NSCLC, and the review is ongoing. © 2021 MJH Life Sciences and Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways. Highest Risk (HST) M918T+All MEN2B. NCCN. Thyroid cancer is clinically divided into papillary cancer, follicular cancer, undifferentiated cancer, and medullary cancer and so on. A high TSH result often means an underactive thyroid gland caused by failure of the gland (hypothyroidism).Very rarely, a high TSH result can indicate a problem with the pituitary gland, such as a tumour, in what is known as secondary hyperthyroidism.A high TSH value can also occur in people with underactive thyroid glands who have been receiving too little thyroid …
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