High serum sodium predicts immunotherapy response in metastatic renal cell and urothelial carcinoma.

OBJECTIVES: The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. METHODS: We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. RESULTS: We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. CONCLUSIONS: Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Integration of on-treatment modified Glasgow prognostic score (mGPS) to improve imaging-based prediction of outcomes in patients with non-small cell lung cancer on immune checkpoint inhibition.

INTRODUCTION: A large number of patients with non-small cell lung cancer (NSCLC) on immune checkpoint inhibition (ICI) achieve stable disease (SD) as the best overall response, which is associated with heterogeneous outcomes. In this context, complementary biomarkers that improve outcome prediction are needed. We have recently demonstrated that measuring the on-treatment modified Glasgow prognostic score (mGPS), which is based on the two serum markers C-reactive protein (CRP) and albumin, can improve outcome prediction complementary to radiological staging in metastatic renal cell carcinoma. However, this concept has not been assessed for patients with NSCLC on ICI. METHODS: We assessed the prognostic and predictive value of on-treatment mGPS at week six in patients with NSCLC treated with atezolizumab or docetaxel in the phase 3 OAK trial (NCT02008227) comprising n = 750 patients and validated the findings in the phase 2 BIRCH (NCT02031458, n = 560). RESULTS: On-treatment mGPS assessed at week six demonstrated valuable prognostic information (Hazard Ratio (HR) for mGPS low-risk vs intermediate risk 2.34 (95 % CI 1.76-3.11, p < 0.001) and vs high risk 3.56, (95 % CI 2.57-4.91, p < 0.001) in the atezolizumab-treated subgroup. On-treatment mGPS predicted overall survival more accurately than imaging using RECIST criteria (concordance index: on-treatment mGPS 0.646 (95 % CI 0.615-0.677) vs RECIST 0.606 (95 % CI 0.575-0.637)). On-treatment mGPS provides additional prognostic information to imaging-assessed treatment response at first staging, especially for the patient subgroup with SD. These findings were validated in the BIRCH trial. CONCLUSIONS: We highlight the novel concept of integrating on-treatment mGPS for improved outcome prediction in conjunction with radiological imaging for patients with NSCLC on ICI.

Pretreatment albumin is a prognostic and predictive biomarker for response to atezolizumab across solid tumors.

Objectives: Reliable predictive biomarkers for response to immune checkpoint inhibition (ICI) are lacking. Pretreatment serum albumin, a known prognostic and predictive factor in ICI-treated patients, has been proposed as a potential pharmacokinetic surrogate marker for anti-PD1/PD-L1 antibodies, as it shares a homeostatic pathway with IgG. However, this hypothesis is currently based on theoretical considerations and limited evidence from retrospective data. Therefore, we comprehensively investigated the prognostic and predictive value of pretreatment albumin and its relationship with anti-PD-L1 IgG levels. Methods: We analysed pretreatment albumin and atezolizumab serum levels and clinical response in four trials (IMvigor210, IMvigor211, IMmotion151 and OAK) of patients with metastatic lung-, renal- or urothelial cancer who received atezolizumab alone or in combination. Results: A total of 3391 patients were analysed. Correlation between serum albumin and atezolizumab levels was weak (Pearson's coefficient 0.23). We found a strong prognostic value for pretreatment serum albumin across all trials. Both atezolizumab serum levels and serum albumin were independently correlated with overall survival. Importantly, in the three randomised phase III clinical trials, the survival benefit for immunotherapy compared with the active comparator arm was limited to patients with pretreatment serum albumin > 35 g L-1. Conclusion: Our data do not support the hypothesis that albumin serves as a surrogate for atezolizumab pharmacokinetics. However, we show that albumin on its own exerts strong prognostic value for patients treated with immunotherapy. As benefit from immunotherapy was limited to patients with normal/elevated serum albumin levels, baseline albumin could potentially be used as a predictive marker for immune checkpoint inhibition.

On-treatment Modified Glasgow Prognostic Score Provides Predictive Information Complementary to Radiological Staging in Metastatic Urothelial Carcinoma on Immunotherapy.

In the immunotherapy era it is difficult to predict patient prognosis on the basis of radiological staging alone, especially for the subgroup with stable disease (SD), which encompasses a wide range of clinical outcomes. Thus, there is need for reliable and, ideally, cost-efficient biomarkers to improve the accuracy of outcome prediction. We evaluated the on-treatment modified Glasgow Prognostic Score (mGPS)-a known predictor of outcomes in several cancers that is based on serum C-reactive protein and albumin-in patients with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibition (ICI) in the phase 2 IMvigor210 and phase 3 IMvigor211 trials. On-treatment mGPS provides valuable prognostic information complementary to radiological staging, particularly for patients with SD. In IMvigor210, on-treatment mGPS predicts outcomes as early as 6 wk after ICI initiation, considerably before the first routine staging typically performed after 10-12 wk. Our study suggests that on-treatment mGPS complements radiological imaging in predicting outcomes for patients with mUC undergoing ICI. PATIENT SUMMARY: For patients with metastatic bladder cancer receiving immunotherapy, it is difficult to predict treatment outcomes from imaging scans alone. Our study results suggest that a score called the modified Glasgow Prognostic Score based on just two proteins (C-reactive protein and albumin) measured in blood can accurately predict outcomes. Use of the mGPS along with imaging scans may be better in predicting the survival benefit from immunotherapy.

PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma.

PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

Integrating On-Treatment Modified Glasgow Prognostic Score and Imaging to Predict Response and Outcomes in Metastatic Renal Cell Carcinoma.

Importance: In the era of immuno-oncology, imaging alone seems to be insufficient to capture treatment responses, as patients with stable disease treated with immunotherapy have a wide range of clinical outcomes. There is an unmet need for complementary (ideally cost-efficient) markers that enable assessment of therapy response and outcomes in conjunction with imaging. Objectives: To examine whether longitudinal changes in the modified Glasgow prognostic score (mGPS), which is based on C-reactive protein and albumin, can predict responses and outcomes in patients with metastatic renal cell carcinoma (mRCC). Design, Setting, and Participants: This post hoc analysis, conducted from October 2022 to April 2023, evaluated the prognostic and predictive performance of on-treatment mGPS in patients with mRCC being treated with atezolizumab (plus bevacizumab) or sunitinib in 2 randomized clinical trials: the phase 3 IMmotion151 study (discovery cohort) and the phase 2 IMmotion150 study (validation cohort). Main Outcomes and Measures: Outcomes were investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and overall survival (OS) for survival analyses. To compare the prognostic value of the on-treatment mGPS with radiologic staging, we used RECIST assessed by the Independent Review Committee (IRC-RECIST) to ensure high data quality. Results: Of the 915 patients with mRCC in the IMmotion151 discovery cohort, baseline mGPS was available for 861 patients and on-treatment mGPS for 691. The IMmotion150 validation cohort included 305 patients with mRCC, and on-treatment mGPS could be evaluated for 199. In the IMmotion150 study, on-treatment mGPS predicted outcomes as early as 6 weeks following therapy initiation, thereby opening a window for early therapy adjustments. In both clinical trials, on-treatment mGPS provided valuable prognostic information regardless of imaging-assessed treatment response at first staging. Of note, in the disease control subgroup, on-treatment mGPS exhibited superior and independent prognostic information compared with IRC-RECIST (available for 611 patients; C-index, 0.651 [95% CI, 0.588-0.714] for the mGPS during treatment vs 0.574 [95% CI, 0.528-0.619] for IRC-RECIST). Conclusions and Relevance: These data support the concept of integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging to improve clinical care at a low cost for patients with mRCC.

Early C-reactive protein kinetics predicts immunotherapy response in non-small cell lung cancer in the phase III OAK trial.

Static biomarkers like programmed death-ligand 1 (PD-L1) are insufficient to accurately predict response to immune checkpoint inhibition. Therefore, on-treatment biomarkers, which measure immediate therapy-associated changes, are currently shifting into the focus of immuno-oncology. A prime example of a simple predictive on-treatment biomarker is the early C-reactive protein (CRP) kinetics with its predictive CRP flare-response phenomenon. Here, we were able to confirm the predictive value of CRP flare-response kinetics in the pivotal phase III OAK trial (NCT02008227), which compared atezolizumab with docetaxel in patients with non-small cell lung cancer. Of note, CRP flare-response predicted favorable outcomes only in the immune checkpoint inhibition-treated subgroup, which suggests that it is an immunotherapy-specific phenomenon. In conclusion, we have for the first time validated the high predictive value of early CRP kinetics in a pivotal phase III trial, justifying the broad use of this cost-effective and easy-to-implement on-treatment biomarker to optimize therapy monitoring for patients with non-small cell lung cancer.

Two cases of EBV infection preceding lymphoma.

Infection of lymphocytes with the Epstein-Barr virus (EBV) is a well-documented risk factor for developing lymphoma. The incidence of EBV positivity in lymphoma depends on the subtype and can range from 10% in diffuse large B-cell lymphoma (DLBCL) to 100% in endemic Burkitt lymphoma (BL), (Shannon-Lowe and Rickinson, Front Oncol 9:713, 2019). However, in most cases, EBV infection remains unnoticed until diagnosis of lymphoma is made. EBV seropositivity is present in > 90% of the world's population. Although mostly asymptomatic, in some cases, EBV can cause clinical symptoms, the most common of which are fever, lymphadenopathy and pharyngitis in infectious mononucleosis. Less common presentations include lymphomatoid granulomatosis and mucocutaneous ulcer. Here we report two cases of patients, who were initially diagnosed with localized EBV infection and reactive B-cell proliferation. After B-cell-directed treatment, both patients developed overt lymphoma, in one case classical Hodgkin's lymphoma (cHL) and in the other case angioimmunoblastic T-cell lymphoma (AITL).

C-reactive protein flare predicts response to anti-PD-(L)1 immune checkpoint blockade in metastatic urothelial carcinoma.

PURPOSE: Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response. METHODS: We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS). RESULTS: Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P < 0.001). CRP flare response was associated with prolonged PFS and OS (P < 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P < 0.001). CONCLUSION: CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

C reactive protein flare predicts response to checkpoint inhibitor treatment in non-small cell lung cancer.

Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.