High levels of expression of Trop-2 in thymic epithelial tumors.

BACKGROUND: Trophoblastic antigen 2 (Trop2) is a cell surface glycoprotein expressed in multiple types of cancers, including breast cancer, non-small cell lung cancer, and gastrointestinal cancers. Trop2 expression and the use of Trop2-directed therapy such as antibody-drug conjugate (ADC) have not yet been investigated in thymic epithelial tumors (TETs). METHODS: Patients with TETs treated at MedStar Georgetown University Hospital were retrospectively identified. Of the patients for whom tumor samples and normal thymus tissue were available, immunohistochemistry (IHC) membranous staining for Trop2 and PD-L1 were performed. Positivity for Trop2 required at least 10% of the tumor cells to be stained, with an intensity scored of 1+ (weak), 2+ (moderate), and 3+ (strong). Cases with CPS ≥ 5% were considered positive for PD-L1. RESULTS: 30 TET samples from 29 patients (17 patients with thymoma and 12 patients with thymic carcinoma) were identified. One patient with thymic carcinoma had two samples from different time points. From the same set of patients, 13 samples of normal thymus tissue were available. In normal thymus tissue, eight samples (62%) showed no positivity of Trop2, while five samples (38%) showed 1 + IHC staining. In the thymoma samples, four (24%) showed 0 or 1 + IHC staining, while 13 (76%) showed 2 + or 3 + staining. Of the 13 thymic carcinoma samples, three samples (23%) showed 1 + IHC staining while seven (54%) showed 2 + staining and three (23%) showed 3 + staining. There was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in thymoma or thymic carcinoma. CONCLUSIONS: Trop2 is readily expressed in TETS with a higher degree of expression in thymic carcinoma. The expression of Trop-2 was lower in normal thymic tissue compared with TETs. The increased expression of Trop-2 in TETs suggests that Trop2 is an attractive therapeutic target for Trop-2 directed therapy.

Response to selpercatinib in a patient with RET fusion-positive pulmonary large-cell neuroendocrine carcinoma: A case report.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of non-small-cell lung cancer associated with a poor prognosis. LCNEC is genetically heterogeneous, and studies have revealed distinct molecular subtypes of LCNEC, which may have therapeutic implications. Herein, we present a case of a patient with stage IV LCNEC harboring a KIF5B-RET fusion whose disease responded to the selective RET inhibitor selpercatinib both extra- and intra-cranially, highlighting the importance of comprehensive molecular testing in LCNEC for selection of optimal treatment.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

BACKGROUND: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. METHODS: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. RESULTS: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01). CONCLUSIONS: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

PET/CT scan and biopsy-driven approach for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma.

BACKGROUND: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions. METHODS: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma. RESULTS: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy. CONCLUSIONS: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.

Pembrolizumab-induced cytokine release syndrome in a patient with metastatic lung adenocarcinoma: a case report.

Cytokine release syndrome (CRS) is a well-described immune-related adverse event following chimeric antigen receptor T-cell therapy, but has rarely been reported following anti-programmed death ligand-1 therapy. We report the case of a 55-year-old man with metastatic lung adenocarcinoma who presented with fever, chills and hypotension. Initial labs were notable for highly elevated serum ferritin levels and mildly elevated triglyceride levels. He was ultimately diagnosed with pembrolizumab-induced CRS complicated by multiorgan failure. The patient was treated with steroids and tocilizumab with normalization of inflammatory markers and resolution of renal failure. This case not only highlights the importance of considering CRS in patients who have developed multiorgan failure after immune checkpoint inhibitor therapy, but also demonstrates clinical similarities between CRS and other hyperinflammatory states such as hemophagocytic lymphohistiocytosis.

A patient with melanoma that became sensitized to immunotherapy after treatment with a CDK4/6 inhibitor.

Background: Despite the profound effect that checkpoint inhibitors and BRAF/MEK inhibitors have had on survival in patients with metastatic melanoma, treatment options remain limited for those who demonstrate poor response or develop resistance to these modalities. The prospect of tumor sensitization to these treatments is therefore an attractive one. Results: We describe the case of a patient who developed a sustained response to trametinib and pembrolizumab, despite prior resistance to both these therapies, after receiving treatment with a CDK4/6 inhibitor. Discussion: We further outline the preclinical data supporting a possible role for the use of CDK4/6 inhibitors in tumor sensitization to immunotherapy.

Immune checkpoint inhibitor use and tuberculosis: a systematic review of the literature.

BACKGROUND: An amassing body of evidence exists to support an association between the use of immune checkpoint inhibitors (ICIs) and the development of tuberculosis (TB). METHODS: We performed a systematic review of the literature to assess the nature of this relationship using PubMed, EMBASE and meeting proceedings. RESULTS: We have identified 16 patients who developed active TB during immunotherapy. Median age was 61 (range: 49-87). Twelve (75%) were male and 4 (25%) were female. Lung cancer was the most common type of cancer (n = 8), followed by melanoma (n = 3) and head and neck cancer (n = 3). Median time to TB reactivation after initiation of ICI therapy was 6.3 months (range: 1-24 months). Two (13%) patients died of complications of TB (spinal cord compression, GI perforation). TB reactivation in organs (pericardium, bone, liver, and GI track; one each) other than the lungs has been documented. We did not find any cases of TB reactivation that occurred during anti-CTLA-4 therapy. CONCLUSION: Findings from our systematic review indicate that PD-(L)1 inhibitors are linked to TB reactivation. TB activation can occur in various organs and TB-related fatalities have been reported. TB screening before starting immunotherapy should be considered in high-risk patient populations. Further research, including prospective studies with patients whose baseline TB status is known, is necessary to better understand the incidence of TB reactivation during ICI therapy and how best to manage TB that develops during immunotherapy.

NF-κB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progression is needed. Work presented here indicates that mesenchymal NSCLC upregulates glutamine-fructose-6-phosphate transaminase 2 (GFPT2). GFPT2 is the rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the obligate activator of O-linked N-acetylglucosamine transferase (OGT). METHODS: Analysis of our transcriptomic data indicates that GFPT2 is one of the most significantly upregulated metabolic genes in mesenchymal NSCLC. Ectopic GFPT2 expression, as well as gene silencing strategies were used to determine the importance of this metabolic enzyme in regulating EMT-driven processes of cell motility and invasion. RESULTS: Our work demonstrates that GFPT2 is transcriptionally upregulated by NF-κB and repressed by the NAD+-dependent deacetylase SIRT6. Depletion of GFPT2 expression in NSCLC highlights its importance in regulating cell migration and invasion during EMT. CONCLUSIONS: Consistent with GFPT2 promoting cancer progression, we find that elevated GFPT2 expression correlates with poor clinical outcome in NSCLC. Modulation of GFPT2 activity offers a potentially important therapeutic target to combat NSCLC disease progression.