Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma.

INTRODUCTION: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128). METHODS: We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study. RESULTS: Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications. CONCLUSION: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

Neoadjuvant therapy to improve resectability of advanced thyroid cancer: A real-world experience.

BACKGROUND: Experience with targeted neoadjuvant treatment for locoregionally advanced thyroid cancer is nascent. METHODS: Multicenter retrospective case series examining targeted neoadjuvant treatment for locoregionally advanced thyroid cancer. The primary outcome was change in surgical morbidity as measured by two metrics developed for use in clinical trials to characterize surgical complexity and morbidity. Secondary outcomes included percentage of patients proceeding to surgery and percentage receiving an R0/R1 resection. RESULTS: Seventeen patients with varied molecular alterations, pathologies, and treatment regimens were included. Mean surgical complexity scores decreased between time points for baseline and postneoadjuvant treatment, postneoadjuvant treatment and surgery, and between baseline and surgery. Eleven patients (64.7%) underwent surgical resection, with 10 (58.8%) receiving an R0/R1 resection. CONCLUSIONS: Neoadjuvant treatment of advanced thyroid cancer improves resectability and decreases the morbidity of required surgical procedures. However, treatment is not uniformly effective.

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma: A Review and Multidisciplinary 2023 Update.

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.

Recovery of Recurrent Laryngeal Nerve Function With Neoadjuvant Treatment: Neural Characterization.

OBJECTIVES: Neoadjuvant targeted therapy has emerged as a promising treatment strategy for locally aggressive thyroid cancer. Its impact on tumor and adjacent tissues remains a nascent area of study. Here we report on a series of six subjects with locally advanced thyroid cancer and recurrent laryngeal nerve (RLN) paralysis who experienced recovery of RLN function with neoadjuvant treatment and describe the morphologic and electrophysiologic characteristics of these recovered nerves. METHODS: This is a multicenter retrospective review. Descriptive analysis was conducted to examine the following parameters for recovered nerves: (1) nerve morphology, characterized as Type A (involving epineurium only) versus Type B (extending beyond epineurium); (2) proximal stimulability (normal vs. abnormal vs. absent); and (3) surgical management (resection vs. preservation). RESULTS: Six subjects with unilateral VFP were identified. Median time to return of VF mobility was 3 months (range 2-13.5). All nerves (100%) were noted to have Type A morphology at surgery. Proximal stimulability was normal in four subjects (66.7%), abnormal in one (16.7%), and absent in one (16.7%). Nerves that had improvement of function through neoadjuvant therapy were able to be surgically preserved in five subjects (83.3%). CONCLUSIONS: This represents the first characterization of RLNs that have recovered function with neoadjuvant treatment of locally advanced thyroid cancer. Although much remains unknown, our findings indicate carcinomatous neural invasion is a reversible process and recovered nerves may demonstrate normal morphology and electrophysiologic activity. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Real-world practice patterns and outcomes for RAI-refractory differentiated thyroid cancer.

Background: The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population). Methods: In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated. Results: Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively. Conclusions: Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance. Registration: NCT02303444.

Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer.

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

Amygdalar activity measured using FDG-PET/CT at head and neck cancer staging independently predicts survival.

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.

Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas: A Review.

Importance: Thyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions. Observations: The relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy. Conclusions and Relevance: This review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.

Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma.

Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SIGNIFICANCE: HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.

Medullary Thyroid Cancer: Updates and Challenges.

A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.

Challenges and Strategies to Combat Resistance Mechanisms in Thyroid Cancer Therapeutics.

Background: BRAFV600E and N/H/K RAS mutations and oncogenic kinase fusions involving neurotrophin tyrosine receptor kinase (NTRK), RET, anaplastic lymphoma kinase (ALK), and ROS1 have been identified as actionable targets in thyroid cancer. These driver alterations lead to oncogene addiction, which has been successfully exploited through tyrosine kinase inhibitors. Acquired resistance may develop following an initial response requiring a therapeutic pivot to new therapies. Summary: Several pathways for development of acquired resistance have been identified. These encompass acquired on-target gene mutation impeding drug activity and upregulation of bypass kinase signaling pathways leading to tumor progression. Biopsy of resistant lesions (liquid or tissue) and subsequent molecular analysis can assist with new therapeutic strategies. Conclusions: Progression-free survival is curtailed by developing acquired resistance. To minimize this therapeutic liability, clinicians must be anticipatory in identifying the drivers and characterizing mechanisms of on-target resistance.

