Detection of Copy-Number Variation in Circulating Cell-Free DNA in Patients With Uveal Melanoma.

PURPOSE: Somatic chromosomal alterations, particularly monosomy 3 and 8q gains, have been associated with metastatic risk in uveal melanoma (UM). Whole genome-scale evaluation of detectable alterations in cell-free DNA (cfDNA) in UM could provide valuable prognostic information. Our pilot study evaluates the correlation between genomic information using ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA in UM and associated clinical outcomes. MATERIALS AND METHODS: ULP-WGS of cfDNA was performed on 29 plasma samples from 16 patients, 14 metastatic UM (mUM) and two non-metastatic, including pre- and post-treatment mUM samples from 10 patients treated with immunotherapy and one with liver-directed therapy. We estimated tumor fraction (TFx) and detected copy-number alterations (CNAs) using ichorCNA. Presence of 8q amplification was further analyzed using the likelihood ratio test (LRT). RESULTS: Eleven patients with mUM (17 samples) of 14 had detectable circulating tumor DNA (ctDNA). 8q gain was detected in all 17, whereas monosomy 3 was detectable in 10 of 17 samples. TFx generally correlated with disease status, showing an increase at the time of disease progression (PD). 8q gain detection sensitivity appeared greater with the LRT than with ichorCNA at lower TFxs. The only patient with mUM with partial response on treatment had a high pretreatment TFx and undetectable on-treatment ctDNA, correlating with her profound response and durable survival. CONCLUSION: ctDNA can be detected in mUM using ULP-WGS, and the TFx correlates with DS. 8q gain was consistently detectable in mUM, in line with previous studies indicating 8q gains early in primary UM and higher amplification with PD. Our work suggests that detection of CNAs by ULP-WGS, particularly focusing on 8q gain, could be a valuable blood biomarker to monitor PD in UM.

Tofacitinib is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis.

Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal.1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited.2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023.3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time.

Tebentafusp in the Treatment of Metastatic Uveal Melanoma: Patient Selection and Special Considerations.

Uveal melanoma (UM) is a rare type of melanoma with distinct features from cutaneous melanoma, low response rates to immune checkpoint inhibition, and poor survival rates. Tebentafusp, a bispecific antibody engaging T cells with gp 100 on HLA-A*02:01, was recently approved by the FDA as the first drug of its class and the first treatment approved by the FDA to treat UM. In this review, we summarize the preclinical and clinical data on tebentafusp for UM. We additionally discuss patient selection and the relevant challenges. For the literature search, PubMed search and relevant articles presented at international conferences were used.

Salvage systemic therapy for metastatic urothelial carcinoma: an unmet clinical need.

INTRODUCTION: Metastatic urothelial carcinoma (mUC) remains a fatal malignancy, despite the recent addition of immune check point inhibitors (ICIs), an FGFR inhibitor and an antibody-drug conjugate (ADC) to the therapeutic armamentarium. The survival rates are particularly dismal after first-line treatment failure, entailing an urgent need for more effective therapies. Advances in understanding biomarkers and identifying targetable molecules have broadened the pathways under investigation in mUC. AREAS COVERED: This review summarizes mUC salvage therapy options, including chemotherapy, ICI, and novel promising agents, including targeted therapies, ADCs, cytotoxic agents and vaccines. For the literature review, a PubMed search and relevant data presented at international conferences were used. EXPERT OPINION: The approval of ICIs, FGFR inhibitor erdafitinib and ADC enfortumab vedotin in the salvage setting has transformed the mUC landscape. Yet there are additional promising agents currently under study. Toxicities are observed with ADCs and FGFR inhibitors, but appear manageable in most patients. The molecular heterogeneity and complex tumor biology are challenging barriers for progress in the therapy of mUC. Advances in molecular profiling, defining validated predictive markers, rational combinations of agents and therapeutically actionable targets will help develop personalized compounds with higher efficacy and less toxicity with hopes to improve outcomes for mUC.

Erdafitinib for the treatment of metastatic bladder cancer.

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15-20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.