Faculty Bibliography

BACKGROUND:High C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma. METHODS:The effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay. RESULTS:In vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients. CONCLUSIONS:in melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT01783938 and NCT02983006.

In the past 10 years, immune checkpoint inhibitors (ICIs) have become an additional pillar of cancer therapy by activating the immune system to treat a number of different malignancies. Many patients receiving ICIs develop immune-related adverse events (irAEs) that mimic some features of classical autoimmune diseases. Unfortunately, patients with underlying autoimmune conditions, many of whom have an increased risk for malignancy, have been excluded from clinical trials of ICIs due to a concern that they will have an increased risk of irAEs. Retrospective data from patients with autoimmune diseases and concomitant malignancy treated with ICIs are encouraging and suggest that ICIs may be tolerated safely in patients with specific autoimmune diseases, but there are no prospective data to guide management. In this manuscript, we review the relationship between pre-existing autoimmune disease and irAEs from checkpoint inhibitors. In addition, we assess the likelihood of autoimmune disease exacerbations in patients with pre-existing autoimmunity receiving ICI.

PURPOSE/OBJECTIVE:To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS:ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS:A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. RECOMMENDATIONS/CONCLUSIONS:-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

Objectives. To determine the effect of new therapies and trends toward reduced mortality rates of melanoma.Methods. We reviewed melanoma incidence and mortality among Whites (the group most affected by melanoma) in 9 US Surveillance, Epidemiology, and End Results registry areas that recorded data between 1986 and 2016.Results. From 1986 to 2013, overall mortality rates increased by 7.5%. Beginning in 2011, the US Food and Drug Administration approved 10 new treatments for metastatic melanoma. From 2013 to 2016, overall mortality decreased by 17.9% (annual percent change [APC] = -6.2%; 95% confidence interval [CI] = -8.7%, -3.7%) with sharp declines among men aged 50 years or older (APC = -8.3%; 95% CI = -12.2%, -4.1%) starting in 2014. This recent, multiyear decline is the largest and most sustained improvement in melanoma mortality ever observed and is unprecedented in cancer medicine.Conclusions. The introduction of new therapies for metastatic melanoma was associated with a significant reduction in population-level mortality. Future research should focus on developing even more effective treatments, identifying biomarkers to select patients most likely to benefit, and renewing emphasis on public health approaches to reduce the number of patients with advanced disease. (Am J Public Health. Published online ahead of print March 19, 2020: e1-e3. doi:10.2105/AJPH.2020.305567).

Phenotyping of immune cell subsets in clinical trials is limited to well-defined phenotypes, due to technological limitations of reporting flow cytometry multi-dimensional phenotyping data. We developed a multi-dimensional phenotyping analysis tool and applied it to detect nitric oxide (NO) levels in peripheral blood immune cells before and after adjuvant ipilimumab co-administration with a peptide vaccine in melanoma patients. We analyzed inhibitory and stimulatory markers for immune cell phenotypes that were felt to be important in the NO analysis. The pipeline allows visualization of immune cell phenotypes without knowledge of clustering techniques and to categorize cells by association with relapse-free survival (RFS). Using this analysis, we uncovered the potential for a dichotomous role of NO as a pro- and anti-melanoma factor. NO was found in subsets of immune-suppressor cells associated with shorter-term (≤ 1 year) RFS, whereas NO was also present in immune-stimulatory effector cells obtained from patients with significant longer-term (> 1 year) RFS. These studies provide insights into the cell-specific immunomodulatory role of NO. The methods presented herein can be applied to monitor the pro- and anti-tumor effects of a variety of immune-based therapeutics in cancer patients. Clinical Trial Registration Number: NCT00084656 (https://clinicaltrials.gov/ct2/show/NCT00084656).

Pembro has robust antitumor activity and durable responses in pts with advanced melanoma. The prognostic value of an initial SD assessment with pembro treatment is unclear. This post hoc analysis of pts with melanoma treated with pembro in KEYNOTE-001 and KEYNOTE-006 evaluates long-term outcomes of pts with SD, CR, or PR at wk 12 (n = 284) and 24 (n = 241) from randomization. PFS and OS rates were estimated at 1 y, 2 y, and 3 y from the 24-wk assessment per Kaplan-Meier method. Of the 241 pts included in this analysis, 212 were treatment-naive; 29 received only BRAF+/-MEK inhibitors as prior therapy; 42 had CR, 160 had PR, and 39 had SD by central review at wk 24 (initial CR, PR, SD, respectively). At baseline, most pts, regardless of initial response, had ECOG PS of 0 and M1c disease. At data cutoff (Sep 1, 2017, KEYNOTE-001; Dec 4, 2017, KEYNOTE-006), pts with initial CR had 1-y PFS rate of 92.9%, 2-y PFS rate of 82.5%, 3-y PFS rate was not reached; pts with initial CR had 1-y OS rate of 100%; 2-y and 3-y OS rates were 97.6%. 32 (20%) pts with initial PR had CR as BOR; pts with initial PR had 1-y PFS rate of 79.2%, 2-y rate of 66.5%, 3-y rate of 44.4%; pts with initial PR had 1-y OS rate of 94.4%, 2-y rate of 87.5%, 3-y rate of 79.7%. Of pts with initial SD (n = 39), 1 (2.6%) had a BOR of CR, 13 (33.3%) had PR, and 25 (64.1%) remained SD. Pts with initial SD had 1-y PFS rate of 58.8% and 2-y and 3-y rates of 49.1%; pts with initial SD had 1-y OS rate of 97.4%, 2-y rate of 82.0%, 3-y rate of 73.5%. Of 241 pts, 21 (10.4%) had persistent SD. Similar analysis at wk 12 from randomization will be presented. Pembro treatment elicits a response, albeit delayed, in a substantial proportion of pts (35.9%) with initial SD. These results may inform treatment expectation for pts with initial SD with pembro and aid in future trial design

Background: Melanoma that metastasizes to the brain has a poor prognosis, and accounts for up to 54% of melanoma deaths. Clinical data show that treatment with BRAF-targeted agents induces responses in BRAFV600-mutant MBM. The BRAF/MEK-targeted combination encorafenib + binimetinib demonstrated favorable efficacy and safety for patients with BRAFV600-mutant melanoma in the COLUMBUS study, but excluded patients with active MBM. The aim of this study is to evaluate encorafenib + binimetinib in patients with BRAFV600-mutated active MBM. A higher dose of combination therapy will be studied versus a standard dose to evaluate whether greater efficacy may be achieved with acceptable safety for patients with BRAFV600 MBM.
Method(s): Eligible patients in this multicenter, randomized, open-label phase 2 study adults with BRAFV600-mutant MBM will have at least 1 measurable MBM, no prior local MBM therapy, no corticosteroids for MBM, and no prior BRAF or MEK inhibitors in the metastatic setting. One prior line of checkpoint inhibitor or adjuvant BRAF or MEK inhibitors is permitted. Patients will be randomized (1:1) to either the standard dose (450 mg orally QD and binimetinib 45 mg orally BID) or high-dose (encorafenib 300 mg BID and binimetinib 45 mg BID) stratified by baseline tumor burden (1-2 vs. >=3 brain lesions at baseline) and prior checkpoint inhibitor (yes vs. no). The first 9 evaluable patients in the high-dose arm will constitute the safety lead-in cohort. If the high-dose is not tolerated, subsequent patients will receive standard-dose therapy. Assessments include intracranial response (per modified RECIST), extracranial response, global response rate, DCR, DOR, PFS, OS, PK, and safety. The study will enroll approximately 100 patients. (NCT03911869)