Ryder, Mabel

Abstract Background This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer. Methods Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. Results Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 13.4 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0–not reached) and median overall survival was 19.2 months (95% CI, 4.6–not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. Conclusion CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. Clinical Trial Registration NCT03914300

3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . [Table: see text]

Importance Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma—with which it was formerly classified—and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.

Objective: Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage 131 I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT. Methods: This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF -MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose 131 I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose 131 I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received 131 I therapy. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following 131 I therapy in select patients with RAIR-DTC, particularly those with RAS -driven “follicular” phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic anaplastic transformation.

Abstract Disclosure: S. Tella: None. J.C. Morris: None. M. Rivera: None. S. Gupta: None. M.M. Ryder: None. Introduction: NUT carcinoma is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT-fusion oncoproteins with a very dismal prognosis. Recent data showed that NUTM1 rearranged carcinoma of the thyroid can mimic other thyroid primaries but NSD3-NUTM1 fusions aid in the diagnosis. Other than systemic chemotherapy with ifosfamide-based therapies and bromodomain inhibitors, therapeutic options for metastatic NUTM1 rearranged carcinoma of thyroid are limited. Herein, we describe a case of NUTM1 carcinoma of thyroid that had an impressive response to lenvatinib. Clinical case: We describe a case of a 41-year-old Caucasian male who presented to urgent care with acute onset aphonia and was eventually diagnosed with poorly differentiated thyroid carcinoma of size 4 x 4 cms extending into the internal jugular vein. He was managed with partial resection of the mass, internal jugular vein ligation, and a right select neck dissection. He had R2 resection due to possible vascular or airway invasion. As such, he received external beam radiation 70 Gy with 35 fractions with concurrent cisplatin followed by 200 mci radio-iodine therapy. The radiation therapy was complicated by the formation of a tracheo-esophageal fistula. A follow-up FDG-avid PET scan demonstrated residual thyroid bed disease and oligometastatic disease in bones. He received a couple of Stereotactic Body Radiation Therapy twice for bone lesions. Unfortunately, he had rapid disease progression with large pleural-based nodules and histology showed poorly differentiated thyroid carcinoma. NUT1 IHC stain was negative. We simultaneously obtained next-generation sequencing (NGS) and started him on lenvatinib 20 mg. Interestingly, NGS showed NSD3-NUTM1 fusions favoring the diagnosis of NUTM1 rearranged carcinoma of thyroid. He had an impressive partial response to lenvatinib within 4 weeks of initiation of lenvatinib and the response is sustained on 8-month follow-up. He tolerated lenvatinib reasonably without any unexpected complications. In an event of progression, we intend to consider a clinical trial, chemotherapy in combination with bromodomain inhibitors, or another anti-angiogenic tyrosine kinase inhibitor therapy. Conclusions: We noticed an impressive and sustained partial response in NUTM1 rearranged carcinoma of thyroid with anti-angiogenic multi-kinase inhibitor, lenvatinib opening new avenues of targeted therapy in the therapeutic landscape of NUT1 carcinomas. Importantly, NUT1 stain could be negative and NGS is the gold standard for accurate diagnosis. Although our study is limited by one case report, we hope that by highlighting the spectrum of this disease that more cases will be recognized, facilitating risk stratification and improved treatment, and further enabling future studies to explore the clinical management and biology of NUTM1 rearranged carcinoma of thyroid. Presentation: Thursday, June 15, 2023

