Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care whose backbone consists of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGF). For ccRCC, pembrolizumab-axitinib, pembrolizumab-lenvatinib, and avelumab-axitinib or nivolumab-cabozantinib are now FDA-approved frontline options for all risk groups while nivolumab-ipilimumab is reserved for intermediate- and poor-risk groups. Monotherapy with pembrolizumab or nivolumab is a potential option for patients who are unable to take VEGFR-tyrosine kinase inhibitors. While outcomes have improved with the adoption of ICI therapies, many patients develop therapy-resistant disease, creating an unmet need for further investigation. The efficacy of novel therapies as well as novel combinations in the post-ICI era is unclear. This review summarizes the most significant clinical trials involving dual ICI/ICI and ICI/VEGFR therapies, in addition to other selected combination therapies that are likely to inform management in the near future.

Purpose: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages. Patients and Methods: Adult patients with B-NHL who had received at least two prior lines of systemic therapy were included in this single-arm phase I study (NCT05025800). Evorpacept was administered intravenously, in a 28-day cycle, until progression at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1) or 60 mg/Kg on day 1 (DL2); rituximab 375 mg/m2 i.v. was given weekly during cycle 1 and on D1 during cycles 2 to 6; and lenalidomide 20 mg was given orally from D1 to D21 during cycles 1 to 6. Single-cell RNA sequencing was performed on tumor biopsies collected before treatment and during cycle 1. Results: Twenty patients were included in this study. The median age was 61 (27–85) years, and 18 patients (90%) had indolent B-NHL. Three patients were treated at DL1, 17 at DL2, and no dose-limiting toxicity was observed. The most common grade 3 to 4 adverse events included neutropenia (60%), infections (30%), and alanine transferase increase (15%). Sixteen (80%) patients achieved complete response, and after a median follow-up of 28 months, 2-year progression-free survival rate was 69%. During treatment, a significant increase in T cells and macrophages was observed, and macrophage pathways associated with anti-tumoral activity were upregulated. Conclusions: Evorpacept plus lenalidomide and rituximab has a safe toxicity profile and promising anti-tumoral activity, and induces favorable biological effects on the tumoral immune microenvironment.

Biomarkers have the potential to guide treatment selection and clinical care in metastatic renal cell carcinoma (mRCC) in an expanding treatment landscape. We report baseline neutrophil-to-eosinophil ratios (NER) in patients with mRCC treated with immune checkpoint inhibitors (CPIs) and their association with clinical outcomes. We conducted a retrospective review of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015 to 2020 in the United States of America (USA). Demographics, disease characteristics, and laboratory data, including complete blood counts (CBC) were described at the initiation of CPIs. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) associated with baseline lab values. A total of 184 patients were included with a median follow-up time of 25.4 months. Patients with baseline NER were categorized into high or low subgroups; high group was defined as NER >49.2 and low group was defined as NER <49.2 with 25% of patients in the high NER group. Univariate analyses (UVA) and multivariable analyses (MVA) identified decreased overall survival (OS) associated with elevated NER. In MVA, patients with a high baseline NER group had a hazard ratio (HR) of 1.68 (95%CI, 1.01-2.82, P = .048) for OS; however, there was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. We conclude that elevated baseline NER may be associated with worse clinical outcomes in mRCC. Although results require further validation, NER is a feasible biomarker in patients with CPI-treated mRCC.

Introduction: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with a poor prognosis and an unmet need for biomarkers. We performed a retrospective evaluation of real-world efficacy, safety outcomes, and baseline inflammatory biomarkers in patients with advanced pSCC treated with immune checkpoint inhibitors (ICIs). Methods: We performed a retrospective review of patients with advanced pSCC who received ICIs from 2012 to 2023 at the Winship Cancer Institute of Emory University in Atlanta, GA. Demographics, disease characteristics, and optimal cutoffs of baseline biomarkers obtained before ICI initiation were described. Human papillomavirus (HPV)/p16+ status was determined by immunohistochemistry. Programmed death-ligand 1 (PD-L1) positivity was defined as >1%. Immune-related adverse events (irAEs) were graded per Common Terminology Criteria for Adverse Events criteria and captured through clinical documentation. Clinical benefit was defined as complete response, partial response, or stable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier method and univariate Cox regression (UVA) using a significance level set at p < 0.05. Neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR), and neutrophil-to-eosinophil ratios (NER) were collected from complete blood count data. Results: Twenty-one patients were included of whom 71.4% were White and 28.6% were Black. Median age at ICI initiation was 56 years (38–76 years). Most patients had Eastern Cooperative Oncology Group performance status ≥2 (61.9%). At diagnosis, 4.8%, 33.3%, and 61.9% were stage 2, 3, and 4, respectively, of whom eight patients had initial distal metastases. Of patients with available data, 7 of 11 patients (63.6%) were PD-L1+ and 8 of 9 (89%) patients were HPV+. Median follow-up was 8.4 months and median time to ICI treatment from diagnosis was 15.6 months. ICI was first line (1L) in 1 patient (4.8%), 2L in 13 (61.9%), 3L in 6 (28.6%), and 4L in 1 (4.8%). Five patients achieved clinical benefit of whom three had partial response and two had stable disease. Median OS was 8.2 months (95% CI, 2.3–15.7) and PFS was 1.9 months (95% CI, 1.3–3.2). Notably, three patients with PD-L1 positivity, microsatellite instability (MSI)-high, or high tumor mutational burden (TMB) demonstrated response to ICI. Higher baseline NLR (hazard ratio, 10.0; 95% CI, 2.73–54.2) at optimal cutoff was associated with shorter OS and PFS on UVA. Three patients (14.3%) developed grade 3/4 ICI-related adverse events. Conclusions: Our real-world analysis summarizes our institutional experience and provides granular clinical and molecular attributes of patients with therapeutic response, which may aid in patient stratification within ICI-based clinical trials. Overall, we confirm poor response rates of pSCC to ICI in an unselected approach, consistent with multicenter studies. ICIs may be effective and tolerable therapy in a subset of patients. NLR may be a potential biomarker to assess ICI response in pSCC.