Search

OBJECTIVE: Many patients with melanoma treated with immune checkpoint inhibitors (ICIs) do not derive response. Preclinical and retrospective studies identified that inhibition of the cyclooxygenase (COX) pathway may improve response to ICI treatment. METHODS: This prospective single site phase II trial accrued patients with advanced/metastatic melanoma. Participants underwent high-dose aspirin daily combined with pembrolizumab and ipilimumab every 3 weeks for 4 cycles followed by high-dose aspirin and pembrolizumab monotherapy. The primary endpoint was objective response rate (ORR). Longitudinal sampling of blood was performed to assess peripheral immune correlates. RESULTS: Twenty-seven subjects were enrolled with median follow-up of 32 months. An ORR of 62.9% was reached prior to discontinuation due to low likelihood of achieving the pre-specified ORR of 80%. 17 patients (63%) experienced a treatment-related adverse event (TRAEs) grade 3 or higher. A per-protocol analysis showed that patients able to continue aspirin alongside ICI through the induction period experienced significant survival benefit. Ten cytokines and increased regulatory T cells in the periphery correlated with beneficial response. CONCLUSIONS: The addition of high-dose aspirin to combination ICI within this study results in response comparable to ICI alone. Future clinical studies of COX inhibition will need to focus on mitigation of AEs to establish the clinical utility of this combination.

BackgroundThe frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade.MethodsPretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.ResultsOf the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis.ConclusionThe results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

Simple Summary: Patients with locoregional head and neck cancer often receive radiation and/or surgery with curative intent. Chemotherapy is often used as a radiation sensitizer or adjunctively to improve treatment effect. However, these modalities are often associated with significant and potentially debilitating adverse events, which negatively impacts quality of life. HPV-associated oropharyngeal head and neck cancer has been shown to be more responsive to treatment compared to HPV-negative disease. Therefore, various de-escalation strategies have been under investigation in hopes of optimizing therapeutic response while also minimizing toxicity from treatment. The incidence of HPV-related oropharyngeal cancers has increased in recent decades. While cure rates exceed those of HPV-negative head and neck cancers, both acute and long-term sequelae of chemotherapy, radiation and surgery have led to clinical investigation into de-escalation of treatment. De-escalation trials have sought to reduce long-term treatment-related morbidity by altering or omitting chemotherapy, reducing radiation, or incorporating less invasive surgical resection through transoral surgery. More recent approaches include the use of novel agents such as immunotherapy in place of cisplatin. With the advent of tumor-tissue-modified HPV DNA detection and monitoring in blood, new strategies incorporating this biomarker are being developed. [ABSTRACT FROM AUTHOR]