Ryder, Mabel

Background There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. Methods A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. Results Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. Conclusions In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

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.

Background: Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14 + CD16 + monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates ( n = 9) and peripheral blood ( n = 7) as compared with healthy thyroid samples ( n = 5) and healthy volunteer blood samples ( n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4 − CD8 − T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8 + T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4 + PD1 + T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8 + PD1 + T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4 + CD8 + , CD4 − CD8 − T, gamma – delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8 + and CD4 − CD8 − T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

Background: Thyroid immune-related adverse events (IRAEs) have been reported more frequently with programmed cell death protein-1 (PD-1) inhibitors than cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, but there is limited data describing endocrinopathies from programmed cell death protein–ligand 1 (PD-L1) inhibitors. This study characterizes thyroid IRAEs in cancer patients treated with PD-L1 inhibitors and examines the impact on overall survival. Methods: This is a retrospective cohort study of cancer patients treated with atezolizumab and avelumab at the Mayo Clinic, Rochester, Minnesota, from June 1, 2016 to January 30, 2018, and followed for a median of 10.1 months. Thyroid IRAEs were characterized as new onset hypothyroidism, thyrotoxicosis, and worsening of pre-existing hypothyroidism. Results: Of 91 patients treated with a PD-L1 inhibitor, 19 (21%) developed new onset thyroid dysfunction, of whom 14 presented with hypothyroidism and 5 with thyrotoxicosis (3 progressed to hypothyroidism and 2 returned to euthyroidism), and 4 (4%) had worsening of pre-existing hypothyroidism. Thyroid IRAEs occurred after a median of two doses (6 weeks), 48% required thyroid hormone replacement, and none required steroids or discontinuation of immunotherapy. Two out of four patients with thyroid peroxidase (TPO) antibody >9 IU/mL at baseline developed thyroid IRAEs. Median TPO antibody titer was not different between those with and without thyroid IRAEs but was higher in those with overt than those with subclinical hypothyroidism (5 vs. 0.3 IU/mL, p = 0.003) and those prescribed thyroid hormone replacement as compared with observation (5.5 vs. 0.3, p = 0.008). Diffusely increased thyroid 18-fluorodeoxyglucose ( 18 FDG) uptake on positron emission tomography (PET) scan occurred in 71% with thyroid IRAE as compared with 6% without thyroid IRAEs ( p = 0.001). Patients who developed thyroid IRAEs had longer overall survival ( p = 0.027) and lower mortality (hazard ratio 0.49 [95% CI 0.25–0.99], p = 0.034) after adjusting for potential confounders. Conclusions: PD-L1 inhibitors lead to immune-mediated thyroiditis, the most frequent endocrine IRAE. In most cases, management is supportive without requiring steroids or discontinuation of immunotherapy. Diffusely increased thyroid 18 FDG uptake on PET scan may predict the occurrence of thyroiditis, whereas TPO antibodies may help identify its severity. Thyroiditis may be a biomarker for antitumor immune response, highlighting the need to further characterize its underlying mechanism.

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.

Abstract The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer and a number of other commercially available drugs that have been studied for this indication. Although most of the US Food and Drug Administration (FDA)–approved drugs are antiangiogenic multikinase inhibitors—vandetanib, cabozantinib, sorafenib, lenvatinib—there are two FDA indications that are mutation specific—dabrafenib/trametinib for BRAF-mutated anaplastic thyroid cancer and larotrectinib for NTRK-fusion thyroid cancer. Furthermore, other mutation-specific drugs, immunotherapies, and novel strategies for advanced thyroid cancer are under investigation. Understanding the molecular basis of thyroid cancer, the drugs of interest for treatment of advanced thyroid cancer, and how these drugs can be administered safely and in the appropriate clinical scenario are the topics of this review.

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 and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org .