Hilger, Crystal

Abstract Background The overall survival of patients with advanced thyroid cancers that have progressed following targeted therapies is limited, indicating a strong need for salvage treatments. Methods We retrospectively analyzed patients with refractory advanced thyroid cancer treated with pemetrexed‐carboplatin (PC) at Mayo Clinic since 2019. Results Eleven patients, three with anaplastic thyroid cancer (ATC), seven with differentiated or poorly differentiated thyroid cancer (DTC), and one with oncocytic carcinoma of the thyroid, were treated with novel salvage PC. Patients with DTC ( n = 7) had durable responses with a median progression‐free survival of 29 months. One responder included a patient with ATC whose disease progressed following pembrolizumab/axitinib, lenvatinib, and dabrafenib/trametinib. On this fourth line treatment, the patient remains on therapy to date, over 12 months after initial response. Conclusions This case series reinforces prior published phase I clinical trial data and shows that pemetrexed can have potent efficacy in the treatment of the most advanced thyroid cancers.

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: 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

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.

Abstract Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

e20605 Background: Intravenous (IV) fosaprepitant is a potent antiemetic, commonly used in patients receiving chemotherapy. The purpose of this study was to investigate the incidence of IV fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin and cyclophosphamide (AC) chemotherapy at Mayo Rochester. Methods: A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC chemotherapy from January 2011 to April 2012. Data collected from the EMR included baseline demographics, antiemetic regimen, documentation of ISAEs and type of IV access (peripheral vs. central). Descriptive statistics (mean and standard deviation or percentages) were summarized overall and by type of IV access and initially administered antiemetic. Results: 148 patients were included, with a median age of 54 years (range 28-76). 98 patients initially received IV fosaprepitant; 44 oral aprepitant; 6 neither. 132 (89%) initially had peripheral IV access and 16 (11%) had central venous access. Overall, 33 patients (34%) experienced an IV fosaprepitant associated ISAE including: erythema (n=22), pain (n=26), swelling (n=12), infusion site hives (n=5), extravasation (n=4), deep venous thrombosis (n=3), superficial thrombosis (n=7), phlebitis/thrombophlebitis (n=5), venous discoloration (n=1), venous engorgement (n=1), venous hardening/induration (n=4) and local scarring (n=1). Only 1 patient (2%) experienced an oral aprepitant associated ISAE, which was infusion site pain. This patient had previously had a fosaprepitant associated ISAE at the same site. All experienced ISAEs occurred in patients with peripheral IV access. Conclusions: The incidence and severity of ISAEs associated with IV fosaprepitant administration among a group of patients receiving doxorubicin/cyclophosphamide chemotherapy is significant and is appreciably higher than what has been noted in other reports. The higher incidence observed is likely related to the predominance of peripheral venous access used in the studied cohort.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

6087 Background: NTRK1-3 fusions, identified in pediatric radiation-associated thyroid cancers, are low frequency oncogenic drivers that can trigger constitutive activation of TrK1-3 tyrosine kinase domains with responsively heightened downstream signaling through RAS-MAPK, PI3K-AKT, and/or PLCγ-PKC. NTRK point mutations are rare and of largely uninvestigated oncogenic potential, but some appear oncogenic. Methods: Advanced thyroid cancer (TC) patients (pts) requiring systemic therapy at Mayo Clinic sites underwent tumor genetic interrogation using Foundation One analyses with the goal of informing salvage therapeutic strategies. In this IRB-approved study, data from pts with TCs bearing NTRK point mutations were retrospectively analyzed, as this occurrence was unexpected but potentially of prognostic and/or therapeutic relevance. Results: Five of 55 pts (9%) with advanced TCs subject to Foundation One tumor interrogation had NTRK1-3 point mutations (allele frequency, AF, 15-49%); none had fusions. All 5 tumors had microsatellite stability; 4/5 had low tumor mutation burden (2-5 mutations/megabase). NTRK mutations in 3 anaplastic TC (ATC) pts (15% prevalence) were: NTRK3 I749M (AF 15%; overall survival, OS, 15 mos), NTRK1 R744H (AF not available; OS 9.5 mos), and NTRK1 R583H (AF 20.1%; OS > 4.9 mos); NTRK2 S167Y (AF 49%; OS > 51 mos) or NTRK1 R6W (AF 42%; OS > 60 mos) were found in one papillary (PTC) and one Hürthle cell (HCC) TC pt respectively (summary table below). Conclusions: NTRK point mutations, but not fusions, were unexpectedly identified in 9% of assessed advanced TCs - but remarkably in 15% of ATCs. Mutated NTRKs, along with oncogenic p53 and TERT, may contribute to TC progression, especially in ATC, consequent to downstream activation of MAPK and PI3K-AKT pathways. We posit that NTRK point mutations may have therapeutic implications for treatment of refractory disease. [Table: see text]

Background: Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. Methods: A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Results: Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2–3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57–84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. Conclusion: This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.