Abstract Disclosure: D. Toro-Tobon: None. J.C. Morris: None. C. Hilger: None. C.S. Peskey: None. D.M. Jolanta: None. M.M. Ryder: None. Objective: Patients with metastatic differentiated thyroid cancer (DTC) that are radioactive iodine (RAI) refractory (RAIR) have a poor prognosis. Redifferentiation therapy (RDT) has emerged as a potential approach to restore RAI avidity in this disease. The aim of this study was to examine the efficacy and predictors of RAI restoration in RAIR disease, as well as examine the outcomes of patients re-treated with high dose RAI following RDT. Methods: A retrospective review was conducted of 33 patients with RECIST-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic. All patients underwent genomic profiling, and either MEK inhibitor alone or combination BRAF-MEK inhibitors were prescribed for 4 weeks. At week 3, Thyrogen-stimulated I-123 whole body scans were performed. Those with increased RAI avidity in metastatic foci received high dose I-131 therapy using a previously published modified dosimetry protocol. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 12 of 23 (52%) with papillary thyroid cancers (PTC), 4 of 4 (100%) with follicular variant PTCs (FV-PTC), and 7 of 7 (100%) with follicular thyroid cancers (FTC) had restored RAI avidity following RDT using dabrafenib/trametinib (7 for BRAF mutant disease) or trametinib monotherapy (12 for RAS mutant disease). All 11 (100%) RAS mutant tumors (2 PTC, 3 FV-PTC, and 6 FTC) had RAI avidity restoration compared to 7 (36%) with BRAF mutant disease (6 PTC, and 1 FV-PTC). Of the 19 patients (57%) with restored RAI avidity (responders), 18 (94%) received I-131 with a median dose of 294 mCi. The median thyroglobulin (Tg) in responders was 294 mIU/L as compared to 29 mIU/L in non-responders. Following RDT-facilitated I-131 treatment, 94.7% achieved RECIST defined objective response (complete or partial response, stable disease, non-complete response/non-progressive disease) with a median progression free survival of 18 months and an overall survival of 30 months. Overall, patients with FTC (p=0.01), RAS mutation (p<0.001), Tg of 294 mIU/L or more (p=0.03), largest tumor diameter of 1.7 cm or less (p=0.05), bone metastasis (p=0.007), and without locoregional nodal disease (p=0.04), were more likely to demonstrate restored RAI avidity following RDT. Of the entire cohort, 2 (6%) patients experienced histologic transformation to anaplastic thyroid cancer and 5 (15%) patients died, all had had RAI restoration and received high-dose RAI following RDT. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following I-131 therapy in select patients with RAIR-DTC, particularly those with RAS mutations and ‘follicular’ phenotypes. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic transformation. Presentation Date: Saturday, June 17, 2023

SAGE-Journals-Accessible-Video-Player 10.1089/ve.2023.0020.M1 sj-vid-1-vde-10.1089_ve.2023.0020

Abstract Purpose: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. Experimental Design: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case–control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. Results: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. Conclusions: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visitNCCN.org.

Abstract Context Metastatic pheochromocytomas and paragangliomas (mPPGL) are rare vascular neuroendocrine tumors that highly express vascular growth factors. Systemic treatment options in cases of unresectable multisite disease are limited. Multikinase inhibitors that inhibit angiogenesis, such as lenvatinib, have proven effective in several other malignancies, and may be a viable option for mPPGL. Objective We aimed to evaluate the efficacy of lenvatinib as salvage therapy in mPPGLs. Methods This was a retrospective analysis of mPPGL patients ≥ 18 years of age who received lenvatinib from 2015 to 2020 at a tertiary referral center. Patients were started on lenvatinib 20 mg daily and dose was adjusted according to tolerance or disease progression. Results Eleven patients were included. Median treatment duration was 14.7 months (95% CI, 2.3-NE). Treatment was discontinued due to disease progression, adverse events, or death. Overall survival at 12 months was 80.8% (95% CI, 42.3-94.9%) but its median was not reached. Median progression-free survival was 14.7 months (95% CI, 1.7-NE). Among the 8 patients with measurable disease, overall response rate was 63%, as 5/8 experienced a partial response and 3/8 had stable disease. Worsening hypertension and anemia were the most common adverse events. Conclusion Lenvatinib may be a viable treatment option for mPPGL, although at the potential risk of worsening hypertension. Larger, multicenter studies are needed to better characterize treatment efficacy.