Biomarkers predictive of response to pembrolizumab in head and neck cancer.

BACKGROUND: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored. METHODS: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). RESULTS: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. CONCLUSIONS: TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.

Case Report of CCDC149-ALK Fusion: A Novel Genetic Alteration and a Clinically Relevant Target in Metastatic Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, usually with an indolent course. ALK fusions are rare in PTC but may give rise to a more aggressive behavior. We report a novel ALK fusion, CCDC149-ALK, not previously described in PTC, detected by next-generation sequencing in a 30-year-old woman with progressive widely metastatic radioiodine-refractory (RAIR) disease to lung, muscle, and brain. The patient was started on alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor. Within eight weeks, her palpable disease had completely regressed, and the serum thyroglobulin decreased dramatically. Restaging imaging demonstrated an objective partial response. Our case highlights the role of ALK fusions in thyroid cancer and highlights its clinical significance in PTC. We recommend deep mutational sequencing in BRAFV600E-negative RAIR PTC to identify targetable genetic alterations, including gene fusions, that may result in dramatic therapeutic benefits.

LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naïve RET-mutant medullary thyroid cancer.

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib.

Selpercatinib (also known by the brand name Retevmo^®/Retsevmo^®) is a new treatment available in multiple countries for people with advanced or metastatic RET-mutant medullary thyroid cancer (MTC). Thyroid cancer starts in your thyroid gland and may spread or metastasize to other parts of the body, including lungs, bones, and occasionally the brain, which means the cancer is likely to be advanced. Advanced thyroid cancer can be driven by a gene in your body, one of which is RET. This is a summary of the LIBRETTO-531 study which compares selpercatinib, which is a strong and selective inhibitor of RET, with two approved drugs, cabozantinib and vandetanib. Patients with advanced or metastatic RET-mutant MTC who have not already received treatment with kinase inhibitors are being enrolled. This trial will evaluate how long people during and after treatment live with the disease without it getting worse. Selpercatinib may affect both healthy cells and tumor cells, which can result in side effects, which will also be evaluated in this study. This study is active and currently recruiting new patients. Clinical Trial Registration: NCT04211337 (ClinicalTrials.gov).

The Prediction of Cardiac Events Using Contemporary Risk Prediction Models after Radiation Therapy for Head and Neck Cancer.

This study aims to evaluate the efficacy of the Pooled Cohort Equation (PCE), U.S. Preventative Services Task Force (USPSTF), and Framingham Risk Score (FRS) models in predicting ASCVD events among patients receiving radiation therapy (RT) for head and neck cancer (HNCA). From a large cohort of HNCA patients treated with RT, ASCVD events were adjudicated. Observed vs. predicted ASCVD events were compared. We compared rates by statin eligibility status. Regression models and survival analysis were used to identify the relationship between predicted risk and post-RT outcomes. Among the 723 identified patients, 274 (38%) were statin-eligible based on USPSTF criteria, 359 (49%) based on PCE, and 234 (32%) based on FRS. During follow-up, 17% developed an ASCVD, with an event rate of 27 per 1000 person-years, 68% higher than predicted (RR 1.68 (95% CI: 1.02, 2.12), p < 0.001). In multivariable regression, there was no difference in event rates by statin eligibility status (p > 0.05). Post-RT, the observed event rate was higher than the predicted ASCVD risk across all grades of predicted risk (p < 0.05) and the observed risk of an ASCVD event was high even among patients predicted to have a low risk of ASCVD. In conclusion, current ASCVD risk calculators significantly underestimate the risk for ASCVD among patients receiving RT for HNCA.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs). METHODS: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated. RESULTS: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9). CONCLUSIONS: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.