Durable local control with hypofractionated radiation therapy for unresectable or metastatic melanoma.

Background And Purpose: As patients with advanced melanoma live longer in the context of systemic therapy advancements, better strategies for durable control of bulky tumors are needed. In this study, we evaluated if dose-escalated hypofractionated radiation therapy (HFRT) can provide durable local control and improve tumor-associated symptoms in patients with unresectable or bulky metastatic melanoma for whom stereotactic ablative radiotherapy (RT) approaches are not feasible due to tumor size or location.

Materials And Methods: We retrospectively reviewed 49 patients with unresectable or bulky metastatic melanoma who were treated to a total of 53 tumor targets with 12-17 fractions HFRT at our institution between 2015-2022.

Project Optimus Elicits the "Holistic" Benefits of PK/PD Modeling of Immunotherapy.

Leveraging a heterogeneous dataset, a recent article demonstrated the application of pharmacometric modeling to inform the dosing of nivolumab-relatlimab fixed-dose combination in special populations, including adolescents lacking clinical data. The use of model-informed approaches during clinical drug development can be cost-effective, which ensures fast access to drugs and enhances patient outcomes. See related article by Zhao et al.

Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.

Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care.

Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.

Background: Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.

Methods: Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible.

Neoadjuvant Immunotherapy in Melanoma: The Paradigm Shift.

Clinical stage III melanoma, defined as resectable RECIST measurable nodal disease with or without in-transit metastases, represents approximately 15% of new melanoma diagnoses every year with additional cases presenting as recurrent nodal disease following previous treatment of a primary melanoma. The standard of care for patients with resectable clinical stage III melanoma is surgical resection, consisting of therapeutic lymph node dissection and/or resection of in-transit disease and consideration of adjuvant systemic therapy and occasionally adjuvant radiation. These patients have high rates of regional recurrence and progression to metastatic disease postsurgery, highlighting the need for better treatment options.

Neoadjuvant checkpoint inhibitor immunotherapy for resectable mucosal melanoma.

Background: Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting.

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy.

Gynecologic tract melanoma in the contemporary therapeutic era: High rates of local and distant disease progression.

Background: Gynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era.

Methods: Patterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up.

Neoadjuvant immunotherapy across cancers: meeting report from the Immunotherapy Bridge-December 1st-2nd, 2021.

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making.

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.

Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma.

Purpose: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination.

Patients And Methods: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II).

Outcomes After Sphincter-Sparing Local Therapy for Anorectal Melanoma: 1989 to 2020.

Purpose: The treatment paradigm for patients with anorectal melanoma eligible for sphincter-sparing excision has evolved over time. This study examines outcomes across a 30-year era in this rare disease with poor prognosis.

Methods And Materials: This retrospective cohort study included all patients with pelvis-confined anorectal melanoma undergoing sphincter-sparing local excision and adjuvant radiation therapy (RT) at our institution between 1989 and 2020.

Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma.

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.

Experimental Design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use.

Coenzyme A fuels T cell anti-tumor immunity.

Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8 T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation.

Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance.

Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.

Background: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response.

Methods: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT.